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| 3-hydroxyglutaric acid |
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| CHEBI:39980 |
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| A 3 hydroxy carboxylic acid that is glutaric acid which is substituted by a hydroxy group at position 3. It is a diagnostic marker for glutaric aciduria type I. |
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This entity has been manually annotated by the ChEBI Team.
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| No supplier information found for this compound. |
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Molfile
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SDF
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more structures >>
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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__5315714983887809__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__5315714983887809__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:39980","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__5315714983887809__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"5315714983887809","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__5315714983887809__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol Marvin 09130717073D starting HoverWatcher_5 Time for openFile( Marvin 09130717073D 18 17 0 0 0 0 999 V2000 0.0000 -0.9530 0.9960 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.6950 0.6380 -0.0830 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.4770 0.0790 -0.1490 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.3640 -1.0940 -0.4140 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.2490 0.9150 0.1070 C 0 0 0 0 0 0 0 0 0 0 0 0 0.0000 0.0430 -0.0300 C 0 0 1 0 0 0 0 0 0 0 0 0 1.2490 0.9150 0.1070 C 0 0 0 0 0 0 0 0 0 0 0 0 2.4770 0.0790 -0.1490 C 0 0 0 0 0 0 0 0 0 0 0 0 2.3640 -1.0940 -0.4140 O 0 0 0 0 0 0 0 0 0 0 0 0 3.6950 0.6380 -0.0830 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.4830 0.1020 -0.2480 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2950 1.3290 1.1150 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2060 1.7280 -0.6180 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0000 -0.4410 -1.0060 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0000 -0.4840 1.8410 H 0 0 0 0 0 0 0 0 0 0 0 0 1.2060 1.7280 -0.6180 H 0 0 0 0 0 0 0 0 0 0 0 0 1.2950 1.3290 1.1150 H 0 0 0 0 0 0 0 0 0 0 0 0 4.4830 0.1020 -0.2480 H 0 0 0 0 0 0 0 0 0 0 0 0 1 6 1 0 0 0 0 1 15 1 0 0 0 0 2 3 1 0 0 0 0 2 11 1 0 0 0 0 3 4 2 0 0 0 0 3 5 1 0 0 0 0 5 6 1 0 0 0 0 5 12 1 0 0 0 0 5 13 1 0 0 0 0 6 7 1 0 0 0 0 6 14 1 0 0 0 0 7 8 1 0 0 0 0 7 16 1 0 0 0 0 7 17 1 0 0 0 0 8 9 2 0 0 0 0 8 10 1 0 0 0 0 10 18 1 0 0 0 0 M END): 15 ms reading 18 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 18 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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| InChI=1S/C5H8O5/c6-3(1-4(7)8)2-5(9)10/h3,6H,1-2H2,(H,7,8)(H,9,10) |
| ZQHYXNSQOIDNTL-UHFFFAOYSA-N |
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Homo sapiens
(NCBI:txid9606)
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Found in
blood
(UBERON:0000178).
See:
PubMed
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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 plasma
(BTO_0000131).
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
urine
(BTO:0001419).
See:
PubMed
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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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human urinary metabolite
Any metabolite (endogenous or exogenous) found in human urine samples.
human blood serum metabolite
Any metabolite (endogenous or exogenous) found in human blood serum samples.
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View more via ChEBI Ontology
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3-hydroxypentanedioic acid
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3-hydroxy-glutaric acid
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HMDB
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β-hydroxyglutaric acid
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ChEBI
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1705476
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Reaxys Registry Number
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Reaxys
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638-18-6
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CAS Registry Number
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ChemIDplus
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Peters V, Morath M, Mack M, Liesert M, Buckel W, Hoffmann GF, Vockley J, Ghisla S, Zschocke J (2019)
Formation of 3-hydroxyglutaric acid in glutaric aciduria type I: in vitro participation of medium chain acyl-CoA dehydrogenase.
JIMD reports 47, 30-34 [PubMed:31240164]
[show Abstract]
3-Hydroxyglutaric acid (3-OH-GA) in urine has been identified as the most reliable diagnostic marker for glutaric aciduria type I (GA I). We showed that hydratation of glutaconyl-CoA to 3-hydroxyglutaryl-CoA, which is subsequently hydrolyzed to 3-OH-GA, is efficiently catalyzed by 3-methylglutaconyl-CoA hydratase (3-MGH). We have now investigated whether mitochondrial acyl-CoA-dehydrogenases can convert glutaryl-CoA to glutaconyl-CoA. Short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD) accepted glutaryl-CoA as a substrate. The highest k cat of glutaryl-CoA was found for MCAD (0.12 ± 0.01 second-1) and was about 26-fold and 52-fold higher than those of LCAD and SCAD, respectively. The turnover of MCAD for glutaryl-CoA was about 1.5% of that of its natural substrate octanoyl-CoA. Despite high K m (above 600 μM) and low turnover rate, the oxidation of glutaryl-CoA by MCAD in combination with 3-MGH could explain the urinary concentration of 3-OH-GA in GA I patients. | Pokora P, Jezela-Stanek A, Różdżyńska-Świątkowska A, Jurkiewicz E, Bogdańska A, Szymańska E, Rokicki D, Ciara E, Rydzanicz M, Stawiński P, Płoski R, Tylki-Szymańska A (2019)
Mild phenotype of glutaric aciduria type 1 in polish patients - novel data from a group of 13 cases.
Metabolic brain disease 34, 641-649 [PubMed:30570710]
[show Abstract]
Glutaric aciduria type 1 is a neurometabolic disorder, caused by riboflavin-dependent glutaryl-CoA dehydrogenase deficiency. As its consequence, accumulation of the putatively neurotoxic metabolites (glutaric and 3-hydroxyglutaric acids) in body tissues, but especially within the brain, is observed. Estimated incidence of the disease is 1 in 110,000 newborns, The prevalence however may be higher, depending on a specific ethnic group, and result in phenotypic variation as well. In this paper we present clinical data of 13 patients of Polish nationality. They all present a mild phenotype and clinical course of glutaric aciduria type 1. Based on their clinical data, presented herein, we like to pay attention to the phenotypic and neuroimaging features important for the diagnosis of mild form of this disease. Moreover, we present novel molecular data, which may correlate with such a manifestation. | Cudré-Cung HP, Remacle N, do Vale-Pereira S, Gonzalez M, Henry H, Ivanisevic J, Schmiesing J, Mühlhausen C, Braissant O, Ballhausen D (2019)
Ammonium accumulation and chemokine decrease in culture media of Gcdh-/- 3D reaggregated brain cell cultures.
Molecular genetics and metabolism 126, 416-428 [PubMed:30686684]
[show Abstract]
Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain. We analyzed morphological and biochemical features of 3D brain cell aggregates issued from Gcdh-/- mice at two different developmental stages, day-in-vitro (DIV) 8 and 14, corresponding to the neonatal period and early childhood. We also induced a metabolic stress by exposing the aggregates to 10 mM l-lysine (Lys). Significant amounts of GA and 3-OHGA were detected in Gcdh-/- aggregates and their culture media. Ammonium was significantly increased in culture media of Gcdh-/- aggregates at the early developmental stage. Concentrations of GA, 3-OHGA and ammonium increased significantly after exposure to Lys. Gcdh-/- aggregates manifested morphological alterations of all brain cell types at DIV 8 while at DIV 14 they were only visible after exposure to Lys. Several chemokine levels were significantly decreased in culture media of Gcdh-/- aggregates at DIV 14 and after exposure to Lys at DIV 8. This new in vitro model for brain damage in GA-I mimics well in vivo conditions. As seen previously in WT aggregates exposed to 3-OHGA, we confirmed a significant ammonium production by immature Gcdh-/- brain cells. We described for the first time a decrease of chemokines in Gcdh-/- culture media which might contribute to brain cell injury in GA-I. | Simon GA, Wierenga A (2018)
Quantitation of plasma and urine 3-hydroxyglutaric acid, after separation from 2-hydroxyglutaric acid and other compounds of similar ion transition, by liquid chromatography-tandem mass spectrometry for the confirmation of glutaric aciduria type 1.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 1097-1098, 101-110 [PubMed:30218917]
[show Abstract]
BackgroundGlutaric aciduria type 1, a deficiency of glutaryl-CoA dehydrogenase, causes an accumulation of neurotoxic metabolites glutaric acid and 3-hydroxyglutaric acid (3-HGA). Testing of these analytes is routinely done by GC-MS but seldom account for interference from isomers or compounds with similar ion transitions. We developed a liquid chromatography tandem mass spectrometry method that accurately measures 3-HGA in urine and plasma specimens, while utilizing similar reagents and instrumentation used for the routine performance of amino acid and acylcarnitine analysis in determining the diagnosis of several metabolic disorders.MethodPlasma and urine samples were added aliquots of the deuterated 3-HGA internal standard and acetonitrile. The protein-free supernatant was brought to dryness, and the residue derivatized using 3 M HCL in 1-butanol with heating. The dried derivative was then reconstituted in 50% methanol-water solution and aliquot transferred to an HPLC vial for analysis by LC-MS/MS. Separation was performed using a C8 HPLC column under flow gradient conditions of 0.2% formic acid in water and methanol, respectively. Ionization was by ESI and detection of selected precursor-product ion transitions by multiple reaction monitoring (MRM) in positive mode.ResultsThe butyl-ester derivative of 3-HGA eluted at 7.82 min while 2-hydroxyglutaric acid (2-HGA) eluted at 8.21 min. This was equivalent to a separation factor of 1.05 and a resolution of 1.03, respectively. The 3-HGA calibration curve was linear over the range 6.20-319 ng mL-1 (r2 = 0.9996), and the reportable range determined by the linearity was found to be 1.54-384 ng mL-1. The calculated limits of detection and quantitation were 0.348 and 1.56 ng mL-1, respectively. Intra- and Inter-assay %CVs for quality control plasma and urine samples ranged from 2 to 18%, with recoveries of 66-115%. The method correlated to the gold standard GC-MS method for both serum (r2 ≥ 0.996) and urine analysis (r2 ≥ 0.949). The concentration of 3-HGA in normal, non-GA1 individuals was ≤25.2 ng mL-1 (in plasma) and ≤ 35.0 μmol mmol-1 of creatinine (in urine).ConclusionsThis LC-MS/MS method accurately quantified plasma and urine 3-HGA concentration after successful resolution from 2-HGA and other compounds with similar ion transitions. This method is suitable for confirmatory testing of 3-HGA, as a follow-up to an abnormal newborn screen test result, with concern for GA type 1. | Komatsuzaki S, Ediga RD, Okun JG, Kölker S, Sauer SW (2018)
Impairment of astrocytic glutaminolysis in glutaric aciduria type I.
Journal of inherited metabolic disease 41, 91-99 [PubMed:29098534]
[show Abstract]
Glutaric aciduria type I is a rare, autosomal recessive, inherited defect of glutaryl-CoA dehydrogenase. Deficiency of this protein in L-lysine degradation leads to the characteristic accumulation of nontoxic glutarylcarnitine and neurotoxic glutaric acid (GA), glutaryl-CoA, and 3-hydroxyglutaric acid. Untreated patients develop bilateral lesions of basal ganglia resulting in a complex movement disorder with predominant dystonia in infancy and early childhood. The current pathomechanistic concept strongly focuses on imbalanced neuronal energy metabolism due to accumulating metabolites, whereas little is known about the pathomechanistic role of astrocytes, which are thought to be in constant metabolic crosstalk with neurons. We found that glutaric acid (GA) causes astrocytic cell death under starvation cell culture conditions, i.e. low glucose, without glutamine and fetal calf serum. Glutamine completely abolished GA-induced toxicity, suggesting involvement of glutaminolysis. Increasing dependence on glutaminolysis by chemical induction of hypoxia signaling-potentiated GA-induced toxicity. We further show that GA disturbs glutamine degradation by specifically inhibiting glutamate dehydrogenase. Summarizing our study shows that pathologically relevant concentrations of GA block an important step in the metabolic crosstalk between neurons and astrocytes, ultimately leading to astrocytic cell death. | Al-Dirbashi OY, Kölker S, Ng D, Fisher L, Rupar T, Lepage N, Rashed MS, Santa T, Goodman SI, Geraghty MT, Zschocke J, Christensen E, Hoffmann GF, Chakraborty P (2011)
Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry.
Journal of inherited metabolic disease 34, 173-180 [PubMed:20978942]
[show Abstract]
Accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3HGA) in body fluids is the biochemical hallmark of type 1 glutaric aciduria (GA1), a disorder characterized by acute striatal degeneration and a subsequent dystonia. To date, methods for quantification of 3HGA are mainly based on stable isotope dilution gas chromatography mass spectrometry (GC-MS) and require extensive sample preparation. Here we describe a simple liquid chromatography tandem MS (LC-MS/MS) method to quantify this important metabolite in dried urine spots (DUS). This method is based on derivatization with 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole (DAABD-AE). Derivatization was adopted to improve the chromatographic and mass spectrometric properties of the studied analytes. Derivatization was performed directly on a 3.2-mm disc of DUS as a sample without extraction. Sample mixture was heated at 60°C for 45 min, and 5 μl of the reaction solution was analyzed by LC-MS/MS. Reference ranges obtained were in excellent agreement with the literature. The method was applied retrospectively for the analysis of DUS samples from established low- and high-excreter GA1 patients as well as controls (n = 100). Comparison of results obtained versus those obtained by GC-MS was satisfactory (n = 14). In populations with a high risk of GA1, this approach will be useful as a primary screening method for high- or low-excreter variants. In these populations, however, DUS analysis should not be implemented before completing a parallel comparative study with the standard screening method (i.e., molecular testing). In addition, follow-up DUS GA and 3HGA testing of babies with elevated dried blood spot C5DC acylcarnitines will be useful as a first-tier diagnostic test, thus reducing the number of cases requiring enzymatic and molecular analyses to establish or refute the diagnosis of GA1. | Sauer SW, Okun JG, Fricker G, Mahringer A, Müller I, Crnic LR, Mühlhausen C, Hoffmann GF, Hörster F, Goodman SI, Harding CO, Koeller DM, Kölker S (2006)
Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency.
Journal of neurochemistry 97, 899-910 [PubMed:16573641]
[show Abstract]
Glutaric acid (GA) and 3-hydroxyglutaric acids (3-OH-GA) are key metabolites in glutaryl co-enzyme A dehydrogenase (GCDH) deficiency and are both considered to be potential neurotoxins. As cerebral concentrations of GA and 3-OH-GA have not yet been studied systematically, we investigated the tissue-specific distribution of these organic acids and glutarylcarnitine in brain, liver, skeletal and heart muscle of Gcdh-deficient mice as well as in hepatic Gcdh-/- mice and in C57Bl/6 mice following intraperitoneal loading. Furthermore, we determined the flux of GA and 3-OH-GA across the blood-brain barrier (BBB) using porcine brain microvessel endothelial cells. Concentrations of GA, 3-OH-GA and glutarylcarnitine were significantly elevated in all tissues of Gcdh-/- mice. Strikingly, cerebral concentrations of GA and 3-OH-GA were unexpectedly high, reaching similar concentrations as those found in liver. In contrast, cerebral concentrations of these organic acids remained low in hepatic Gcdh-/- mice and after intraperitoneal injection of GA and 3-OH-GA. These results suggest limited flux of GA and 3-OH-GA across the BBB, which was supported in cultured porcine brain capillary endothelial cells. In conclusion, we propose that an intracerebral de novo synthesis and subsequent trapping of GA and 3-OH-GA should be considered as a biochemical risk factor for neurodegeneration in GCDH deficiency. | Mühlhausen C, Ott N, Chalajour F, Tilki D, Freudenberg F, Shahhossini M, Thiem J, Ullrich K, Braulke T, Ergün S (2006)
Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I.
Pediatric research 59, 196-202 [PubMed:16439578]
[show Abstract]
Infants with glutaric aciduria type 1 (GA1) are subject to intracranial vascular dysfunction. Here, we demonstrate that the disease-specific metabolite 3-hydroxyglutaric acid (3-OH-GA) inhibits basal and vascular endothelial growth factor (VEGF)-induced endothelial cell migration. 3-OH-GA affects the morphology of VEGF-induced endothelial tubes in vitro because of partial disintegration of endothelial cells. These effects correlate with Ve-cadherin loss. Remarkably, 3-OH-GA treatment of human dermal microvascular endothelial cells leads to disruption of actin cytoskeleton. Local application of 3-OH-GA alone or in combination with VEGF in chick chorioallantoic membrane induces abnormal vascular dilatation and hemorrhage in vivo. The study demonstrates that 3-OH-GA reduces endothelial chemotaxis and disturbs structural vascular integrity in vitro and in vivo. These data may provide insight in the mechanisms of 3-OH-GA-induced vasculopathic processes and suggest N-methyl-D-aspartate receptor-dependent and -independent pathways in the pathogenesis of GA1. | Fu Z, Runquist JA, Forouhar F, Hussain M, Hunt JF, Miziorko HM, Kim JJ (2006)
Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria.
The Journal of biological chemistry 281, 7526-7532 [PubMed:16330550]
[show Abstract]
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase is a key enzyme in the ketogenic pathway that supplies metabolic fuel to extrahepatic tissues. Enzyme deficiency may be due to a variety of human mutations and can be fatal. Diminished activity has been explained based on analyses of recombinant human mutant proteins or, more recently, in the context of structural models for the enzyme. We report the experimental determination of a crystal structure at 2.1 A resolution of the recombinant human mitochondrial HMG-CoA lyase containing a bound activator cation and the dicarboxylic acid 3-hydroxyglutarate. The enzyme adopts a (betaalpha)(8) barrel fold, and the N-terminal barrel end is occluded. The structure of a physiologically relevant dimer suggests that substrate access to the active site involves binding across the cavity located at the C-terminal end of the barrel. An alternative hypothesis that involves substrate insertion through a pore proposed to extend through the barrel is not compatible with the observed structure. The activator cation ligands included Asn(275), Asp(42),His(233), and His(235); the latter three residues had been implicated previously as contributing to metal binding or enzyme activity. Arg(41), previously shown to have a major effect on catalytic efficiency, is also located at the active site. In the observed structure, this residue interacts with a carboxyl group of 3-hydroxyglutarate, the hydrolysis product of the competitive inhibitor 3-hydroxyglutaryl-CoA required for crystallization of human enzyme. The structure provides a rationale for the decrease in enzyme activity due to clinical mutations, including H233R, R41Q, D42H, and D204N, that compromise active site function or enzyme stability. | Shigematsu Y, Hata I, Tanaka Y, Tajima G, Sakura N, Naito E, Yorifuji T (2005)
Stable-isotope dilution gas chromatography-mass spectrometric measurement of 3-hydroxyglutaric acid, glutaric acid and related metabolites in body fluids of patients with glutaric aciduria type 1 found in newborn screening.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 823, 7-12 [PubMed:16055049]
[show Abstract]
We developed a simple and sensitive stable-isotope dilution method for the quantification of 3-hydroxyglutaric acid (3HGA) and glutaric acid (GA) in body fluids. In our method, tert-butyldimethylsilyl (tBDMS) derivatives of 3HGA and GA were measured with a conventional electron-impact ionization (EI) mode in gas chromatography-mass spectrometry (GC-MS). The control values for 3HGA in nmol/ml were 0.15+/-0.08 (serum; n=10) and 0.07+/-0.03 (CSF; n=10). In addition, glutarylcarnitine and free carnitine were quantified by electrospray tandem mass spectrometry. Using these methods, we monitored 3HGA, GA, and glutarylcarnitine in the body fluids of three patients with glutaric aciduria type 1 found during newborn screening. None of the patients had experienced neurological strokes, which are possibly caused by the accumulation of 3HGA, at 15-24 months of age under a disease-specific treatment, including carnitine supplementation. Our data showed that 3HGA levels were relatively high in some serum samples with lower glutarylcarnitine and carnitine levels, suggesting that carnitine supplementation may play a role in preventing the accumulation of 3HGA in patients with this disease. | Latini A, Scussiato K, Leipnitz G, Dutra-Filho CS, Wajner M (2005)
Promotion of oxidative stress by 3-hydroxyglutaric acid in rat striatum.
Journal of inherited metabolic disease 28, 57-67 [PubMed:15702406]
[show Abstract]
The pathophysiology of the striatum degeneration characteristic of patients affected by the inherited neurometabolic disorder glutaryl-CoA dehydrogenase deficiency (GDD), also known as glutaric aciduria type I, is still in debate. We have previously reported that 3-hydroxyglutaric acid (3-OH-GA) considered the main neurotoxin in this disorder, induces oxidative stress in rat cerebral cotex. In the present work, we extended these studies by investigating the in vitro effect of 3-OH-GA, at concentrations ranging from 0.01 to 1.0 mmol/L on the brain antioxidant defences by measuring total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and glutathione (GSH) levels, and on the production of hydrogen peroxide (H(2)O(2)), nitric oxide (NO) and malondialdehyde in striatum homogenates from young rats. We observed that TRAP, TAR and GSH levels were markedly reduced (by up to 50%) when striatum homogenates were treated with 3-OH-GA. In contrast, H(2)O(2) (up to 44%), NO (up to 95%) and malondialdehyde levels (up to 28%) were significantly increased by 3-OH-GA. These data indicate that total nonenzymatic antioxidant defences (TRAP) and the tissue capacity to handle an increase of reactive species (TAR) were reduced by 3-OH-GA in the striatum. Furthermore, the results also reflect an increase of lipid peroxidation, probably secondary to 3-OH-GA-induced free radical production. Thus, it may be presumed that oxidative stress is involved in the neuropathology in GDD. | Latini A, Rodriguez M, Borba Rosa R, Scussiato K, Leipnitz G, Reis de Assis D, da Costa Ferreira G, Funchal C, Jacques-Silva MC, Buzin L, Giugliani R, Cassina A, Radi R, Wajner M (2005)
3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats.
Neuroscience 135, 111-120 [PubMed:16111821]
[show Abstract]
3-Hydroxyglutaric acid (3HGA) accumulates in the inherited neurometabolic disorder known as glutaryl-CoA dehydrogenase deficiency. The disease is clinically characterized by severe neurological symptoms, frontotemporal atrophy and striatum degeneration. Because of the pathophysiology of the brain damage in glutaryl-CoA dehydrogenase deficiency is not completed clear, we investigated the in vitro effect of 3HGA (0.01-5.0mM) on critical enzyme activities of energy metabolism, including the respiratory chain complexes I-V, creatine kinase isoforms and Na(+),K(+)-ATPase in cerebral cortex and striatum from 30-day-old rats. Complex II activity was also studied in rat C6-glioma cells exposed to 3HGA. The effect of 3HGA was further investigated on the rate of oxygen consumption in mitochondria from rat cerebrum. We observed that 1.0mM 3HGA significantly inhibited complex II in cerebral cortex and C6 cells but not the other activities of the respiratory chain complexes. Creatine kinase isoforms and Na(+),K(+)-ATPase were also not affected by the acid. Furthermore, no inhibition of complex II activity occurred when mitochondrial preparations from cerebral cortex or striatum homogenates were used. In addition, 3HGA significantly lowered the respiratory control ratio in the presence of glutamate/malate and succinate under stressful conditions or when mitochondria were permeabilized with digitonin. Since 3HGA stimulated oxygen consumption in state IV and compromised ATP formation, it can be presumed that this organic acid might act as an endogenous uncoupler of mitochondria respiration. Finally, we observed that 3HGA changed C6 cell morphology from a round flat to a spindle-differentiated shape, but did not alter cell viability neither induced apoptosis. The data provide evidence that 3HGA provokes a moderate impairment of brain energy metabolism and do not support the view that 3HGA-induced energy failure would solely explain the characteristic brain degeneration observed in glutaryl-CoA dehydrogenase deficiency patients. | Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njølstad PR, Jellum E, Søvik O (2004)
Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation.
Diabetes 53, 221-227 [PubMed:14693719]
[show Abstract]
Inappropriately elevated insulin secretion is the hallmark of persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also denoted congenital hyperinsulinism. Causal mutations have been uncovered in genes coding for the beta-cell's ATP-sensitive potassium channel and the metabolic enzymes glucokinase and glutamate dehydrogenase. In addition, one hyperinsulinemic infant was recently found to have a mutation in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an enzyme participating in mitochondrial fatty acid oxidation. We have studied a consanguineous family with severe neonatal hypoglycemia due to increased insulin levels and where well-established genetic causes of hyperinsulinism had been eliminated. A genome-wide, microsatellite-based screen for homozygous chromosomal segments was performed. Those regions that were inherited in accordance with the presupposed model were searched for mutations in genes encoding metabolic enzymes. A novel, homozygous deletion mutation was found in the gene coding for the SCHAD enzyme. The mutation affected RNA splicing and was predicted to lead to a protein lacking 30 amino acids. The observations at the molecular level were confirmed by demonstrating greatly reduced SCHAD activity in the patients' fibroblasts and enhanced levels of 3-hydroxybutyryl-carnitine in their blood plasma. Urine metabolite analysis showed that SCHAD deficiency resulted in specific excretion of 3-hydroxyglutaric acid. By the genetic explanation of our family's cases of severe hypoglycemia, it is now clear that recessively inherited SCHAD deficiency can result in PHHI. This finding suggests that mitochondrial fatty acid oxidation influences insulin secretion by a hitherto unknown mechanism. | Wajner M, Kölker S, Souza DO, Hoffmann GF, de Mello CF (2004)
Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency.
Journal of inherited metabolic disease 27, 825-828 [PubMed:15505388]
[show Abstract]
Although the precise mechanisms underlying the CNS degeneration of patients with glutaryl-CoA dehydrogenase (GCDH) deficiency are still the subject of intense debate, many studies have highlighted that excitotoxicity plays a fundamental role in the neuropathology of this disease, particularly involving the N-methyl-D-aspartate receptor subtype of ionotropic glutamate receptors. Modulation of the glutamatergic system by these compounds involves an inhibition of glutamate uptake into synaptosomes and synaptic vesicles, and a decrease in glutamate binding. Furthermore, glutaric and 3-hydroxyglutaric acids inhibit glutamate decarboxylase, the key enzyme of GABA synthesis, and striatal GABAergic medium-spiny neurons are highly vulnerable to 3-hydroxyglutaric acid-induced neurotoxicity. In conclusion, glutaric acid and 3-hydroxyglutaric acid induce an imbalance in glutamatergic and GABAergic neurotransmission. | Freudenberg F, Lukacs Z, Ullrich K (2004)
3-Hydroxyglutaric acid fails to affect the viability of primary neuronal rat cells.
Neurobiology of disease 16, 581-584 [PubMed:15262270]
[show Abstract]
Glutaric aciduria type I (GA I) is an autosomal recessive inherited metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCD) resulting in the accumulation of 3-hydroxyglutaric acid (3OHG), glutaric acid and glutaconic acid in body fluids. GA I is characterized by a specific age- and brain region-dependent neuropathology. Previous studies using organotypic slice cultures of rats and primary chick embryo telencephalon cell cultures indicated that death of neurons is a consequence of an excitotoxic mechanism induced by 3OHG. We used primary neuronal cells of neonatal rats as a model system to test cell viability after treatment with 3OHG. Western blot analysis was used to prove the expression of functional N-methyl-D-aspartate (NMDA) receptors revealing no alteration in the expression of NMDA-2a and -2b receptor subtypes in response to 3OHG. When neuronal cells cultured for 10 or 20 days were treated with 1 mM glutamate, the viability of cells was reduced by 40%. This effect could be prevented by coincubation with the NMDA receptor antagonist MK801. In contrast, incubation of cells with 3OHG for up to 24 h in concentrations of 4-8 mM did not cause increased cell death as compared with untreated control cultures. These results indicate that 3OHG is not excitotoxic in this model of neuronal rat cell cultures despite the presence of functional NMDA receptors. Therefore, alternative or additional pathomechanisms than excitotoxicity may be relevant for neurodegeneration in GA I. | Kölker S, Hoffmann GF, Schor DS, Feyh P, Wagner L, Jeffrey I, Pourfarzam M, Okun JG, Zschocke J, Baric I, Bain MD, Jakobs C, Chalmers RA (2003)
Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen.
Neuropediatrics 34, 253-260 [PubMed:14598231]
[show Abstract]
The neurometabolic disorder glutaryl-CoA dehydrogenase (GCDH) deficiency is biochemically characterised by an accumulation of the marker metabolites 3-hydroxyglutaric acid, glutaric acid, and glutarylcarnitine. If untreated, the disease is complicated by acute encephalopathic crises, resulting in neurodegeneration of vulnerable brain regions, in particular the putamen. 3-hydroxyglutaric acid is considered the major neurotoxin in this disease. There are only preliminary data concerning glutaric acid concentrations in the brains of affected children and the distribution of 3-hydroxyglutaric acid and glutarylcarnitine has not been described. In the present study, we investigated post mortem the distribution of 3-hydroxyglutaric and glutaric acids as well as glutarylcarnitine in 14 different brain regions, internal organs, and body fluids (urine, plasma, cerebrospinal fluid) in a 14-year-old boy. 3-Hydroxyglutaric acid showed the highest concentration (62 nmol/g protein) in the putamen among all brain areas investigated. The glutarylcarnitine concentration was also highest in the putamen (7.1 nmol/g protein). We suggest that the regional-specific differences in the relative concentrations of 3-hydroxyglutaric acid contribute to the pattern of neuronal damage in this disease. These results provide an explanatory basis for the high vulnerability of the putamen in this disease, adding to the strong corticostriatal glutamatergic input into the putamen and the high excitotoxic susceptibility of neostriatal medium spiny neurons. | de Mello CF, Kölker S, Ahlemeyer B, de Souza FR, Fighera MR, Mayatepek E, Krieglstein J, Hoffmann GF, Wajner M (2001)
Intrastriatal administration of 3-hydroxyglutaric acid induces convulsions and striatal lesions in rats.
Brain research 916, 70-75 [PubMed:11597592]
[show Abstract]
Glutaryl-CoA dehydrogenase deficiency is an inherited neurometabolic disease complicated by precipitation of acute encephalopathic crises during a vulnerable period of brain development. These crises result in bilateral striatal damage and subsequently a dystonic dyskinetic movement disorder. In previous in vitro studies neuronal damage in this disease has been linked to an excitotoxic mechanism mediated in particular by one of the accumulating metabolites, 3-hydroxyglutaric acid. However, nothing is known about the in vivo effects of this organic acid. In the present study, we used a stereotaxic intrastriatal injection technique to investigate the behavioral and neurotoxic effects of 3-hydroxyglutaric acid exposure in rats. Here, we report that 3-hydroxyglutaric acid induced an increase in convulsion frequency and duration as determined by open field measurement. Nissl-stained coronal sections from treated rats revealed a pale lesion in the striatum following 3-hydroxyglutaric acid exposure. N-methyl-D-aspartate (NMDA) receptor blockade by MK-801 and stimulation of GABA(A) receptors by muscimol prevented the induction of convulsions and striatal damage by 3-hydroxyglutaric acid, whereas blockade of non-NMDA receptors by 6,7-dinitroquinoxaline-2,3-dione (DNQX) was not protective. We conclude that 3-hydroxyglutaric acid induces convulsions and striatal damage via initiation of an imbalance in the excitatory glutamatergic and the inhibitory GABAergic neurotransmission, resulting in an enhanced excitatory input in striatal neurons. These results support the hypothesis of NMDA receptor-mediated excitotoxic cell damage in glutaryl-CoA dehydrogenase deficiency and represent the basis for the development of new neuroprotective treatment strategies. | Bjugstad KB, Zawada WM, Goodman S, Freed CR (2001)
IGF-1 and bFGF reduce glutaric acid and 3-hydroxyglutaric acid toxicity in striatal cultures.
Journal of inherited metabolic disease 24, 631-647 [PubMed:11768583]
[show Abstract]
Glutaric acid (GA) and 3-hydroxyglutaric acid (3GA) are thought to contribute to the degeneration of the caudate and putamen that is seen in some children with glutaric acidaemia type I, a metabolic disorder caused by a glutaryl-CoA dehydrogenase deficiency. This study assessed the neurotoxicity of GA and 3GA (0-50 mmol/L) compared to quinolinic acid (QUIN) in striatal and cortical cultures. All three acids were neurotoxic in a dose-dependent manner; however, GA and 3GA were both more toxic than QUIN. The neurotoxic effects of low concentrations of GA or 3GA were additive to QUIN toxicity. A series of hormones and growth factors were tested for protection against GA and 3GA toxicity. Insulin (5-500 microU /ml), basic fibroblast growth factor (bFGF; 10 ng/ml), insulin-like growth factor (IGF-1; 50 ng/ml), brain-derived neurotrophic factor (BDNF; 10 ng/ml), glial-derived neurotrophic factor (GDNF; 10 ng/ml), and two glutamate antagonists were evaluated in brain cultures to which 7 mmol/L GA or 3GA were added. GA and 3GA neurotoxicities were prevented by bFGF. Attenuation of 3GA-induced neurotoxicity was seen with insulin (5 microU/ml) and IGF-1. BDNF and GDNF had no effects on neuronal survival. Glutamate antagonists MK801 (10 micromol/L) and NBQX (10 micromol/L) failed to prevent GA or 3GA neurotoxicity. We conclude that GA and 3GA are neurotoxic in cultures of embryonic rat striatum and cortex. Striatal neurons were rescued from death by bFGF and IGF-1 but not by glutamate antagonist, suggesting that toxicity in this embryonic system is not necessarily mediated by glutamate receptors. | Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF (1999)
Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I.
Journal of inherited metabolic disease 22, 867-881 [PubMed:10604139]
[show Abstract]
Glutaric aciduria type I (GA I) is a recessive disorder caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). The biochemical hallmark of the disease is the accumulation of glutaric acid and, to a lesser degree, of 3-hydroxyglutaric acid and glutaconic acid in body fluids and tissues. A substantial number of patients show only slightly, intermittently elevated or even normal urinary excretion of glutaric acid, which makes early diagnosis and treatment to prevent the severe neurological sequelae difficult. Furthermore, elevated urinary excretion of glutaric acid can also be found in a number of other disease states, mostly related to mitochondrial dysfunction. Stable-isotope dilution assays were designed for both glutaric acid and 3-hydroxyglutaric acid and their diagnostic sensitivity and specificity were evaluated. Control ranges of glutaric acid in urine were 1.1-9.7 mmol/mol creatinine before and 4.1-32 after hydrolysis. The respective values of 3-hydroxyglutaric acid were 1.4-8.0 and 2.6-11.7 mmol/mol creatnine. For other body fluids, control ranges in mumol/l/L were: for glutaric acid 0.55-2.9 (plasma), 0.18-0.63 (cerebrospinal fluid) and 0.19-0.7 (amniotic fluid); and for 3-hydroxyglutaric acid, 0.2-1.36 (plasma), < 0.2 (cerebrospinal fluid) and 0.22-0.41 (amniotic fluid). Twenty-five patients with GCDH deficiency were studied. Low excretors (12 patients) were defined by a urinary glutaric acid below 100 mmol/mol creatinine down into the normal range, while high excretors (13 patients) had glutaric acid excretions well above this value. With and without hydrolysis there was an overlap of glutaric acid values between patients and controls. Diagnostic sensitivity and specificity of 100% could only be achieved by the quantitative determination of 3-hydroxyglutaric acid with the newly developed stable-isotope dilution assay, allowing an accurate diagnosis of all patients, regardless of the amount of glutaric acid excreted in urine. | Nyhan WL, Zschocke J, Hoffmann G, Stein DE, Bao L, Goodman S (1999)
Glutaryl-CoA dehydrogenase deficiency presenting as 3-hydroxyglutaric aciduria.
Molecular genetics and metabolism 66, 199-204 [PubMed:10066389]
[show Abstract]
Two siblings who were found to have deficiency of glutaryl-CoA dehydrogenase were identified by the presence of large amounts of 3-hydroxyglutaric acid in the urine. Patients with this disease, termed glutaric acidemia or glutaric acidemia Type I, usually present with large amounts of glutaric acid in the urine, and amounts of 3-hydroxyglutaric acid found are less. Patients were ataxic and dystonic. Intelligence was normal. 3-Hydroxyglutaric acid in the urine was quantified by organic acid analysis via gas chromatography mass spectrometry (GCMS) and by stable isotope-dilution (internal standard) GCMS. Glutaryl-CoA dehydrogenase activity in cultured fibroblasts was found to be 2% of the control level. The nature of the mutations was identified, and both patients were found to be compound heterozygotes for R227P, which changed an arginine to a proline, and E365K, which changed a glutamate to a lysine. | Flott-Rahmel B, Falter C, Schluff P, Fingerhut R, Christensen E, Jakobs C, Musshoff U, Fautek JD, Deufel T, Ludolph A, Ullrich K (1997)
Nerve cell lesions caused by 3-hydroxyglutaric acid: a possible mechanism for neurodegeneration in glutaric acidaemia I.
Journal of inherited metabolic disease 20, 387-390 [PubMed:9266362] | Haworth JC, Booth FA, Chudley AE, deGroot GW, Dilling LA, Goodman SI, Greenberg CR, Mallory CJ, McClarty BM, Seshia SS (1991)
Phenotypic variability in glutaric aciduria type I: Report of fourteen cases in five Canadian Indian kindreds.
The Journal of pediatrics 118, 52-58 [PubMed:1986098]
[show Abstract]
We describe 14 patients with glutaric aciduria type 1 in five Canadian Indian kindreds living in Manitoba and northwest Ontario. The patients had marked clinical variability of the disease, even within families. Eight followed the typical clinical course of normal early growth and development until the onset of neurologic abnormalities, often precipitated by infection, between 6 weeks and 7 1/2 months of age. Five patients had early developmental delay; one was thought to be normal until 8 years of age. Three patients died, seven are severely mentally and physically handicapped, and four have only mild mental retardation or incoordination. Six patients had macrocephaly in the neonatal period. Computed tomography was done for 12 patients, and findings were abnormal in 11. Glutaric acid and 3-hydroxyglutaric acid were detected in increased amounts in the urine of all patients, but the concentrations were much lower than those in most other reported patients. Glutaryl coenzyme A dehydrogenase activity in skin fibroblasts, interleukin-2-dependent lymphocytes, or both, ranged from 0% to 13% of control values. There was no correlation between clinical severity and urine glutaric acid concentration or level of residual enzyme activity. We recommend that organic acid analysis of the urine be done in patients with unexplained cerebral palsy-like disorders, especially if the computed tomographic scan is abnormal. If there is suspicion of glutaric aciduria, glutaryl-coenzyme A dehydrogenase should be measured in fibroblasts or lymphocytes even if glutaric acid is not increased in the urine. |
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