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| Biotin (also known as vitamin B7 or vitamin H) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name biotin, borrowed from the German Biotin, derives from the Ancient Greek word βίοτος (bíotos; 'life') and the suffix "-in" (a suffix used in chemistry usually to indicate 'forming'). Biotin appears as a white, needle-like crystalline solid.
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Read full article at Wikipedia
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InChI=1S/C10H16N2O3S/c13- 8(14)4-2-1-3-7-9-6(5-16-7)11-10(15)12-9/h6-7,9H,1-5H2,(H,13,14)(H2,11,12,15)/t6-,7-,9-/m0/s1 |
| YBJHBAHKTGYVGT-ZKWXMUAHSA-N |
| [H][C@]12CS[C@@H](CCCCC(O)=O)[C@@]1([H])NC(=O)N2 |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
saliva
(UBERON:0001836).
See:
Sugimoto et al. (2013) Physiological and environmental parameters associated with mass spectrometry-based salivary metabolomic profiles.
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Homo sapiens
(NCBI:txid9606)
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Found in
cerebrospinal fluid
(UBERON:0001359).
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
blood
(UBERON:0000178).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 130. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp. Basel, Switzerland c1981-1992.
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Homo sapiens
(NCBI:txid9606)
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Found in
urine
(BTO:0001419).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 130. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp. Basel, Switzerland c1981-1992.
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Homo sapiens
(NCBI:txid9606)
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From MetaboLights
See:
MetaboLights Study
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Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
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prosthetic group
A tightly bound, specific nonpolypeptide unit in a protein determining and involved in its biological activity.
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
cofactor
An organic molecule or ion (usually a metal ion) that is required by an enzyme for its activity. It may be attached either loosely (coenzyme) or tightly (prosthetic group).
fundamental metabolite
Any metabolite produced by all living cells.
coenzyme
A low-molecular-weight, non-protein organic compound participating in enzymatic reactions as dissociable acceptor or donor of chemical groups or electrons.
human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
Saccharomyces cerevisiae metabolite
Any fungal metabolite produced during a metabolic reaction in Baker's yeast (Saccharomyces cerevisiae ).
Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
water-soluble vitamin (role)
Any vitamin that dissolves in water and readily absorbed into tissues for immediate use. Unlike the fat-soluble vitamins, they are not stored in the body and need to be replenished regularly in the diet and will rarely accumulate to toxic levels since they are quickly excreted from the body via urine.
(via B vitamin )
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nutraceutical
A product in capsule, tablet or liquid form that provide essential nutrients, such as a vitamin, an essential mineral, a protein, an herb, or similar nutritional substance.
(via B vitamin )
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View more via ChEBI Ontology
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5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoic acid
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biotin
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WHO MedNet
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biotina
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WHO MedNet
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biotine
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WHO MedNet
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biotinum
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WHO MedNet
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(+)-cis-Hexahydro-2-oxo-1H-thieno[3,4]imidazole-4-valeric acid
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HMDB
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(3aS,4S,6aR)-Hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-valeric acid
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HMDB
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5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoic acid
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HMDB
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BIOTIN
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PDBeChem
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cis-(+)-Tetrahydro-2-oxothieno[3,4]imidazoline-4-valeric acid
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HMDB
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cis-Hexahydro-2-oxo-1H-thieno(3,4)imidazole-4-valeric acid
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HMDB
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cis-Tetrahydro-2-oxothieno(3,4-d)imidazoline-4-valeric acid
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HMDB
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Coenzyme R
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KEGG COMPOUND
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D-(+)-biotin
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NIST Chemistry WebBook
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D-Biotin
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KEGG COMPOUND
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vitamin B7
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NIST Chemistry WebBook
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Vitamin H
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KEGG COMPOUND
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149962
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ChemSpider
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373
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DrugCentral
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Biotin
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Wikipedia
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BIOTIN
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MetaCyc
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BTN
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PDBeChem
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C00000756
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KNApSAcK
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C00120
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KEGG COMPOUND
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D00029
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KEGG DRUG
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DB00121
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DrugBank
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FDB014510
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FooDB
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HMDB0000030
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HMDB
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LSM-3994
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LINCS
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MOL000144
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COMe
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| View more database links |
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1918703
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Gmelin Registry Number
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Gmelin
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58-85-5
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CAS Registry Number
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KEGG COMPOUND
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58-85-5
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CAS Registry Number
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ChemIDplus
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58-85-5
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CAS Registry Number
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NIST Chemistry WebBook
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86838
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Reaxys Registry Number
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Reaxys
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Ramamoorthy K, Sabui S, Srinivasan P, Al-Juburi S, Pham Q, Chu BD, Simoes RD, Fleckenstein JM, Said HM (2021)
Effect of chronic alcohol exposure on gut vitamin B7 uptake: involvement of epigenetic mechanisms and effect of alcohol metabolites.
American journal of physiology. Gastrointestinal and liver physiology 321, G123-G133 [PubMed:34077272]
[show Abstract]
Vitamin B7 (biotin) is essential for normal health and its deficiency/suboptimal levels occur in a variety of conditions including chronic alcoholism. Mammals, including humans, obtain biotin from diet and gut-microbiota via absorption along the intestinal tract. The absorption process is carrier mediated and involves the sodium-dependent multivitamin transporter (SMVT; SLC5A6). We have previously shown that chronic alcohol exposure significantly inhibits intestinal/colonic biotin uptake via suppression of Slc5a6 transcription in animal and cell line models. However, little is known about the transcriptional/epigenetic factors that mediate this suppression. In addition, the effect of alcohol metabolites (generated via alcohol metabolism by gut microbiota and host tissues) on biotin uptake is still unknown. To address these questions, we first demonstrated that chronic alcohol exposure inhibits small intestinal and colonic biotin uptake and SMVT expression in human differentiated enteroid and colonoid monolayers. We then showed that chronic alcohol exposures of both, Caco-2 cells and mice, are associated with a significant suppression in expression of the nuclear factor KLF-4 (needed for Slc5a6 promoter activity), as well as with epigenetic alterations (histone modifications). We also found that chronic exposure of NCM460 human colonic epithelial cells as well as human differentiated colonoid monolayers, to alcohol metabolites (acetaldehyde, ethyl palmitate, ethyl oleate) significantly inhibited biotin uptake and SMVT expression. These findings shed light onto the molecular/epigenetic mechanisms that mediate the inhibitory effect of chronic alcohol exposure on intestinal biotin uptake. They further show that alcohol metabolites are also capable of inhibiting biotin uptake in the gut.NEW & NOTEWORTHY Using complementary models, including human differentiated enteroid and colonoid monolayers, this study shows the involvement of molecular and epigenetic mechanisms in mediating the inhibitory effect of chronic alcohol exposure on biotin uptake along the intestinal tract. The study also shows that alcohol metabolites (generated by gut microbiota and host tissues) cause inhibition in gut biotin uptake. | Motahari H, Thumma S, Menon L (2021)
Biotin Supplementation Creates the Misleading Diagnosis of Secondary Adrenal Insufficiency
Journal of the Endocrine Society 5, A120-A121 [PubMed Central:PMC8089577]
[show Abstract]
Abstract Introduction: Biotin (vitamin B7) is a water-soluble vitamin and an essential cofactor for the metabolism of fatty acids, glucose, and amino acids. Cases of biotin interference with laboratory testing have been described, most of which involve interference with thyroid function tests. Interference with gonadal steroids, adrenal, and pituitary hormones are rare. We report a case of T3 thyrotoxicosis in which biotin supplementation created the appearance of secondary adrenal insufficiency (AI). Case: A 66-year-old woman was referred for the evaluation of low TSH. She had chronic fatigue, low libido, and dizziness on standing. Vitals were stable with BP 135/64 mmHg and BMI 23.5. No evidence of mucosal or cutaneous hyperpigmentation. Laboratory evaluation revealed low ACTH <5 (7.2–63.3 pg/mL), low morning cortisol 3.8 and high DHEA-S 174 (13–130 ug/dL). TSH was low at 0.32 (0.32–5.60 uIU/mL) with normal prolactin and appropriately elevated FSH and LH. The labs raised concern for secondary AI. Cosyntropin stimulation test (CST) was done with a peak cortisol of 17.4 ug/dL. In the setting of suppressed ACTH and failed CST, she was started on Hydrocortisone therapy. Subsequently, CT of abdomen was obtained due to high DHEA-S which showed normal appearance of both adrenals. Pituitary MRI was normal. A detailed review of the medication list revealed that the patient was taking a Biotin containing multivitamin. Repeat labs 1 week after stopping biotin showed normalization of ACTH 13.8 (7.2–63.3). Repeat CST showed a peak cortisol response of 24 ug/dL. Hydrocortisone was discontinued and the patient remained stable on subsequent follow-ups, without the need for further glucocorticoid replacement therapy. Thyroid lab abnormalities persisted after biotin cessation which led to the diagnosis of T3 thyrotoxicosis, the treatment of which caused resolution of the patient’s symptoms. Discussion: The recommended daily intake of biotin for adults is 30 µg/d. Many over-the-counter products, specifically those marketed for hair, skin, and nail growth, contain biotin 100-fold higher than the recommended intake. Biotin interference with competitive immunoassays can cause falsely elevated hormone levels, whereas biotin interference with immunometric “sandwich” assays falsely lowers hormone levels. In our case, low ACTH was clinically misleading, prompting numerous unnecessary radiographic and laboratory testing and treatment with hydrocortisone. The US Food and Drug Administration issued a safety communication regarding biotin interference with laboratory tests. Education and communication between laboratorians, providers, and patients play an important role in investigating potential lab interference and the need for alternative lab assays for an accurate diagnosis. Patients should be asked to stop taking biotin supplements for at least 48 hours prior to specimen collection if possible. | Weimann A, Plomgaard P, Hilsted LM, Poulsen HE, Larsen EL (2021)
Quantification of biotin in plasma samples by column switching liquid chromatography - tandem mass spectrometry.
Scandinavian journal of clinical and laboratory investigation 81, 127-136 [PubMed:33461365]
[show Abstract]
Biotin (or Vitamin B7) is a vitamin where deficiency can be caused by inadequate intake. Biotin deficiency is rare, as most people get enough biotin from diet, since many foods contain biotin. In addition to biotin from food, intestinal bacteria can synthesize biotin, which can then be absorbed by the body. Supplementation with biotin has been advocated, mainly due to proposed beneficial effects on skin, nail and hair growth. There is no evidence that high biotin intakes are toxic, but a high intake may interfere with diagnostic assays that use biotin-streptavidin technology. These tests are commonly used to measure plasma concentrations of a wide range of hormones. Erroneous results may lead to misdiagnosis of various endocrine disorders. Supplementation with high-dose biotin has been used experimental for the treatment of diseases (e.g. multiple sclerosis) and high doses are used to obtain effect on nail and hair growth. On this background a demand for tests to determine if there is a risk of obtaining false test results when using biotin-streptavidin based tests have appeared. In this paper we present a method based on column switching liquid chromatography tandem mass spectrometry for the quantification of biotin in plasma and serum and explore the effects of biotin on an immunoassay based on biotin strept(avidin) chemistry. | Lipner SR (2020)
Update on Biotin Therapy in Dermatology: Time for a Change.
Journal of drugs in dermatology : JDD 19, 1264-1265 [PubMed:33346513]
[show Abstract]
Biotin (vitamin B7 or H) is found in milk, nuts, egg yolks, cereals, supplements, synthesized by intestinal bacteria, and is required for gluconeogenesis, fatty acid synthesis and amino acid catabolism. | Nunomura S, Ohtsubo-Yoshioka M, Okayama Y, Terui T, Ra C (2015)
FcRγ promotes contact hypersensitivity to oxazolone without affecting the contact sensitisation process in B6 mice.
Experimental dermatology 24, 204-208 [PubMed:25515858]
[show Abstract]
The process of sensitisation by specific contact allergens is indispensable for the induction of allergic contact dermatitis. Oxazolone is a well-characterised contact allergen. Previous studies suggested that immune cells bearing the FcRγ subunit are essential for oxazolone-induced contact hypersensitivity, but the biological functions of the FcRγ subunit in the process of sensitisation to oxazolone remain unknown. In this study, we show that FcRγ deficiency decreases ear-swelling responses to oxazolone in mice. However, we found that oxazolone-sensitised FcRγ(-/-) mice and oxazolone-sensitised wild-type (WT) mice have comparable numbers of CD11c(+) MHCII(hi) dendritic cells (DCs) in their draining lymph nodes (LNs). In addition, oxazolone-sensitised LN cells from both FcRγ(-/-) and WT mice showed considerable production of interferon-gamma (IFNγ), interleukin-4 (IL-4) and IL-17A upon oxazolone-keyhole limpet haemocyanin loading. Consistent with these data, oxazolone-sensitised FcRγ(-/-) and FcRγ(+/+) LN cells conferred contact hypersensitivity to WT naïve mice challenged with the hapten. Our findings clearly indicate that, in an experimental mouse model, the FcRγ subunit positively regulates contact hypersensitivity to oxazolone without affecting the contact sensitisation process. | Zempleni J, Teixeira DC, Kuroishi T, Cordonier EL, Baier S (2012)
Biotin requirements for DNA damage prevention.
Mutation research 733, 58-60 [PubMed:21871906]
[show Abstract]
Biotin serves as a covalently bound coenzyme in five human carboxylases; biotin is also attached to histones H2A, H3, and H4, although the abundance of biotinylated histones is low. Biotinylation of both carboxylases and histones is catalyzed by holocarboxylase synthetase. Human biotin requirements are unknown. Recommendations for adequate intake of biotin are based on the typical intake of biotin in an apparently healthy population, which is only a crude estimate of the true intake due to analytical problems. Importantly, intake recommendations do not take into account possible effects of biotin deficiency on impairing genome stability. Recent studies suggest that biotin deficiency causes de-repression of long terminal repeats, thereby causing genome instability. While it was originally proposed that these effects are caused by loss of biotinylated histones, more recent evidence suggests a more immediate role of holocarboxylase synthetase in forming multiprotein complexes in chromatin that are important for gene repression. Holocarboxylase synthetase appears to interact physically with the methyl-CpG-binding domain protein 2 and, perhaps, histone methyl transferases, thereby creating epigenetic synergies between biotinylation and methylation events. These observations might offer a mechanistic explanation for some of the birth defects seen in biotin-deficient animal models. | Larrieta E, Vega-Monroy ML, Vital P, Aguilera A, German MS, Hafidi ME, Fernandez-Mejia C (2012)
Effects of biotin deficiency on pancreatic islet morphology, insulin sensitivity and glucose homeostasis.
The Journal of nutritional biochemistry 23, 392-399 [PubMed:21596550]
[show Abstract]
Several studies have revealed that physiological concentrations of biotin are required for the normal expression of critical carbohydrate metabolism genes and for glucose homeostasis. However, the different experimental models used in these studies make it difficult to integrate the effects of biotin deficiency on glucose metabolism. To further investigate the effects of biotin deficiency on glucose metabolism, we presently analyzed the effect of biotin deprivation on glucose homeostasis and on pancreatic islet morphology. Three-week-old male BALB/cAnN Hsd mice were fed a biotin-deficient or a biotin-control diet (0 or 7.2 μmol of free biotin/kg diet, respectively) over a period of 8 weeks. We found that biotin deprivation caused reduced concentrations of blood glucose and serum insulin concentrations, but increased plasma glucagon levels. Biotin-deficient mice also presented impaired glucose and insulin tolerance tests, indicating defects in insulin sensitivity. Altered insulin signaling was linked to a decrease in phosphorylated Akt/PKB but induced no change in insulin receptor abundance. Islet morphology studies revealed disruption of islet architecture due to biotin deficiency, and an increase in the number of α-cells in the islet core. Morphometric analyses found increased islet size, number of islets and glucagon-positive area, but a decreased insulin-positive area, in the biotin-deficient group. Glucagon secretion and gene expression increased in islets isolated from biotin-deficient mice. Our results suggest that biotin deficiency promotes hyperglycemic mechanisms such as increased glucagon concentration and decreased insulin secretion and sensitivity to compensate for reduced blood glucose concentrations. Variations in glucose homeostasis may participate in the changes observed in pancreatic islets. | Zhou J, Wang D, Schlegel V, Zempleni J (2011)
Development of an internet based system for modeling biotin metabolism using Bayesian networks.
Computer methods and programs in biomedicine 104, 254-259 [PubMed:21356565]
[show Abstract]
Biotin is an essential water-soluble vitamin crucial for maintaining normal body functions. The importance of biotin for human health has been under-appreciated but there is plenty of opportunity for future research with great importance for human health. Currently, carrying out predictions of biotin metabolism involves tedious manual manipulations. In this paper, we report the development of BiotinNet, an internet based program that uses Bayesian networks to integrate published data on various aspects of biotin metabolism. Users can provide a combination of values on the levels of biotin related metabolites to obtain the predictions on other metabolites that are not specified. As an inherent feature of Bayesian networks, the uncertainty of the prediction is also quantified and reported to the user. This program enables convenient in silico experiments regarding biotin metabolism, which can help researchers design future experiments while new data can be continuously incorporated. | Yu J, Niu C, Wang D, Li M, Teo W, Sun G, Wang J, Liu J, Liu J, Gao Q (2011)
MMAR_2770, a new enzyme involved in biotin biosynthesis, is essential for the growth of Mycobacterium marinum in macrophages and zebrafish.
Microbes and infection 13, 33-41 [PubMed:20974274]
[show Abstract]
Biotin, which functions as an essential cofactor for certain carboxylases and decarboxylases, is synthesized by a multistep pathway in microorganisms and plants. Biotin biosynthesis has not been studied in detail in mycobacteria. In this study, we isolated a mutant of Mycobacterium marinum in which MMAR_2770, a previously uncharacterized gene encoding a predicted short-chain dehydrogenase/reductase, was inactivated. We found that this mutant is a biotin auxotroph that cannot grow in a minimal medium (Sauton) unless biotin is supplemented. Complementation of the mutant with an intact MMAR_2770 or its homolog Rv1882c of Mycobacterium tuberculosis restored the growth of the mutant, suggesting that MMAR_2770 is involved in biotin biosynthesis. We further showed that the mutant was unable to grow in cultured macrophages and was attenuated in zebrafish. Taken together, our results demonstrate that biotin biosynthesis is essential for the growth of mycobacteria in vitro and in vivo and have provided validation for targeting biotin biosynthetic enzymes for antimycobacterial drug development. The potential role of MMAR_2770 in mycobacterial biotin biosynthesis is discussed. | Plażuk D, Zakrzewski J, Salmain M (2011)
Biotin as acylating agent in the Friedel-Crafts reaction. Avidin affinity of biotinyl derivatives of ferrocene, ruthenocene and pyrene and fluorescence properties of 1-biotinylpyrene.
Organic & biomolecular chemistry 9, 408-417 [PubMed:20967359]
[show Abstract]
(D)-Biotin was used for Friedel-Crafts acylation of electron-rich aromatic molecules--ferrocene, ruthenocene and pyrene. The reaction carried out in the presence of trifluoroacetic anhydride and trifluoromethanesulfonic acid afforded the corresponding biotinylarenes in moderate yields. These compounds, although lacking an amide bond, exhibited high affinity for avidin, with the ability to displace 2-(4'-hydroxyphenylazo)-benzoic acid (HABA) in its complex with avidin. Their affinity for avidin was determined by a solid-phase competitive enzymatic assay, which gave IC(50) values in the range of 33-58 nM (under the same conditions biotin showed IC(50) = 24 ± 7 nM). 1-Biotinylpyrene (1c) excited at 355 nm displayed fluorescence emission in aqueous solutions with λ(max) = 461 nm. The fluorescence maximum was shifted to 425 nm upon binding of 1c to avidin. Formation of the avidin-1c complex was also evidenced by quenching of the fluorescence from the protein tryptophan residues (342 nm) and appearance of the emission band of the avidin-bound 1c at 430 nm as a result of a Förster resonance energy transfer (FRET) phenomenon. | Rizzi L, Braschi M, Colombo M, Vaiana N, Tibolla G, Norata GD, Catapano AL, Romeo S, Prosperi D (2011)
Novel biotinylated bile acid amphiphiles: micellar aggregates formation and interaction with hepatocytes.
Organic & biomolecular chemistry 9, 2899-2905 [PubMed:21373679]
[show Abstract]
Amphiphilic bile acids linked through an oligoethylene glycol to a biotin moiety were synthesized and shown to create micellar structures in aqueous environment, interact with avidin and be efficiently incorporated into hepatocyte cells, suggesting their potential as a drug delivery system against liver diseases. | Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Spencer HJ, Moran JH, Mock DM (2011)
Urinary excretion of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans.
The Journal of nutrition 141, 353-358 [PubMed:21248194]
[show Abstract]
Mounting evidence indicates that marginal biotin deficiency is not rare, contrary to previous assumptions. Accordingly, robust indicators of biotin status would be useful. In a study of 10 healthy adults, we recently provided evidence that abnormally increased plasma concentration of 3-hydroxyisovaleryl carnitine (3HIA-carnitine) is a sensitive indicator of marginal biotin deficiency. We sought to determine whether urinary excretion of 3HIA-carnitine (expressed as the ratio to urinary creatinine) significantly increases in marginal biotin deficiency. Marginal, asymptomatic biotin deficiency was induced experimentally in the same 10 healthy adults (8 women) by feeding undenatured egg white with meals for 28 d. Biotin status was repleted by a mixed general diet plus biotin supplementation. Urinary excretion of 3HIA-carnitine was determined by liquid chromatography-tandem MS on d 0, 14, and 28 (depletion) and on d 35 and 50 (repletion). Mean urinary 3HIA-carnitine concentration increased with depletion (P < 0.0001; d 0 vs. 28) and decreased with repletion (P = 0.0002; d 28 vs. 50). Urinary 3HIA-carnitine excretion was greater than the upper limit of normal in 9 of 10 participants by d 14 and decreased to within normal limits by d 50 in all participants. This study provides evidence that urinary excretion of 3HIA-carnitine is an early and sensitive indicator of marginal biotin deficiency. The ease of collection of untimed urine samples and application of a new analytical method with simplified sample preparation suggest that urinary 3HIA-carnitine is likely to be a useful indicator for large population studies. | Pratesi A, Bucelli F, Mori I, Chinol M, Verdoliva A, Paganelli G, Rivieccio V, Gariboldi L, Ginanneschi M (2010)
Biotin derivatives carrying two chelating DOTA units. Synthesis, in vitro evaluation of biotinidases resistance, avidin binding, and radiolabeling tests.
Journal of medicinal chemistry 53, 432-440 [PubMed:19928962]
[show Abstract]
The synthesis of four biotin derivatives carrying two DOTA moieties for each ligand (BisDOTA set) is reported, for increasing radiation/dose ratio and improving efficiency in the pretargeted avidin-biotin radioimmunotherapy. The biotin-containing scaffold of two BisDOTA was similar to the mono-DOTA derivative previously described. Then the scaffold was elongated by trifunctionalized spacers of different length and conjugated with one of the COOH groups of two DOTA. Two others were prepared starting from a on-resin lysine residue. The lysine alpha-NH2 was bonded to biotin, and then spacers were appended to the epsilon-NH2 and conjugated with two DOTA molecules. One compound contained a p-aminobenzoic acid spacer, which ensured higher head-to-tail distance and increased rigidity of the chain. These last two compounds had a very high ability to bond avidin and were labeled with 90Y at high specific activity. All the compounds were resistant to the action of serum biotinidases. | Zempleni J, Wijeratne SS, Hassan YI (2009)
Biotin.
BioFactors (Oxford, England) 35, 36-46 [PubMed:19319844]
[show Abstract]
Biotin is a water-soluble vitamin and serves as a coenzyme for five carboxylases in humans. Biotin is also covalently attached to distinct lysine residues in histones, affecting chromatin structure and mediating gene regulation. This review describes mammalian biotin metabolism, biotin analysis, markers of biotin status, and biological functions of biotin. Proteins such as holocarboxylase synthetase, biotinidase, and the biotin transporters SMVT and MCT1 play crucial roles in biotin homeostasis, and these roles are reviewed here. Possible effects of inadequate biotin intake, drug interactions, and inborn errors of metabolism are discussed, including putative effects on birth defects. | Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM (2009)
Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
Nature 457, 910-914 [PubMed:19212411]
[show Abstract]
Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity. | Taniguchi A, Watanabe T (2008)
Transplacental transport and tissue distribution of biotin in mice at midgestation.
Congenital anomalies 48, 57-62 [PubMed:18452485]
[show Abstract]
Biotin is a water-soluble vitamin which functions as a coenzyme of carboxylases in glucose and amino acid metabolism and fatty acid synthesis. Biotin is also essential for maintaining reproductive function. Biotin deficiency during gestation induces cleft palate, micrognathia and limb hypoplasia in mouse fetuses at near term. Maternal biotin deficiency is severely tetatogenic in mammals. However, the relationship between abnormal morphogenesis and biotin deficiency is not sufficiently clear. This study was conducted to elucidate the mechanism of biotin transport from dams to embryos and the nutritional roles of biotin in ICR mice. Pregnant mice were given either a biotin-deficient or biotin-supplemented diet, and biotin and biotinidase activity were determined in dams and fetuses. It became evident that biotin was supplied from dams to growing embryos during morphogenesis. In particular, a large amount of biotin was transported to palates and mandibles on days 12-15 of gestation. The transportation of biotin to fetuses differed among fetal growth periods and organs. These results suggest that biotin is an essential nutrient and may play an important role in embryonic growth. | Zempleni J, Hassan YI, Wijeratne SS (2008)
Biotin and biotinidase deficiency.
Expert review of endocrinology & metabolism 3, 715-724 [PubMed:19727438]
[show Abstract]
Biotin is a water-soluble vitamin that serves as an essential coenzyme for five carboxylases in mammals. Biotin-dependent carboxylases catalyze the fixation of bicarbonate in organic acids and play crucial roles in the metabolism of fatty acids, amino acids and glucose. Carboxylase activities decrease substantially in response to biotin deficiency. Biotin is also covalently attached to histones; biotinylated histones are enriched in repeat regions in the human genome and appear to play a role in transcriptional repression of genes and genome stability. Biotin deficiency may be caused by insufficient dietary uptake of biotin, drug-vitamin interactions and, perhaps, by increased biotin catabolism during pregnancy and in smokers. Biotin deficiency can also be precipitated by decreased activities of the following proteins that play critical roles in biotin homeostasis: the vitamin transporters sodium-dependent multivitamin transporter and monocarboxylate transporter 1, which mediate biotin transport in the intestine, liver and peripheral tissues, and renal reabsorption; holocarboxylase synthetase, which mediates the binding of biotin to carboxylases and histones; and biotinidase, which plays a central role in the intestinal absorption of biotin, the transport of biotin in plasma and the regulation of histone biotinylation. Symptoms of biotin deficiency include seizures, hypotonia, ataxia, dermatitis, hair loss, mental retardation, ketolactic acidosis, organic aciduria and also fetal malformations. This review focuses on the deficiencies of both biotin and biotinidase, and the medical management of such cases. | Purushothaman S, Gupta G, Srivastava R, Ramu VG, Surolia A (2008)
Ligand specificity of group I biotin protein ligase of Mycobacterium tuberculosis.
PloS one 3, e2320 [PubMed:18509457]
[show Abstract]
BackgroundFatty acids are indispensable constituents of mycolic acids that impart toughness & permeability barrier to the cell envelope of M. tuberculosis. Biotin is an essential co-factor for acetyl-CoA carboxylase (ACC) the enzyme involved in the synthesis of malonyl-CoA, a committed precursor, needed for fatty acid synthesis. Biotin carboxyl carrier protein (BCCP) provides the co-factor for catalytic activity of ACC.Methodology/principal findingsBPL/BirA (Biotin Protein Ligase), and its substrate, biotin carboxyl carrier protein (BCCP) of Mycobacterium tuberculosis (Mt) were cloned and expressed in E. coli BL21. In contrast to EcBirA and PhBPL, the approximately 29.5 kDa MtBPL exists as a monomer in native, biotin and bio-5'AMP liganded forms. This was confirmed by molecular weight profiling by gel filtration on Superdex S-200 and Dynamic Light Scattering (DLS). Computational docking of biotin and bio-5'AMP to MtBPL show that adenylation alters the contact residues for biotin. MtBPL forms 11 H-bonds with biotin, relative to 35 with bio-5'AMP. Docking simulations also suggest that bio-5'AMP hydrogen bonds to the conserved 'GRGRRG' sequence but not biotin. The enzyme catalyzed transfer of biotin to BCCP was confirmed by incorporation of radioactive biotin and by Avidin blot. The K(m) for BCCP was approximately 5.2 microM and approximately 420 nM for biotin. MtBPL has low affinity (K(b) = 1.06x10(-6) M) for biotin relative to EcBirA but their K(m) are almost comparable suggesting that while the major function of MtBPL is biotinylation of BCCP, tight binding of biotin/bio-5'AMP by EcBirA is channeled for its repressor activity.Conclusions/significanceThese studies thus open up avenues for understanding the unique features of MtBPL and the role it plays in biotin utilization in M. tuberculosis. | Ferreira G, Weiss WP (2007)
Effect of biotin on activity and gene expression of biotin-dependent carboxylases in the liver of dairy cows.
Journal of dairy science 90, 1460-1466 [PubMed:17297119]
[show Abstract]
Biotin is a cofactor of the gluconeogenic enzymes pyruvate carboxylase (PC) and propionyl-coenzyme A carboxylase (PCC). We hypothesized that biotin supplementation increases the activity and gene expression of PC and PCC and the gene expression of phosphoenol-pyruvate carboxykinase (PEPCK) in the liver of lactating dairy cows. Eight multiparous Holstein cows (40 +/- 2 kg/d of milk yield and 162 +/- 35 d in milk) were randomly assigned to 1 of 2 diet sequences in a crossover design with two 22-d periods. Treatments consisted of a basal diet (60% concentrate) containing 0 or 0.96 mg/kg of supplemental biotin. On d 21 of each period, liver tissue was collected by percutaneous liver biopsy. Activities of PC and PCC were determined by measuring the fixation of [14C]O2 in liver homogenates. Abundance of mRNA for PCC, PC, and PEPCK was determined by quantitative reverse-transcription PCR. Biotin supplementation did not affect milk production or composition. Biotin supplementation increased the activity of PC but had no effect on PCC activity. Biotin supplementation did not affect the gene expression of PC, PCC, and PEPCK. The increased activity of PC without changes in mRNA abundance may have been caused by increased activation of the apoenzymes by holocarboxylase synthetase. In conclusion, biotin supplementation affected the activity of PC in the liver of lactating dairy cows, but whether biotin supplementation increases glucose production in the liver remains to be determined. | Taniguchi A, Watanabe T (2007)
Roles of biotin in growing ovarian follicles and embryonic development in domestic fowl.
Journal of nutritional science and vitaminology 53, 457-463 [PubMed:18202531]
[show Abstract]
It is well known that biotin deficiency causes morphological anomalies in hatchlings of fowl. An abundance of biotin in the yolk, therefore, is greatly required for maintaining reproductive functions. Although there is growing evidence for the molecular significance of the vitamin in the processes of the reproductive system in mammals, little is known about its use and roles in fowl's yolk. This review focuses on studies on the roles of biotin in the ovarian follicles and embryos of domestic fowl. Recent studies from our laboratory showed an analysis of the mechanism of biotin supply from the maternal body to follicles, or the yolk using the eggs of domestic fowl. In growing ovarian follicles, biotin was incorporated into the follicles, particularly in a large amount immediately before ovulation. Biotin incorporated from the early stage to the growth stage of ovarian follicles was stored in the protein-binding form and became free biotin again immediately before ovulation. This may be because the biotin necessary for the maintenance of embryonic growth and development should be used immediately after fertilization. In embryos, free biotin in the yolk increased shortly after fertilization. A large amount of free biotin was incorporated into the embryo at the age of 3-4 d. Biotin supply to the embryo differed among embryonic growth stages and organs, suggesting involvement in the formation of each tissue and organ. Thus, a large amount of biotin was utilized for embryonic growth, suggesting its important role in normal embryonic growth. These findings show that biotin is an essential nutrient and may play a major role in the normal morphogenesis of embryos in domestic fowl. | Hong YR, Chen YL, Farh L, Yang WJ, Liao CH, Shiuan D (2006)
Recombinant Candida utilis for the production of biotin.
Applied microbiology and biotechnology 71, 211-221 [PubMed:16195795]
[show Abstract]
Biotin is an important nutritional supplement but is difficult to manufacture effectively. Here we present a trial of biotin production using the food yeast Candida utilis. In this system, we cloned the C. utilis biotin synthase (BIO2) gene, the gene of the rate-limiting enzyme for biotin biosynthesis, and assembled it under the control of a strong promoter. A series of plasmids were constructed to direct the integration of the BIO2 gene, either high-copy integration with 18S rDNA fragment or low-copy integration with URA3 or HIS3 fragment. The BIO2 gene can be successfully integrated into the C. utilis chromosome and can drive biotin production using these plasmids. The biotin yield in this system can reach 100-fold above the endogenous level in a small-scale culture. Although the biotin production is not stable if the selection pressure is removed, this system has the potential to produce biotin-rich feed or food additives directly without the requirement of further purification. | Bingham JP, Bian S, Tan ZY, Takacs Z, Moczydlowski E (2006)
Synthesis of a biotin derivative of iberiotoxin: binding interactions with streptavidin and the BK Ca2+-activated K+ channel expressed in a human cell line.
Bioconjugate chemistry 17, 689-699 [PubMed:16704206]
[show Abstract]
Iberiotoxin (IbTx) is a scorpion venom peptide that inhibits BK Ca2+-activated K+ channels with high affinity and specificity. Automated solid-phase synthesis was used to prepare a biotin-labeled derivative (IbTx-LC-biotin) of IbTx by substitution of Asp19 of the native 37-residue peptide with N--(D-biotin-6-amidocaproate)-L-lysine. Both IbTx-LC-biotin and its complex with streptavidin (StrAv) block single BK channels from rat skeletal muscle with nanomolar affinity, indicating that the biotin-labeled residue, either alone or in complex with StrAv, does not obstruct the toxin binding interaction with the BK channel. IbTx-LC-biotin exhibits high affinity (KD = 26 nM) and a slow dissociation rate (koff = 5.4 x 10(-4) s(-1)) in a macroscopic blocking assay of whole-cell current of the cloned human BK channel. Titration of IbTx-LC-biotin with StrAv monitored by high performance size exclusion chromatography is consistent with a stoichiometry of two binding sites for IbTx-LC-biotin per StrAv tetramer, indicating that steric interference hinders simultaneous binding of two toxin molecules on each of the two biotin-binding faces of StrAv. In combination with fluorescent conjugates of StrAv or anti-biotin antibody, IbTx-LC-biotin was used to image the surface distribution of BK channels on a transfected cell line. Fluorescence microscopy revealed a patch-like surface distribution of BK channel protein. The results support the feasibility of using IbTx-LC-biotin and similar biotin-tagged K+ channel toxins for diverse applications in cellular neurobiology. . | Revilla-Monsalve C, Zendejas-Ruiz I, Islas-Andrade S, Báez-Saldaña A, Palomino-Garibay MA, Hernández-Quiróz PM, Fernandez-Mejia C (2006)
Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in nondiabetic subjects with hypertriglyceridemia.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 60, 182-185 [PubMed:16677798]
[show Abstract]
Biotin is a water-soluble vitamin that acts as a prosthetic group of carboxylases. Besides its role as carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism. Several studies have reported a relationship between biotin and blood lipids. In the present work we investigated the effect of biotin administration on the concentration of plasma lipids, as well as glucose and insulin in type 2 diabetic and nondiabetic subjects. Eighteen diabetic and 15 nondiabetic subjects aged 30-65 were randomized into two groups and received either 61.4 micromol/day of biotin or placebo for 28 days. Plasma samples obtained at baseline and after treatment were analyzed for total triglyceride, cholesterol, very low density lipoprotein (VLDL), glucose and insulin. We found that the vitamin significantly reduced (P=0.005) plasma triacylglycerol and VLDL concentrations. Biotin produced the following changes (mean of absolute differences between 0 and 28 day treatment+/-S.E.M.): a) triacylglycerol -0.55+/-0.2 in the diabetic group and -0.92+/-0.36 in the nondiabetic group; b) VLDL: -0.11+/-0.04 in the diabetic group and -0.18+/-0.07 in the nondiabetic group. Biotin treatment had no significant effects on cholesterol, glucose and insulin in either the diabetic or nondiabetic subjects. We conclude that pharmacological doses of biotin decrease hypertriglyceridemia. The triglyceride-lowering effect of biotin suggests that biotin could be used in the treatment of hypertriglyceridemia. | Seki M (2006)
Biological significance and development of practical synthesis of biotin.
Medicinal research reviews 26, 434-482 [PubMed:16676358]
[show Abstract]
Biotin (1), a water-soluble B series vitamin, distributes widely in microorganisms, plants, and animals. Biosynthesis of 1 involves five steps sequence starting from pimelic acid. The last step, a transformation from dethiobiotin (DTB) to 1, includes an iron clusters-mediated radical process. The compound 1 is a cofactor of carboxylation enzymes and plays crucial roles in the metabolism of fatty acids, sugars, and alpha-amino acids. In addition to the increasing application to feed additives, recent reports have revealed that 1 enhances insulin secretion in animals, suggesting it for a promising therapeutic candidate for an anti-diabetes drug. The remarkably strong affinity of 1 with avidin and streptavidin has been extensively applied for such technologies as photoaffinity labeling. Among the number of approaches to 1 so far developed in 50 years, a synthesis using L-cysteine and thiolactone as a starting material and a key intermediate, respectively, represents one of the best routes leading to 1, because of short steps, high yield, use of inexpensive reagents, and ease of operation. | Bhor VM, Dev S, Vasanthakumar GR, Kumar P, Sinha S, Surolia A (2006)
Broad substrate stereospecificity of the Mycobacterium tuberculosis 7-keto-8-aminopelargonic acid synthase: Spectroscopic and kinetic studies.
The Journal of biological chemistry 281, 25076-25088 [PubMed:16769720]
[show Abstract]
Biotin is an essential enzyme cofactor required for carboxylation and transcarboxylation reactions. The absence of the biotin biosynthesis pathway in humans suggests that it can be an attractive target for the development of novel drugs against a number of pathogens. 7-Keto-8-aminopelargonic acid (KAPA) synthase (EC 2.3.1.47), the enzyme catalyzing the first committed step in the biotin biosynthesis pathway, is believed to exhibit high substrate stereospecificity. A comparative kinetic characterization of the interaction of the mycobacterium tuberculosis KAPA synthase with both L- AND D-alanine was carried out to investigate the basis of the substrate stereospecificity exhibited by the enzyme. The formation of the external aldimine with D-alanine (k = 82.63 m(-1) s(-1)) is approximately 5 times slower than that with L-alanine (k = 399.4 m(-1) s(-1)). In addition to formation of the external aldimine, formation of substrate quinonoid was also observed upon addition of pimeloyl-CoA to the preformed d-alanine external aldimine complex. However, the formation of this intermediate was extremely slow compared with the substrate quinonoid with L-alanine and pimeloyl-CoA (k = 16.9 x 10(4) m(-1) s(-1)). Contrary to earlier reports, these results clearly show that D-alanine is not a competitive inhibitor but a substrate for the enzyme and thereby demonstrate the broad substrate stereospecificity of the M. tuberculosis KAPA synthase. Further, d-KAPA, the product of the reaction utilizing D-alanine inhibits both KAPA synthase (Ki = 114.83 microm) as well as 7,8-diaminopelargonic acid synthase (IC50 = 43.9 microm), the next enzyme of the pathway. | Zempleni J (2005)
Uptake, localization, and noncarboxylase roles of biotin.
Annual review of nutrition 25, 175-196 [PubMed:16011464]
[show Abstract]
Evidence is emerging that biotin participates in processes other than classical carboxylation reactions. Specifically, novel roles for biotin in cell signaling, gene expression, and chromatin structure have been identified in recent years. Human cells accumulate biotin by using both the sodium-dependent multivitamin transporter and monocarboxylate transporter 1. These transporters and other biotin-binding proteins partition biotin to compartments involved in biotin signaling: cytoplasm, mitochondria, and nuclei. The activity of cell signals such as biotinyl-AMP, Sp1 and Sp3, nuclear factor (NF)-kappaB, and receptor tyrosine kinases depends on biotin supply. Consistent with a role for biotin and its catabolites in modulating these cell signals, greater than 2000 biotin-dependent genes have been identified in various human tissues. Many biotin-dependent gene products play roles in signal transduction and localize to the cell nucleus, consistent with a role for biotin in cell signaling. Posttranscriptional events related to ribosomal activity and protein folding may further contribute to effects of biotin on gene expression. Finally, research has shown that biotinidase and holocarboxylase synthetase mediate covalent binding of biotin to histones (DNA-binding proteins), affecting chromatin structure; at least seven biotinylation sites have been identified in human histones. Biotinylation of histones appears to play a role in cell proliferation, gene silencing, and the cellular response to DNA repair. Roles for biotin in cell signaling and chromatin structure are consistent with the notion that biotin has a unique significance in cell biology. | Holmberg A, Blomstergren A, Nord O, Lukacs M, Lundeberg J, Uhlén M (2005)
The biotin-streptavidin interaction can be reversibly broken using water at elevated temperatures.
Electrophoresis 26, 501-510 [PubMed:15690449]
[show Abstract]
The biotin-streptavidin system is the strongest noncovalent biological interaction known, having a dissociation constant, K(d), in the order of 4x10(-14) M. The strength and specificity of the interaction has led it to be one of the most widely used affinity pairs in molecular, immunological, and cellular assays. However, it has previously been impossible to re-use any streptavidin solid support, since the conditions needed to break the interaction with biotin has led to the denaturation of the streptavidin. Here, we show that a short incubation in nonionic aqueous solutions at temperatures above 70 degrees C can efficiently break the interaction without denaturing the streptavidin tetramer. Both biotin and the streptavidin remain active after dissociation and both molecules can therefore be re-used. The efficiency of the regeneration allowed solid supports with streptavidin to be used many times, here exemplified with the multiple re-use of streptavidin beads used for sample preparation prior to automated DNA sequencing. The results suggest that streptavidin regeneration can be introduced as an improvement in existing methods and assays based on the streptavidin system as well as emerging solid phase applications in fields, such as microfluidics and nanotechnology. | Guillén-Navarro K, Encarnación S, Dunn MF (2005)
Biotin biosynthesis, transport and utilization in rhizobia.
FEMS microbiology letters 246, 159-165 [PubMed:15899401]
[show Abstract]
Biotin, a B-group vitamin, performs an essential metabolic function in all organisms. Rhizobia are alpha-proteobacteria with the remarkable ability to form a nitrogen-fixing symbiosis in combination with a compatible legume host, a process in which the importance of biotin biosynthesis and/or transport has been demonstrated for some rhizobia-legume combinations. Rhizobia have also been used to delimit the biosynthesis, metabolic effects and, more recently, transport of biotin. Molecular genetic analysis shows that an orthodox biotin biosynthesis pathway occurs in some rhizobia while others appear to synthesize the vitamin using alternative pathways. In addition to its well established function as a prosthetic group for biotin-dependent carboxylases, we are beginning to delineate a role for biotin as a metabolic regulator in rhizobia. | Vilches-Flores A, Fernández-Mejía C (2005)
[Effect of biotin upon gene expression and metabolism].
Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion 57, 716-724 [PubMed:16419467]
[show Abstract]
During the last few decades, an increasing number of vitamin-mediated effects has been discovered at the level of gene expression in addition to their well-known roles as substrates and cofactors; the best recognized examples are the lipophilic vitamins A and D. Although little is known about water-soluble vitamins as genetic modulators, there are increasing examples of their effect on gene expression. Biotin is a hydro soluble vitamin that acts as a prosthetic group of carboxylases. Besides its role as carboxylase cofactor, biotin affects several systemic functions such as development, immunity and metabolism. In recent years, significant progress has been made in the identification of genes that are affected by biotin at the transcriptional and post-transcriptional levels as well as in the elucidation of mechanisms that mediate the effects of biotin on the gene expression. These studies bring new insights into biotin mediated gene expression and will lead to a better under-standing of biotin roles in the metabolism and in systemic functions. | Fujimoto W, Inaoki M, Fukui T, Inoue Y, Kuhara T (2005)
Biotin deficiency in an infant fed with amino acid formula.
The Journal of dermatology 32, 256-261 [PubMed:15863846]
[show Abstract]
Biotin deficiency is rarely encountered in an infant on weaning from breast and formula feeding. It is characterized by alopecia and scaly, erythematous dermatitis distributed around the body orifices. We report a 5-month-old Japanese infant with typical skin lesions who had been diagnosed as a neonate with dyspepsia and fed only an amino acid formula. Serum and urine levels of biotin were below the normal range, but zinc and biotinidase were within normal range. Urinary excretion of 3-methylcrotonylglycine, 3-hydroxyisovaleric acid, and methylcitric acid was significantly elevated. Daily oral supplementation with 1 mg of biotin resulted in dramatic improvement of the periorificial dermatitis and hair growth together with a complete disappearance of the organic aciduria. Our case shows that the characteristic skin manifestations are the most important clue to the diagnosis of biotin deficiency and demonstrated that urinary excretion of biotin and organic aciduria, rather than the serum concentration of biotin, are the sensitive indicators for evaluating the patient's status of biotin deficiency. | Gravel RA, Narang MA (2005)
Molecular genetics of biotin metabolism: old vitamin, new science.
The Journal of nutritional biochemistry 16, 428-431 [PubMed:15992684]
[show Abstract]
Biotin is a water-soluble vitamin that participates as a cofactor in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. It functions as the carboxyl carrier for biotin-dependent carboxylases. Its covalent attachment to carboxylases is catalyzed by holocarboxylase synthetase. Our interest in biotin has been through the genetic disease, "biotin-responsive multiple carboxylase deficiency," caused by deficient activity of holocarboxylase synthetase. As part of these studies, we made the unexpected findings that the enzyme also targets to the nucleus and that it catalyzes the attachment of biotin to histones. We found that patients with holocarboxylase synthetase deficiency have a much reduced level of biotinylated histones, yet the importance of this process is unknown. The dual nature of biotin, as the carboxyl-carrier cofactor of carboxylases and as a ligand of unknown function attached to histones, is an enigma that suggests a much more involved role for biotin than anticipated. It may change our outlook on the optimal nutritional intake of biotin and its importance in biological processes such as development, cellular homeostasis and regulation. | Ginzberg I, Perl A, Genser M, Wininger S, Nemas C, Kapulnik Y (2004)
Expression of streptavidin in tomato resulted in abnormal plant development that could be restored by biotin application.
Journal of plant physiology 161, 611-620 [PubMed:15202718]
[show Abstract]
Biotin is an essential cofactor for a variety of carboxylase and decarboxylase reactions and is involved in diverse metabolic pathways of all organisms. In the present study we tested the hypothesis that controlling biotin availability by the expression of Streptomyces avidinii streptavidin, would impede plant development. Transient expression of streptavidin fused to plant signal peptide, bacterial signal peptide or both, in tomato (Lycopersicon esculentum cv. VF36) plants resulted in various levels of tissue impairment, exhibited as lesion development on 1-week-old tomato seedlings. The least toxic construct was introduced to tomato (stable transformation) under the constitutive CaMV 35S promoter, and lesions appeared on stems, flower morphologies were modified and numbers and sizes of fruits were altered. Furthermore, tissue-specific expression of the streptavidin, by means of the beta-phaseolin or TobRB7 promoters, resulted in localised effects, i.e., impaired seed formation or seedless fruits, respectively, with no alteration in the morphology of the other plant organs. External application of biotin on streptavidin-expressing tomato plants prevented the degeneration symptoms and facilitated normal plant development. It can be concluded that expression of streptavidin in the plant cell can lead to local and temporal deficiencies in biotin availability, impairing developmental processes while biotin application restores plant growth cycle. | Kim HS, Hoja U, Stolz J, Sauer G, Schweizer E (2004)
Identification of the tRNA-binding protein Arc1p as a novel target of in vivo biotinylation in Saccharomyces cerevisiae.
The Journal of biological chemistry 279, 42445-42452 [PubMed:15272000]
[show Abstract]
Biotin is an essential cofactor of cell metabolism serving as a protein-bound coenzyme in ATP-dependent carboxylation, in transcarboxylation, and certain decarboxylation reactions. The involvement of biotinylated proteins in other cellular functions has been suggested occasionally, but available data on this are limited. In the present study, a Saccharomyces cerevisiae protein was identified that reacts with streptavidin on Western blots and is not identical to one of the known biotinylated yeast proteins. After affinity purification on monomeric avidin, the biotinylated protein was identified as Arc1p. Using 14C-labeled biotin, the cofactor was shown to be incorporated into Arc1p by covalent and alkali-stable linkage. Similar to the known carboxylases, Arc1p biotinylation is mediated by the yeast biotin:protein ligase, Bpl1p. Mutational studies revealed that biotinylation occurs at lysine 86 within the N-terminal domain of Arc1p. In contrast to the known carboxylases, however, in vitro biotinylation of Arc1p is incomplete and increases with BPL1 overexpression. In accordance to this fact, Arc1p lacks the canonical consensus sequence of known biotin binding domains, and the bacterial biotin:protein ligase, BirA, is unable to use Arc1p as a substrate. Arc1p was shown previously to organize the association of MetRS and GluRS tRNA synthetases with their cognate tRNAs thereby increasing the substrate affinity and catalytic efficiency of these enzymes. Remarkably, not only biotinylated but also the biotin-free Arc1p obtained by replacement of lysine 86 with arginine were capable of restoring Arc1p function in both arc1Delta and arc1Deltalos1Delta mutants, indicating that biotinylation of Arc1p is not essential for activity. | Harthé C, Claustrat B (2003)
A sensitive and practical competitive radioassay for plasma biotin.
Annals of clinical biochemistry 40, 259-263 [PubMed:12803839]
[show Abstract]
BackgroundBiotin is a water-soluble vitamin which plays an important biochemical role in a variety of carboxylase-mediated metabolic reactions. Determination of biotin status for the diagnosis of biotin deficiency is crucial.MethodsWe describe a solid-phase protein-binding assay involving [(125)I]iodostreptavidin as a tracer for the determination of biotin in plasma. The assay was conducted in one step by incubation of a fixed amount of [(125)I]iodostreptavidin as binding reagent with varying amounts of biotin, diluted in biotin-free plasma (standard curve) or unknown samples in tubes previously coated with biotin linked to goat antirabbit IgG. Increasing amounts of biotin in the standard or unknown samples in tubes previously coated with biotin occupy more sites on iodostreptavidin, resulting in fewer counts bound to tubes. The effects of the incubation time and temperature on the competitive binding of biotin with iodostreptavidin were tested.ResultsThe detection limit of the plasma assay for biotin was 100 pmol/L. Only 100 microL of plasma were necessary for the assay, which was performed within 6 h. The dilutions of plasma and synthetic biotin gave a parallel response. Plasma biotin levels ranged from 0.49 to 1.33 nmol/L (mean 0.76 nmol/L) in healthy subjects. The intra and inter-assay coefficients of variation were 3.5% and 10%, respectively, at a concentration of 0.27 nmol/L.ConclusionsThis assay was suitable for the direct measurement of biotin in human plasma and was robust and sensitive enough for screening for biotin deficiency. | Grafe F, Wohlrab W, Neubert RH, Brandsch M (2003)
Transport of biotin in human keratinocytes.
The Journal of investigative dermatology 120, 428-433 [PubMed:12603856]
[show Abstract]
Biotin is an essential micronutrient for normal cellular function, growth, and development. Biotin deficiency leads to pathologic, dermatologic, and neurocutaneous manifestations in skin and its appendages. Previous studies described the presence of specific biotin transport systems in the epithelia of the intestine, liver, kidney, and placenta, and in blood mononuclear cells. The aim of this study was to examine biotin transport into human keratinocytes. Uptake of [3H]biotin was measured both in the HaCaT cell line and in native keratinocytes in primary culture. Uptake of [3H]biotin (6 nM) in HaCaT cells was linear for up to 5 min of incubation. In the presence of an Na+ gradient total biotin uptake was 4- to 5-fold higher than in the absence of sodium ions. Biotin uptake was not altered by H+ and Cl- gradients. This transport system exhibited a Michaelis-Menten constant for biotin of 22.7+/-1.0 microM and a maximal velocity of 163.6+/-3.5 pmol per 5 min per mg protein. [3H]Biotin uptake (6 nM) was strongly inhibited by lipoic acid (oxidized form, Ki=4.6 microM; reduced form, Ki=11.4 microM), pantothenic acid (Ki=1.2 microM), and desthiobiotin (Ki=15.2 microM), but not by biocytin or biotin methyl ester. Measured at [3H]biotin concentrations of 0.1-10 nM we obtained kinetic evidence for the presence of a second transport component that is saturable at very low biotin concentrations (Kt=2.6+/-0.1 nM). Unlabeled lipoic acid and pantothenic acid (20 nM) did not inhibit the [3H]biotin uptake (1 nM). We conclude that human keratinocytes express the Na+-dependent multivitamin transporter with preference for pantothenate and a very high affinity transport component with specificity for biotin. | McMahon RJ (2002)
Biotin in metabolism and molecular biology.
Annual review of nutrition 22, 221-239 [PubMed:12055344]
[show Abstract]
Biotin is a water-soluble vitamin required by all organisms by virtue of its essential role in carboxylation reactions. Although the metabolism and role of biotin in intermediary metabolism are well established, biotin remains one of the most poorly understood water-soluble vitamins in terms of nutritional requirements and responsiveness to physiological and pharmacological states. Significant advances in the understanding of biotin nutriture have been recently accomplished through the description of the kinetics and regulation of biotin transport and improved methods for biotin status assessment. Additionally, the potential role of biotin in the regulation of gene expression has been strengthened through description of altered gene expression during biotin deficiency and through newly described enzymatic activities of the enzyme biotinidase. Given mounting evidence of suboptimum biotin status, a more complete understanding of these aspects of biotin should lead to a greater appreciation of the ways in which biotin aids in the maintenance of health. | Mardach R, Zempleni J, Wolf B, Cannon MJ, Jennings ML, Cress S, Boylan J, Roth S, Cederbaum S, Mock DM (2002)
Biotin dependency due to a defect in biotin transport.
The Journal of clinical investigation 109, 1617-1623 [PubMed:12070309]
[show Abstract]
We describe a 3-year-old boy with biotin dependency not caused by biotinidase, holocarboxylase synthetase, or nutritional biotin deficiency. We sought to define the mechanism of his biotin dependency. The child became acutely encephalopathic at age 18 months. Urinary organic acids indicated deficiency of several biotin-dependent carboxylases. Symptoms improved rapidly following biotin supplementation. Serum biotinidase activity and Biotinidase gene sequence were normal. Activities of biotin-dependent carboxylases in PBMCs and cultured skin fibroblasts were normal, excluding biotin holocarboxylase synthetase deficiency. Despite extracellular biotin sufficiency, biotin withdrawal caused recurrent abnormal organic aciduria, indicating intracellular biotin deficiency. Biotin uptake rates into fresh PBMCs from the child and into his PBMCs transformed with Epstein Barr virus were about 10% of normal fresh and transformed control cells, respectively. For fresh and transformed PBMCs from his parents, biotin uptake rates were consistent with heterozygosity for an autosomal recessive genetic defect. Increased biotin breakdown was ruled out, as were artifacts of biotin supplementation and generalized defects in membrane permeability for biotin. These results provide evidence for a novel genetic defect in biotin transport. This child is the first known with this defect, which should now be included in the identified causes of biotin dependency. | Fiume MZ, Cosmetic Ingredient Review Expert Panel (2001)
Final report on the safety assessment of biotin.
International journal of toxicology 20 Suppl 4, 1-12 [PubMed:11800048]
[show Abstract]
Biotin is a water-soluble vitamin used as a hair-conditioning agent and a skin-conditioning agent in many cosmetic products at concentrations ranging from 0.0001% to 0.6%. Although Biotin does absorb some ultraviolet (UV) radiation, the absorption shows no peaks in the UVA or UVB region. Biotin is rapidly metabolized and excreted in urine. Little acute oral toxicity is seen in animal tests. Short-term and subchronic toxicity studies likewise found no evidence of toxicity. Although intradermal injection of a small quantity of Biotin (0.1 ml) into guinea pig skin did not produce skin irritation, Biotin (0.1% at pH 7.3) did produce slight, transient ocular irritation in rabbit eyes. Biotin was not mutagenic in bacterial tests, but positive results were found in a Tradescantia micronucleus test. There was evidence of an increase in the number of resorptions in rats receiving Biotin by subcutaneous injection, with concomitant decreases in fetal, uterine, and placental weights. Another study of mice receiving Biotin orally or by subcutaneous injection found no differences between control and treatment groups. Although there is one case study reporting an urticarial reaction in the literature, there are a very large number of individuals exposed to Biotin on a daily basis, and there is not a parallel appearance of irritation, sensitization, or other adverse reactions. Based on these available data, it was concluded that Biotin is safe as used in cosmetic formulations. | Rodríguez-Meléndez R, Cano S, Méndez ST, Velázquez A (2001)
Biotin regulates the genetic expression of holocarboxylase synthetase and mitochondrial carboxylases in rats.
The Journal of nutrition 131, 1909-1913 [PubMed:11435506]
[show Abstract]
Biotin is the cofactor of carboxylases [pyruvate (PC), propionyl-CoA (PCC), 3-methyl crotonyl-CoA and acetyl-CoA], to which it is covalently bound by the action of holocarboxylase synthetase (HCS). We have studied whether biotin also regulates their expression, as it does other, nonrelated enzymes (e.g., glucokinase, phosphoenol pyruvate carboxykinase, guanylate cyclase). For this purpose, HCS, PC and PCC mRNAs were studied in biotin-deficient rat liver, kidney, muscle and brain of biotin-deficient rats. PC- and PCC-specific activities and protein masses were also measured. The 24-h time course of HCS mRNA in deficient rats was examined after biotin supplementation. HCS mRNA was significantly reduced during vitamin deficiency. It increased in deficient rats after biotin was injected, reaching control levels 24 h after administration. These changes seem to be the first known instance in mammals of an effect of a water-soluble vitamin on a mRNA functionally related to it. In contrast, the decreased activities of the carboxylases were associated with reductions in the amounts of their enzyme proteins except in brain. However, their mRNA levels were not affected. There are no reports on these types of vitamin affecting the mRNA or protein levels of their apoenzymes or their products. This work provides evidence for biotin being a modulator of the genetic expression of the enzymes involved in its function as a cofactor. As such, it may be a useful model for probing a similar role for other water-soluble vitamins. | Mock DM, Nyalala JO, Raguseo RM (2001)
A direct streptavidin-binding assay does not accurately quantitate biotin in human urine.
The Journal of nutrition 131, 2208-2214 [PubMed:11481419]
[show Abstract]
In human urine, the biotin concentration assayed directly using an avidin-binding assay (ABA) apparently overestimates "true" biotin concentration as measured by HPLC separation of biotin from biotin metabolites followed by ABA. Because biotin metabolites account for about half of biotin plus biotin metabolites in human urine, we speculate that the error might arise from biotin metabolites. We sought to test the following hypothesis: biotin measured by direct ABA routinely exceeds true biotin in urine due to biotin metabolites; however, if urinary biotin is quantitated using a streptavidin-binding assay (SABA) that does not detect biotin metabolites, results will agree with true biotin. An assay for biotin that uses europium coupled to streptavidin and time-resolved fluorescence was developed and validated. Urine samples were obtained from biotin-deficient, normal and biotin-supplemented adults. In 133 urine samples from 26 subjects, biotin by direct ABA correlated positively and significantly with biotin measured after HPLC separation (P < 0.001; r = 0.78). However, biotin by direct ABA routinely exceeded true biotin. The magnitude of the overestimate correlated strongly with biotin metabolites; r = 0.80 and P < 0.0001. In 92 samples from nine subjects, biotin by direct SABA correlated positively and significantly with true biotin (P = 0.001; r = 0.73) but exceeded true biotin by more than analytical error in 62 of the 92 samples. The error did not correlate significantly with total biotin metabolites. In 62 samples analyzed by both assays, biotin by direct SABA correlated weakly (r = 0.69) but significantly (P < 0.0001) with biotin by direct ABA. These studies provide evidence that direct SABA does not accurately quantitate biotin. Although the errors from direct ABA arise primarily from metabolites, the errors from direct SABA cannot be attributed primarily to biotin metabolites. Whether these interfering substances are biotin metabolites or other unknown substances, the substances are likely separated from the biotin fraction by HPLC. | Alban C, Job D, Douce R (2000)
BIOTIN METABOLISM IN PLANTS.
Annual review of plant physiology and plant molecular biology 51, 17-47 [PubMed:15012185]
[show Abstract]
Biotin is an essential cofactor for a small number of enzymes involved mainly in the transfer of CO2 during HCO-3-dependent carboxylation reactions. This review highlights progress in plant biotin research by focusing on the four major areas of recent investigation: the structure, enzymology, and localization of two important biotinylated proteins (methylcrotonoyl-CoA carboxylase involved in the catabolism of leucine and noncyclic isoprenoids; acetyl-CoA carboxylase isoforms involved in a number of biosynthetic pathways); the biosynthesis of biotin; the biotinylation of biotin-dependent carboxylases, including the characterization of biotin holocarboxylase synthetase isoforms; and the detailed characterization of a novel, seed-specific biotinylated protein. A central challenge for plant biotin research is to determine in molecular terms how plant cells regulate the flow of biotin to sustain the biotinylation of biotin-dependent carboxylases during biosynthetic reactions. | Anagnostouli M, Livaniou E, Nyalala JO, Evangelatos G, Zournas C, Ithakissios DS, Papageorgiou C (1999)
Cerebrospinal fluid levels of biotin in various neurological disorders.
Acta neurologica Scandinavica 99, 387-392 [PubMed:10577274]
[show Abstract]
ObjectivesTo analyse biotin concentrations in human cerebrospinal fluid (CSF) and serum from controls without evidence of nutritional or neurological disorders and patients with common neurological disorders.Patients and methodsCerebrospinal fluid was obtained from patients by lumbar puncture, serum was prepared from freshly drawn whole blood and biotinidase in samples was inhibited before being analysed for biotin by radioligand assay.ResultsAssay characteristics were within an acceptable range (intra-and interassay coefficient of variations were 8.8 and 12.0 respectively, recovery: 91-114% and sensitive, lowest standard concentration 15 ng/l). Significantly lower values for biotin were found in patients with multiple sclerosis (both CSF and serum) in comparison to the controls. Significantly reduced values for cerebrospinal fluid biotin were found in epileptics compared to controls, whereas, in serum the difference was approaching significance. No significant differences were observed in other groups of patients.ConclusionThere is a significant reduction in cerebrospinal fluid biotin in epileptics and patients with multiple sclerosis compared to controls. In epileptics this may be related to competition between biotin and anticonvulsants bearing carbamide ring for absorption. Reduction of biotin levels in patients with multiple sclerosis could be attributed to intestinal malabsorption caused by the underlying disease or a biotin-binding immunoglobulin which may be involved in multiple sclerosis pathogenesis. | Thuy LP, Belmont J, Nyhan WL (1999)
Prenatal diagnosis and treatment of holocarboxylase synthetase deficiency.
Prenatal diagnosis 19, 108-112 [PubMed:10215065]
[show Abstract]
Holocarboxylase synthetase is one of two enzymes known to be involved in the metabolism of biotin. It catalyses the fixation of biotin to inactive apocarboxylases yielding active carboxylases. Deficiency of this enzyme leads to multiple carboxylase deficiency which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase prenatal diagnosis was performed by assay of the enzyme in amniocytes. The Km for biotin was 62.8 nM which was 12 times the control value of 5.0 nM. The Vmax was 2 per cent of the control value. This was confirmed by assay of the activity of propionyl CoA carboxylase (20-26 per cent control), 3-methylcrotonyl CoA carboxylase (14-19 per cent control) and pyruvate carboxylase (12-30 per cent control) and demonstration of biotin responsiveness in vitro. All carboxylase activities were restored to 51-58 per cent of control when amniocytes were cultured in medium containing 1 microM biotin. Diagnosis was ultimately confirmed by assay of holocarboxylase synthetase in lymphocytes from the infant after birth. The Km for biotin of the holocarboxylase synthetase of the infant was 60.3 nM while that of a parallel control was 6.9 nM. Prenatal treatment of the mother with biotin led to a concentration of biotin of 240 nM in the serum of the infant at birth that was four times the Km of the enzyme for biotin. The infant was clinically well at birth, and organic acid analysis of the blood and urine revealed no accumulation of the characteristic metabolites. | Mock DM (1999)
Biotin status: which are valid indicators and how do we know?
The Journal of nutrition 129, 498S-503S [PubMed:10064317]
[show Abstract]
Although estimated average requirements for biotin have been proposed, the human requirements for biotin in specific populations and at various ages remain uncertain, in part because indicators of biotin status have not been validated. With the use of improved methods for measuring biotin and metabolites, a recent study indicated that decreased urinary excretion of biotin and bisnorbiotin is an early and sensitive indicator of biotin deficiency, but decreased serum concentration of biotin is not. Increased urinary excretion of 3-hydroxyisovaleric acid (3-HIA), a leucine metabolite that is excreted in increased quantities with deficiency of the biotin-dependent enzyme beta-methylcrotonyl-CoA carboxylase, is also an early and sensitive indicator of biotin deficiency. When these indicators were assessed longitudinally in 13 pregnant women, biotin excretion was not significantly decreased early in pregnancy but did decrease significantly from early to late pregnancy. Excretion of 3-HIA was abnormally increased in about three-fourths of the women studied in both early and late pregnancy. Thus, each indicator detected biotin deficiency late in pregnancy, but assessment of biotin status for the two indicators conflicted early in pregnancy. Preliminary results from a trial assessing response of 3-HIA excretion to biotin treatment indicate that biotin status is indeed impaired both early and late in pregnancy. | Bussolati G, Gugliotta P, Volante M, Pace M, Papotti M (1997)
Retrieved endogenous biotin: a novel marker and a potential pitfall in diagnostic immunohistochemistry.
Histopathology 31, 400-407 [PubMed:9416479]
[show Abstract]
AimAntigen retrieval (AR) procedures are based on the effect of heating (by either microwave or pressure cooking treatments) on routinely fixed and paraffin embedded tissues. We observed that AR procedures restore the reactivity of endogenous biotin (EB) and report on the distribution of EB following AR in a series of routinely fixed and embedded tissues.Methods and resultsFollowing pressure cooking or microwave treatments, a simple streptavidin-peroxidase staining revealed retrieved endogenous biotin (REB) in normal tissues (such as liver, kidney and adrenal cortex), in oxyphylic cells and in some tumours, especially in carcinomas of the kidney and of the adrenal cortex. In formalin-fixed (but not in alcohol-fixed) tissue sections, the heating procedures caused an intense and finely granular cytoplasmic reaction, following a routine streptavidin-conjugated peroxidase treatment. The staining was prevented by blocking of EB by a sequential avidin-biotin treatment.ConclusionsRetrieval of EB reactivity can cause pitfalls in diagnostic immunohistochemistry but, alternatively, it might also constitute a useful and novel diagnostic marker. | Mock DM, Stadler DD (1997)
Conflicting indicators of biotin status from a cross-sectional study of normal pregnancy.
Journal of the American College of Nutrition 16, 252-257 [PubMed:9176832]
[show Abstract]
ObjectiveTo assess biotin nutritional status during normal human gestation.MethodsUrine samples were obtained in a cross-sectional design from 16 women in early pregnancy (17 +/- 1 weeks, mean +/- 1 SD) and from 13 women in late pregnancy (36 +/- 1 weeks). The urinary excretion of biotin, two metabolites bisnorbiotin (BNB) and biotin sulfoxide (BSO), and the organic acid 3-hydroxyisovaleric acid (3-HIA) were measured by HPLC/avidin-binding assay and GC/MS, respectively. Excretion rates were expressed as concentration ratios to urinary creatinine.ResultsIn both early and late pregnancy, 3-HIA excretion was increased compared to controls (p < 0.0001), suggesting decreased activity of a biotin-dependent enzyme caused by tissue biotin depletion. In early pregnancy, urinary excretion of biotin was normal; in late pregnancy, excretion was increased (p < 0.0002), suggesting biotin status was not decreased. In late pregnancy, urinary excretion of BNB and BSO were increased (p < 0.009).ConclusionThe apparent conflict in the indices of biotin status is not explained by this study but could be resolved by two alternate explanations: 1) Pregnancy caused an impairment of renal reclamation of biotin, BNB, and BSO leading to a paradoxical increase in biotin excretion 2) Pregnancy caused metabolic or renal effects that increased 3-HIA excretion nonspecifically; hence, the increased 3-HIA excretion did not reflect biotin deficiency. We speculate that some of the women studied were marginally biotin deficient and that renal wasting and accelerated breakdown of biotin contributed to the deficiency. | Mock DM, Dyken ME (1997)
Biotin catabolism is accelerated in adults receiving long-term therapy with anticonvulsants.
Neurology 49, 1444-1447 [PubMed:9371938]
[show Abstract]
Using serum biotin concentration as the indicator, a previous study reported biotin deficiency resulting from long-term anticonvulsant therapy. However, serum biotin may not be a good indicator of tissue biotin status. Using better indicators of biotin status in anticonvulsant-treated subjects, we found increased urinary excretion of biotin catabolites and 3-hydroxyisovaleric acid, an organic acid produced in greater quantities secondary to reduced activity of a biotin-dependent carboxylase. We conclude that anticonvulsant treatment led to increased biotin catabolism and probably to reduced biotin status. | Zempleni J, McCormick DB, Mock DM (1997)
Identification of biotin sulfone, bisnorbiotin methyl ketone, and tetranorbiotin-l-sulfoxide in human urine.
The American journal of clinical nutrition 65, 508-511 [PubMed:9022537]
[show Abstract]
In previous studies using the HPLC and avidin-binding assay, five unidentified avidin-binding substances were observed in human urine. The present study investigated the identity of these substances. Urine was collected before and after intravenous administration of 18.5 mumol biotin to healthy adults. Unknown substances 1 and 3 were initially identified as biotin sulfone and bisnorbiotin methyl ketone, respectively, by coelution with authentic standards on HPLC. Identities were confirmed by thin-layer chromatography and by derivatization with p-dimethyl-aminocinnamaldehyde. As expected for biotin metabolites, the urinary excretion of biotin sulfone and bisnorbiotin methyl ketone increased with biotin administration. The urinary excretion of biotin sulfone increased 21-fold from 0.2 nmol/h before to 4.2 nmol/h after administration; the excretion of bisnorbiotin methyl ketone increased 130-fold from 0.4 to 51.8 nmol/h. At presumed steady state in free-living subjects (n = 6), biotin sulfone and bisnorbiotin methyl ketone accounted for 3.6% and 7.9% of total biotin excretion, respectively. Traces of tetranorbiotin-l-sulfoxide were also identified by using thin-layer chromatography and derivatization with p-dimethylaminocinnamaldehyde. However, tetranorbiotin-l-sulfoxide was not detectable in urine by the HPLC and avidin-binding assay because this metabolite has weak avidin-binding affinity. We conclude that biotin sulfone and bisnorbiotin methyl ketone are present in measurable quantities in human urine; their quantitation should allow more accurate studies on human biotin metabolism and turnover. | Mock NI, Malik MI, Stumbo PJ, Bishop WP, Mock DM (1997)
Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency.
The American journal of clinical nutrition 65, 951-958 [PubMed:9094878]
[show Abstract]
To assess the utility of various indicators of biotin status, marginal biotin deficiency was induced experimentally in normal adults. Ten subjects consumed a diet that contained enough avidin to bind seven times more biotin than that in the diet. Blood and 24-h urine samples were collected before the diet began and twice weekly thereafter for 20 d. The urinary excretion and serum concentration of biotin and its two principal inactive metabolites bisnorbiotin and biotin sulfoxide were determined after HPLC separation with an avidin-binding assay. The urinary concentration of 3-hydroxyisovaleric acid, an indicator of reduced activity of a biotin-dependent enzyme, was quantitated by gas chromatography-mass spectrometry. The urinary excretion of 3-hydroxyisovaleric acid increased significantly (P < 0.0001). For all subjects, the urinary excretion of both biotin and bisnorbiotin decreased significantly (P < 0.0001 for each). In contrast, the mean serum concentration of biotin did not decrease significantly (P = 0.06). These data provide evidence that the urinary excretion of 3-hydroxyisovaleric acid and the urinary excretion of biotin are early and sensitive indicators of biotin deficiency and that the serum concentration of biotin is not. | Mock DM, Heird GM (1997)
Urinary biotin analogs increase in humans during chronic supplementation: the analogs are biotin metabolites.
The American journal of physiology 272, E83-5 [PubMed:9038855]
[show Abstract]
In human subjects, the metabolic origins of bisnorbiotin and biotin sulfoxide were determined by measuring the urinary excretion of each after chronic administration of large oral doses of biotin. For 2 wk, 14 adult volunteers consumed 1,200 micrograms of biotin per day, an amount approximately 20 times the daily dietary intake. With the use of a high-performance liquid chromatography/avidin-binding assay in untimed urine samples obtained before the first dose of biotin and after the 14th dose, concentrations of biotin, bisnorbiotin, and biotin sulfoxide were measured. Excretion was expressed as concentration ratios to urinary creatinine. Bisnorbiotin and biotin sulfoxide excretion increased 85-fold (P < 0.0001) and 114-fold (P < 0.0001), respectively. The molar percentages of bisnorbiotin and biotin sulfoxide decreased from 28 to 14% (P = 0.006) and from 9 to 5% (P = 0.017), respectively. These data provide evidence that the bisnorbiotin and biotin sulfoxide found in human urine are biotin metabolites. Furthermore, we infer that chronic consumption of large amounts of biotin does not substantially saturate the human biotin pathways of biotransformation. | Mock DM, Stadler DD, Stratton SL, Mock NI (1997)
Biotin status assessed longitudinally in pregnant women.
The Journal of nutrition 127, 710-716 [PubMed:9164991]
[show Abstract]
This study assessed biotin nutritional status longitudinally during pregnancy as judged by urinary excretion of biotin and biotin metabolites and by serum concentration of biotin. 3-Hydroxyisovaleric acid excretion was also assessed because increased excretion of that acid reflects decreased tissue activity of the biotin-dependent enzyme, methylcrotonyl-CoA carboxylase. Thirteen women provided untimed urine samples during both early and late pregnancy. Twelve nonpregnant women served as controls. Biotin and metabolites were determined by a combined HPLC/avidin-binding assay. 3-Hydroxyisovaleric acid was determined by gas chromatography/mass spectrophotometry. Significance of changes from early to late pregnancy was tested by paired t test; to compare nonpregnant controls with early and late pregnancy, ANOVA was used. During early pregnancy, biotin excretion was not significantly different than controls; however, 3-hydroxyisovaleric acid excretion was significantly increased relative to controls (P < 0.0001) and was greater than the upper limit of normal in 9 of 13 women. From early to late pregnancy, biotin excretion decreased in 10 of 13 women (P < 0.01); by late pregnancy, biotin excretion was less than normal in six women. During late pregnancy, 3-hydroxyisovaleric acid remained significantly increased relative to controls (P < 0.0001). Serum concentrations of biotin were significantly greater than those of controls during early pregnancy (P < 0.0001) and decreased in each woman from early to late pregnancy (P < 0.0001). These data provide evidence that biotin status decreases during pregnancy. | Limat A, Suormala T, Hunziker T, Waelti ER, Braathen LR, Baumgartner R (1996)
Proliferation and differentiation of cultured human follicular keratinocytes are not influenced by biotin.
Archives of dermatological research 288, 31-38 [PubMed:8750932]
[show Abstract]
In humans and in animals, biotin deficiency causes pathological changes in the skin and its appendages. High doses of biotin may also have beneficial effects on skin, hair and fingernails in humans and animals with normal biotin status. Therefore, we investigated the effects of low and high concentrations of biotin on proliferation and differentiation of cultured outer root sheath cells from human hair follicles as an in vitro model for skin. The activities of biotin-dependent carboxylases were measured to evaluate the biotin status of the cells. In monolayer cultures of outer root sheath cells, proliferation and expression of the differentiation-specific keratins K1 and K10 were not influenced by extremely low concentrations of biotin (<2 x 10(-10) mol/l) or by pharmacological doses of biotin (10(-5) mol/l). Biotin deficiency of the cells was confirmed under the former condition by demonstrating decreased activities of the mitochondrial carboxylases. In organotypic cocultures of outer root sheath cells and dermal fibroblasts, in which stratified epithelia resembling epidermis were developed, the biotin concentration had no effect on the expression of all tested epidermal differentiation markers, including the suprabasal keratins K1 and K10, the hyperproliferation-associated keratin K16, involucrin and filaggrin. | Schenker S, Hu ZQ, Johnson RF, Yang Y, Frosto T, Elliott BD, Henderson GI, Mock DM (1993)
Human placental biotin transport: normal characteristics and effect of ethanol.
Alcoholism, clinical and experimental research 17, 566-575 [PubMed:8333586]
[show Abstract]
Biotin, a vitamin essential for many metabolic reactions, is supplied to the fetus exclusively from the mother. Deficiency of biotin in pregnancy leads to impaired fetal growth and development. Alcohol taken in pregnancy likewise may cause fetal growth abnormalities. Normal biotin transport via the placenta and the effects of ethanol on this transport apparently have not been studied. Our aims were to characterize these phenomena for the normal human-term placenta. Using maternal-facing placental membrane vesicles, biotin uptake was sodium- and temperature-dependent, saturable, and inhibited by structural analogs of biotin (desthiobiotin, biocytin, and biotin methyl ester), as well as by 4 and 10 hr exposure to 3 g/liter ethanol. Using the isolated perfused single cotyledon method to measure placental transport of biotin at a perfusion concentration of 1 nM, the overall rate of biotin transport was found to be only 30% that of antipyrine, a freely diffusible marker. Clearance of biotin was approximately 2 ml/hr.g placenta, which was equal to the clearance of passively transferred L-glucose; biotin clearance was similar in both maternal to fetal and fetal to maternal directions. Overall transfer of biotin from maternal to fetal compartments was not inhibited by 500-fold greater concentrations of the three analogs, did not proceed against a biotin concentration gradient, and was not inhibited by 90-240 min exposure to an initial concentration of 4 g/liter ethanol. Concentration of biotin in the fetal compartment at the end of the study was not higher than on the maternal side (after maternal to fetal infusion), but placental concentration was 2- to 3-fold greater. No significant metabolism of biotin was detected. Exposing human placental cultured trophoblast on day 3 to 24 hr of ethanol (2 g/liter) had no effect on the net uptake of biotin by these cells. These studies provide evidence that maternal-facing placental membranes take up biotin by a mediated, carrier-dependent process that is inhibited by ethanol; however, based on the perfusion studies, we conclude that the overall (maternal-fetal) rate-limiting transfer of biotin by the human placenta is most consistent with a passive process, which is not inhibited by short-term exposure to ethanol. | Thuy LP, Sweetman L, Nyhan WL (1991)
A new immunochemical assay for biotin.
Clinica chimica acta; international journal of clinical chemistry 202, 191-197 [PubMed:1814646]
[show Abstract]
A double antibody technique has been developed to separate free biotin from bound biotin after competitive binding of [3H]biotin and unlabelled biotin to avidin. Antiavidin goat antibody was added followed by the addition of antigoat IgG antibody linked to agarose. Centrifugation separated the free biotin from the biotin bound to the avidin complex. The method was suitable for the detection of the amounts of biotin contained in 100-200 microliters of plasma or 5-10 microliters of urine. Normal values for the concentration of biotin in plasma and urine determined by this assay were 1.27 +/- 0.67 nmol/l and 49.1 +/- 35.7 mumol/mol creatinine, respectively. | Bigham SL, Ballard JD, Giles KD, Clelland CS, Jeffcoat R, Griffin KS, Farley TD, Bushman DR, Wright JR (1990)
Synthesis and possible applications of biotin-linked copper clusters.
Physiological chemistry and physics and medical NMR 22, 63-72 [PubMed:2100006]
[show Abstract]
The trifunctional aziridine XAMA-7 (CAS 57116-45-7) has been used to form crosslinks between a deep red-violet copper cluster of the type Cu(I)8Cu(II)6pen12Cl5- (pen=penicillamine) and molecules with biological activity such as d-biotin and proteins. A complex containing biotin, bovine serum albumin and the copper cluster displayed activity toward affinity columns of avidin on Agarose, and the red-violet pigment was immobilized on the gel. This interaction was completely blocked in gels which had been pretreated with d-biotin carboxylic acid. The free and biologically active versions of the cluster have some potential for biomedical applications. For example, the short-lived positron emitter 64Cu (suitable for positron tomography) may be carried in the cluster's structure. The cluster is paramagnetic, but it is a relatively weak effector of water proton spin-lattice relaxation. Other members of this structural group of inorganic compounds may have better magnetic properties, and the crosslinking reaction with aziridines appears to be generally applicable to the group. |
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