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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__8520882729299797__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__8520882729299797__) 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:15753","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__8520882729299797__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"8520882729299797","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__8520882729299797__ 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 OOG - Ideal conformer Mrv1927 06122114073D starting HoverWatcher_5 Time for openFile(OOG - Ideal conformer Mrv1927 06122114073D 19 18 0 0 0 0 999 V2000 2.0170 -0.8050 0.0000 C 0 0 1 0 0 0 0 0 0 0 0 0 0.8240 0.1540 0.0000 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.4770 -0.6510 0.0000 C 0 0 1 0 0 0 0 0 0 0 0 0 -3.0410 -0.2450 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.0900 0.5990 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.2270 -1.4430 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.6510 0.2940 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 3.2990 -0.0130 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 3.2620 1.1940 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 4.4810 -0.6490 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.4660 1.4870 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 1.9780 -1.4340 0.8900 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9780 -1.4340 -0.8900 H 0 0 0 0 0 0 0 0 0 0 0 0 0.8630 0.7820 0.8900 H 0 0 0 0 0 0 0 0 0 0 0 0 0.8630 0.7820 -0.8900 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.5160 -1.2790 -0.8900 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.5160 -1.2790 0.8900 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.9720 0.2030 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 5.2750 -0.0990 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 0 0 0 1 8 1 0 0 0 0 2 3 1 0 0 0 0 3 7 1 0 0 0 0 4 5 1 0 0 0 0 4 6 2 0 0 0 0 4 7 1 0 0 0 0 7 11 2 0 0 0 0 8 9 2 0 0 0 0 8 10 1 0 0 0 0 1 12 1 0 0 0 0 1 13 1 0 0 0 0 2 14 1 0 0 0 0 2 15 1 0 0 0 0 3 16 1 0 0 0 0 3 17 1 0 0 0 0 5 18 1 0 0 0 0 10 19 1 0 0 0 0 M END): 16 ms reading 19 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 19 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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| 2-Oxoadipic acid, also known as α-ketoadipic acid, is an intermediate in the metabolism of lysine and tryptophan. The conjugate base and carboxylate is 2-oxoadipate or α-ketoadipate, which is the biochemically relevant form. |
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Read full article at Wikipedia
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| InChI=1S/C6H8O5/c7-4(6(10)11)2-1-3-5(8)9/h1-3H2,(H,8,9)(H,10,11) |
| FGSBNBBHOZHUBO-UHFFFAOYSA-N |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Glycine max
(NCBI:txid3847)
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From MetaboLights
See:
MetaboLights Study
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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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mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
human urinary metabolite
Any metabolite (endogenous or exogenous) found in human urine samples.
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View more via ChEBI Ontology
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2-ketoadipic acid
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HMDB
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2-oxo-hexanedioic acid
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ChemIDplus
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2-Oxoadipic acid
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KEGG COMPOUND
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α-ketoadipic acid
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ChemIDplus
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α-oxoadipic acid
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HMDB
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1772134
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Reaxys Registry Number
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Reaxys
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3184-35-8
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CAS Registry Number
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ChemIDplus
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3184-35-8
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CAS Registry Number
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NIST Chemistry WebBook
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Cui X, Zhang L, Su G, Kijlstra A, Yang P (2021)
Specific sweat metabolite profile in ocular Behcet's disease.
International immunopharmacology 97, 107812 [PubMed:34091113]
[show Abstract]
BackgroundBehcet's disease (BD) is an autoimmune disorder with the serious possibility of blindness, calling for further research on its pathogenesis. Our aim was to study the metabolite composition of sweat in BD and to identify possible biomarkers.MethodsMetabolomics analysis was performed on sweat samples from 20 BD patients and 18 normal controls by liquid chromatography tandem mass spectrometry.ResultsA significantly different metabolic profile of sweat was observed when BD patients were compared with healthy controls. The result of the orthogonal partial least squared-discrimination analysis (OPLS-DA) showed that these two comparison groups could be separated with a relatively satisfactory fitting degree (R2Y = 0.995 and Q2 = 0.817 in positive ion mode; R2Y = 0.991 and Q2 = 0.721 in negative ion mode). Based on OPLS-DA, a panel of metabolites was selected as candidate biomarkers, including l-citrulline, l-pyroglutamic acid, urocanic acid, 2-oxoadipic acid, cholesterol 3-sulfate, and pentadecanoic acid.ConclusionThis is the first report on the metabolite profile of sweat in BD. Our results demonstrated a significantly different metabolite composition of sweat in BD compared to that of healthy controls. | Quan W, Jiao Y, Xue C, Li Y, Liu G, He Z, Qin F, Zeng M, Chen J (2021)
The Effect of Exogenous Free Nε-(Carboxymethyl)Lysine on Diabetic-Model Goto-Kakizaki Rats: Metabolomics Analysis in Serum and Urine.
Journal of agricultural and food chemistry 69, 783-793 [PubMed:33401897]
[show Abstract]
The current study investigated the effects of exogenous free Nε-(carboxymethyl) lysine (CML) from daily diet on diabetic-model Goto-Kakizaki rats. Rats were fed with free CML (2 mg/kg body weight) for 8 weeks, then metabolomics evaluation was performed on serum and urine, and biochemical and histopathologic examinations were conducted to verify metabolic results. Diabetic rats fed with free CML showed significantly increased (P < 0.05) fasting blood glucose (11.1 ± 1.07 mmol/L) and homeostasis model assessment values (homeostatic model assessment of insulin resistance: 16.0 ± 4.24; homeostatic model assessment of beta cell function: 6.66 ± 2.01; and modified beta cell function index: 11.5 ± 2.66) and a significantly altered (P < 0.05) oxidative stress level when compared to the control group. Serum and urine metabolomics showed a significantly altered (P < 0.05) level of aminomalonic acid, 2-oxoadipic acid, l-malic acid, β-alanine, 2-oxoglutaric acid, d-threitol, N-acetyl-leucine, methylmalonic acid, l-cysteine, thymine, glycine, l-alanine, 4-hydroxyproline, hexadecane, succinic acid, l-ornithine, gluconolactone, maleic acid, l-lactate, tryptophan, 5-methoxyindoleacetate, γ-aminobutyric acid, homoserine, maltose, and quinolinic acid. Our results indicated that these metabolites altered by exposure to exogenous free CML were mapped to the citric acid cycle and amino acid and carbohydrate metabolism, which might be related to increased progression of diabetes and some other diabetic complications, including diabetic brain and neurological diseases, retinopathy, nephropathy, and impaired wound healing. | Hirai M, Hatayama S, Kimata M, Shibata K, Fukuwatari T (2021)
Effects of B-Group Vitamin Administration on Daily Change in Urine 2-Oxo Acids in Young Japanese Women.
Journal of nutritional science and vitaminology 67, 63-67 [PubMed:33642466]
[show Abstract]
B-group vitamins are required in amino acid catabolism, and recent findings suggest that urine 2-oxo acids, catabolites of amino acid, could be functional biomarkers indicating the nutritional status of B-group vitamins. To clarify the relationship between B-group vitamins and urine 2-oxo acids, we investigated the effects of B-group vitamin administration on daily changes in urinary amounts of 2-oxo acids in humans. Twenty-nine young Japanese women collected 24-h urine samples for 8 d, and took B-group vitamins for 7 d beginning on the second day of urine collection. The participants were divided into three groups on the basis of the amounts of total branched-chain 2-oxo acids, 2-oxoglutaric acid, 2-oxoadipic acid, and pyruvic acid excreted in urine. In the upper tertile, but not the middle and lower tertiles, each urine 2-oxo acid decreased from the first day of vitamin administration, and completely decreased to a normal level on the second day of administration. These results indicate that administration of B-group vitamins immediately affects 2-oxo acid metabolism in some young Japanese women. Thus, urinary 2-oxo acids could be useful and functional biomarkers for B-group vitamin status. | Leandro J, Dodatko T, Aten J, Nemeria NS, Zhang X, Jordan F, Hendrickson RC, Sanchez R, Yu C, DeVita RJ, Houten SM (2020)
DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo.
Human molecular genetics 29, 1168-1179 [PubMed:32160276]
[show Abstract]
Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA. Here, we show that loss of DHTKD1 in glutaryl-CoA dehydrogenase-deficient HEK-293 cells leads to a 2-fold decrease in the established GA1 clinical biomarker glutarylcarnitine and demonstrate that oxoglutarate dehydrogenase (OGDH) is responsible for this remaining glutarylcarnitine production. We furthermore show that DHTKD1 interacts with OGDH, dihydrolipoyl succinyltransferase and dihydrolipoamide dehydrogenase to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex. In summary, 2-oxoadipic acid is a substrate for DHTKD1, but also for OGDH in a cell model system. The classical 2-oxoglutaric dehydrogenase complex can exist as a previously undiscovered hybrid containing DHTKD1 displaying improved kinetics towards 2-oxoadipic acid. | Thompson MG, Blake-Hedges JM, Pereira JH, Hangasky JA, Belcher MS, Moore WM, Barajas JF, Cruz-Morales P, Washington LJ, Haushalter RW, Eiben CB, Liu Y, Skyrud W, Benites VT, Barnum TP, Baidoo EEK, Scheller HV, Marletta MA, Shih PM, Adams PD, Keasling JD (2020)
An iron (II) dependent oxygenase performs the last missing step of plant lysine catabolism.
Nature communications 11, 2931 [PubMed:32523014]
[show Abstract]
Despite intensive study, plant lysine catabolism beyond the 2-oxoadipate (2OA) intermediate remains unvalidated. Recently we described a missing step in the D-lysine catabolism of Pseudomonas putida in which 2OA is converted to D-2-hydroxyglutarate (2HG) via hydroxyglutarate synthase (HglS), a DUF1338 family protein. Here we solve the structure of HglS to 1.1 Å resolution in substrate-free form and in complex with 2OA. We propose a successive decarboxylation and intramolecular hydroxylation mechanism forming 2HG in a Fe(II)- and O2-dependent manner. Specificity is mediated by a single arginine, highly conserved across most DUF1338 proteins. An Arabidopsis thaliana HglS homolog coexpresses with known lysine catabolism enzymes, and mutants show phenotypes consistent with disrupted lysine catabolism. Structural and biochemical analysis of Oryza sativa homolog FLO7 reveals identical activity to HglS despite low sequence identity. Our results suggest DUF1338-containing enzymes catalyze the same biochemical reaction, exerting the same physiological function across bacteria and eukaryotes. | Kiliszek A, Rypniewski W, Rząd K, Milewski S, Gabriel I (2019)
Crystal structures of aminotransferases Aro8 and Aro9 from Candida albicans and structural insights into their properties.
Journal of structural biology 205, 26-33 [PubMed:30742897]
[show Abstract]
Aminotransferases catalyze reversibly the transamination reaction by a ping-pong bi-bi mechanism with pyridoxal 5'-phosphate (PLP) as a cofactor. Various aminotransferases acting on a range of substrates have been reported. Aromatic transaminases are able to catalyze the transamination reaction with both aromatic and acidic substrates. Two aminotransferases from C. albicans, Aro8p and Aro9p, have been identified recently, exhibiting different catalytic properties. To elucidate the multiple substrate recognition of the two enzymes we determined the crystal structures of an unliganded CaAro8p, a complex of CaAro8p with the PLP cofactor bound to a substrate, forming an external aldimine, CaAro9p with PLP in the form of internal aldimine, and CaAro9p with a mixture of ligands that have been interpreted as results of the enzymatic reaction. The crystal structures of both enzymes contains in the asymmetric unit a biologically relevant dimer of 55 kDa for CaAro8 and 59 kDa for CaAro9p protein subunits. The ability of the enzymes to process multiple substrates could be related to a feature of their architecture in which the active site resides on one subunit while the substrate-binding site is formed by a long loop extending from the other subunit of the dimeric molecule. The separation of the two functions to different chemical entities could facilitate the evolution of the substrate-binding part and allow it to be flexible without destabilizing the conservative catalytic mechanism. | Shibata K (2018)
Urinary Excretion of 2-Oxo Acids Is Greater in Rats with Streptozotocin-Induced Diabetes.
Journal of nutritional science and vitaminology 64, 292-295 [PubMed:30175794]
[show Abstract]
2-Oxo acids derived from amino acids, glucose, and fatty acids are key intermediates in energy production. During diabetes, energy production is known to be lower than in healthy individuals. However, it was unknown whether the production of 2-oxo acids is impacted by diabetes. In the present study, I compared the quantities of 2-oxo acids (pyruvic acid, oxaloacetic acid, 2-oxoglutaric acid, 2-oxoadipic acid, 2-oxoisovaleric acid, 2-oxo-3-methylvaleric acid, and 2-oxo-4-methylvaleric acid) excreted in the urine of normoglycemic control rats and rats with streptozotocin-induced diabetes, which reflect the quantities of unused 2-oxo acids in the body. Greater urinary excretion of unused 2-oxo acids thus implies an impairment in energy production. The respective quantities of urinary pyruvic acid + oxaloacetic acid (measured together), 2-oxoglutaric acid, 2-oxoadipic acid, 2-oxoisovaleric acid, 2-oxo-3-methylvaleric acid, and 2-oxo-4-methylvaleric acid in the diabetic rats were 2.0- (p<0.0001), 2.5- (p<0.0001), 1.5- (p=0.008), 7.6- (p<0.0001), 6.1- (p<0.0001), and 2.1-fold (p<0.0001) greater than in the control rats per 1 g food intake. Thus, the biggest differences were observed in 2-oxoisovaleric acid (a catabolite of valine) and 2-oxo-3-methylvaleric acid (a catabolite of isoleucine). These findings indicate that energy production in the body is suppressed under diabetic conditions. | Martinez S, Fellner M, Herr CQ, Ritchie A, Hu J, Hausinger RP (2017)
Structures and Mechanisms of the Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Ethylene-Forming Enzyme: Substrate Binding Creates a Twist.
Journal of the American Chemical Society 139, 11980-11988 [PubMed:28780854]
[show Abstract]
The ethylene-forming enzyme (EFE) from Pseudomonas syringae pv. phaseolicola PK2 is a member of the mononuclear nonheme Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenase superfamily. EFE converts 2OG into ethylene plus three CO2 molecules while also catalyzing the C5 hydroxylation of l-arginine (l-Arg) driven by the oxidative decarboxylation of 2OG to form succinate and CO2. Here we report 11 X-ray crystal structures of EFE that provide insight into the mechanisms of these two reactions. Binding of 2OG in the absence of l-Arg resulted in predominantly monodentate metal coordination, distinct from the typical bidentate metal-binding species observed in other family members. Subsequent addition of l-Arg resulted in compression of the active site, a conformational change of the carboxylate side chain metal ligand to allow for hydrogen bonding with the substrate, and creation of a twisted peptide bond involving this carboxylate and the following tyrosine residue. A reconfiguration of 2OG achieves bidentate metal coordination. The dioxygen binding site is located on the metal face opposite to that facing l-Arg, thus requiring reorientation of the generated ferryl species to catalyze l-Arg hydroxylation. Notably, a phenylalanyl side chain pointing toward the metal may hinder such a ferryl flip and promote ethylene formation. Extensive site-directed mutagenesis studies supported the importance of this phenylalanine and confirmed the essential residues used for substrate binding and catalysis. The structural and functional characterization described here suggests that conversion of 2OG to ethylene, atypical among Fe(II)/2OG oxygenases, is facilitated by the binding of l-Arg which leads to an altered positioning of the carboxylate metal ligand, a resulting twisted peptide bond, and the off-line geometry for dioxygen coordination. | Rosa LT, Dix SR, Rafferty JB, Kelly DJ (2017)
Structural basis for high-affinity adipate binding to AdpC (RPA4515), an orphan periplasmic-binding protein from the tripartite tricarboxylate transporter (TTT) family in Rhodopseudomonas palustris.
The FEBS journal 284, 4262-4277 [PubMed:29082669]
[show Abstract]
The tripartite tricarboxylate transporter (TTT) family is a poorly characterised group of prokaryotic secondary solute transport systems, which employ a periplasmic substrate-binding protein (SBP) for initial ligand recognition. The substrates of only a small number of TTT systems are known and very few SBP structures have been solved, so the mechanisms of SBP-ligand interactions in this family are not well understood. The SBP RPA4515 (AdpC) from Rhodopseudomonas palustris was found by differential scanning fluorescence and isothermal titration calorimetry to bind aliphatic dicarboxylates of a chain length of six to nine carbons, with KD values in the μm range. The highest affinity was found for the C6-dicarboxylate adipate (1,6-hexanedioate). Crystal structures of AdpC, either adipate or 2-oxoadipate bound, revealed a lack of positively charged amino acids in the binding pocket and showed that water molecules are involved in bridging hydrogen bonds to the substrate, a conserved feature in the TTT SBP family that is distinct from other types of SBP. In AdpC, both of the ligand carboxylate groups and a linear chain conformation are needed for coordination in the binding pocket. RT-PCR showed that adpC expression is upregulated by low environmental adipate concentrations, suggesting adipate is a physiologically relevant substrate but as adpC is not genetically linked to any TTT membrane transport genes, the role of AdpC may be in signalling rather than transport. Our data expand the known ligands for TTT systems and identify a novel high-affinity binding protein for adipate, an important industrial chemical intermediate and food additive.DatabasesProtein structure co-ordinates are available in the PDB under the accession numbers 5OEI and 5OKU. | Guimarães SL, Coitinho JB, Costa DM, Araújo SS, Whitman CP, Nagem RA (2016)
Crystal Structures of Apo and Liganded 4-Oxalocrotonate Decarboxylase Uncover a Structural Basis for the Metal-Assisted Decarboxylation of a Vinylogous β-Keto Acid.
Biochemistry 55, 2632-2645 [PubMed:27082660]
[show Abstract]
The enzymes in the catechol meta-fission pathway have been studied for more than 50 years in several species of bacteria capable of degrading a number of aromatic compounds. In a related pathway, naphthalene, a toxic polycyclic aromatic hydrocarbon, is fully degraded to intermediates of the tricarboxylic acid cycle by the soil bacteria Pseudomonas putida G7. In this organism, the 83 kb NAH7 plasmid carries several genes involved in this biotransformation process. One enzyme in this route, NahK, a 4-oxalocrotonate decarboxylase (4-OD), converts 2-oxo-3-hexenedioate to 2-hydroxy-2,4-pentadienoate using Mg(2+) as a cofactor. Efforts to study how 4-OD catalyzes this decarboxylation have been hampered because 4-OD is present in a complex with vinylpyruvate hydratase (VPH), which is the next enzyme in the same pathway. For the first time, a monomeric, stable, and active 4-OD has been expressed and purified in the absence of VPH. Crystal structures for NahK in the apo form and bonded with five substrate analogues were obtained using two distinct crystallization conditions. Analysis of the crystal structures implicates a lid domain in substrate binding and suggests roles for specific residues in a proposed reaction mechanism. In addition, we assign a possible function for the NahK N-terminal domain, which differs from most of the other members of the fumarylacetoacetate hydrolase superfamily. Although the structural basis for metal-dependent β-keto acid decarboxylases has been reported, this is the first structural report for that of a vinylogous β-keto acid decarboxylase and the first crystal structure of a 4-OD. | Taberman H, Andberg M, Parkkinen T, Jänis J, Penttilä M, Hakulinen N, Koivula A, Rouvinen J (2014)
Structure and function of a decarboxylating Agrobacterium tumefaciens keto-deoxy-d-galactarate dehydratase.
Biochemistry 53, 8052-8060 [PubMed:25454257]
[show Abstract]
Agrobacterium tumefaciens (At) strain C58 contains an oxidative enzyme pathway that can function on both d-glucuronic and d-galacturonic acid. The corresponding gene coding for At keto-deoxy-d-galactarate (KDG) dehydratase is located in the same gene cluster as those coding for uronate dehydrogenase (At Udh) and galactarolactone cycloisomerase (At Gci) which we have previously characterized. Here, we present the kinetic characterization and crystal structure of At KDG dehydratase, which catalyzes the next step, the decarboxylating hydrolyase reaction of KDG to produce α-ketoglutaric semialdehyde (α-KGSA) and carbon dioxide. The crystal structures of At KDG dehydratase and its complexes with pyruvate and 2-oxoadipic acid, two substrate analogues, were determined to 1.7 Å, 1.5 Å, and 2.1 Å resolution, respectively. Furthermore, mass spectrometry was used to confirm reaction end-products. The results lead us to propose a structure-based mechanism for At KDG dehydratase, suggesting that while the enzyme belongs to the Class I aldolase protein family, it does not follow a typical retro-aldol condensation mechanism. | Hiratsuka C, Fukuwatari T, Shibata K (2012)
Fate of dietary tryptophan in young Japanese women.
International journal of tryptophan research : IJTR 5, 33-47 [PubMed:23150724]
[show Abstract]
The purpose of this study was to determine, using the high-performance liquid chromatographic methods recently modified by us, the fate of dietary tryptophan in 17 healthy female Japanese adults who ate self-selected food. The experimental period was 22 days. The habitual intake of tryptophan was 3328.4 μmol/day. 24-hour urine samples were collected at the beginning of the experiment and then once per week. Blood was collected at the beginning and end of the experiment. Levels of tryptophan and its metabolites were measured in blood and urine. Tryptophan, nicotinamide and 2-oxoadipic acid were the major compounds of the blood. The urinary excretion amounts of tryptophan, 5-hydroxyindole-3-acetic acid, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid were about 40, 20, 4, 1, 10, 4, 3, 5 and 20 μmol/day, respectively. | Shibata K, Yasui M, Sano M, Fukuwatari T (2011)
Fluorometric determination of 2-oxoadipic acid, a common metabolite of tryptophan and lysine, by high-performance liquid chromatography with pre-chemical derivatization.
Bioscience, biotechnology, and biochemistry 75, 185-187 [PubMed:21228461]
[show Abstract]
2-Oxoadipic acid, a key metabolite of tryptophan and lysine, reacted with 1,2-diamino-4,5-methylenebenzene in an acidic solution to produce a fluorescent derivative. The reaction product was separated using a Tosoh ODS-80Ts column with 20 mmol/L of KH₂PO₄-K₂HPO₄ buffer (pH 7.0) containing 26% methanol at a flow rate 0.8 mL/min. The excitation wavelength of detection was 367 nm, and the emission wavelength was 446 nm. The limit of quantification was 1 pmol per injection, sufficiently sensitive for the determination of 2-oxoadipic acid in human and experimental animal urine. | Schulze-Bergkamen A, Okun JG, Spiekerkötter U, Lindner M, Haas D, Kohlmüller D, Mayatepek E, Schulze-Bergkamen H, Greenberg CR, Zschocke J, Hoffmann GF, Kölker S (2005)
Quantitative acylcarnitine profiling in peripheral blood mononuclear cells using in vitro loading with palmitic and 2-oxoadipic acids: biochemical confirmation of fatty acid oxidation and organic acid disorders.
Pediatric research 58, 873-880 [PubMed:16183823]
[show Abstract]
Organic acid (OAD) and fatty acid oxidation disorders (FAOD) are inborn errors of metabolism often presenting with life-threatening metabolic decompensation followed by (irreversible) organ failure, and even death during catabolic state. Most of these diseases are considered as treatable, and metabolic decompensations can be avoided by early diagnosis and start of therapy. Confirmation of suspected diagnosis currently relies on enzymatic and mutation analyses and in vitro loading of palmitic acid in human skin fibroblast cultures. Furthermore, in some cases potentially life-threatening in vivo loading or fasting tests are still performed. In this study, we established a standardized in vitro loading test in peripheral blood mononuclear cells (PBMC) that allows reliable biochemical confirmation of a suspected diagnosis within 1 week. Patients with confirmed diagnosis of short-, medium-, very-long-chain, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies, methylmalonic, propionic, isovaleric acidurias, and glutaric aciduria type I were included in the study. PBMC, isolated from heparinized venous blood samples of these individuals were incubated for 5 days with palmitic acid or 2-oxoadipic acid (glutaric aciduria type I), respectively, and quantitative acylcarnitine profiling was subsequently performed in supernatants using electrospray ionization tandem mass spectrometry. All patients were clearly identified, including those with mild biochemical phenotypes who, in particular, are at risk to be missed under balanced metabolic conditions. In glutaric aciduria type I, the same results were also obtained using lymphoblasts. In conclusion, our assay allows biochemical confirmation of a number of FAOD and OAD and could easily be implemented into the confirmatory diagnostic work-up. | Fiermonte G, Dolce V, Palmieri L, Ventura M, Runswick MJ, Palmieri F, Walker JE (2001)
Identification of the human mitochondrial oxodicarboxylate carrier. Bacterial expression, reconstitution, functional characterization, tissue distribution, and chromosomal location.
The Journal of biological chemistry 276, 8225-8230 [PubMed:11083877]
[show Abstract]
In Saccharomyces cerevisiae, the genes ODC1 and ODC2 encode isoforms of the oxodicarboxylate carrier. They both transport C5-C7 oxodicarboxylates across the inner membranes of mitochondria and are members of the family of mitochondrial carrier proteins. Orthologs are encoded in the genomes of Caenorhabditis elegans and Drosophila melanogaster, and a human expressed sequence tag (EST) encodes part of a closely related protein. Information from the EST has been used to complete the human cDNA sequence. This sequence has been used to map the gene to chromosome 14q11.2 and to show that the gene is expressed in all tissues that were examined. The human protein was produced by overexpression in Escherichia coli, purified, and reconstituted into phospholipid vesicles. It has similar transport characteristics to the yeast oxodicarboxylate carrier proteins (ODCs). Both the human and yeast ODCs catalyzed the transport of the oxodicarboxylates 2-oxoadipate and 2-oxoglutarate by a counter-exchange mechanism. Adipate, glutarate, and to a lesser extent, pimelate, 2-oxopimelate, 2-aminoadipate, oxaloacetate, and citrate were also transported by the human ODC. The main differences between the human and yeast ODCs are that 2-aminoadipate is transported by the former but not by the latter, whereas malate is transported by the yeast ODCs but not by the human ortholog. In mammals, 2-oxoadipate is a common intermediate in the catabolism of lysine, tryptophan, and hydroxylysine. It is transported from the cytoplasm into mitochondria where it is converted into acetyl-CoA. Defects in human ODC are likely to be a cause of 2-oxoadipate acidemia, an inborn error of metabolism of lysine, tryptophan, and hydroxylysine. | Palmieri L, Agrimi G, Runswick MJ, Fearnley IM, Palmieri F, Walker JE (2001)
Identification in Saccharomyces cerevisiae of two isoforms of a novel mitochondrial transporter for 2-oxoadipate and 2-oxoglutarate.
The Journal of biological chemistry 276, 1916-1922 [PubMed:11013234]
[show Abstract]
The nuclear genome of Saccharomyces cerevisiae encodes 35 members of a family of membrane proteins. Known members transport substrates and products across the inner membranes of mitochondria. We have localized two hitherto unidentified family members, Odc1p and Odc2p, to the inner membranes of mitochondria. They are isoforms with 61% sequence identity, and we have shown in reconstituted liposomes that they transport the oxodicarboxylates 2-oxoadipate and 2-oxoglutarate by a strict counter exchange mechanism. Intraliposomal adipate and glutarate and to a lesser extent malate and citrate supported [14C]oxoglutarate uptake. The expression of Odc1p, the more abundant isoform, made in the presence of nonfermentable carbon sources, is repressed by glucose. The main physiological roles of Odc1p and Odc2p are probably to supply 2-oxoadipate and 2-oxoglutarate from the mitochondrial matrix to the cytosol where they are used in the biosynthesis of lysine and glutamate, respectively, and in lysine catabolism. | Barshop BA, Nyhan WL, Naviaux RK, McGowan KA, Friedlander M, Haas RH (2000)
Kearns-Sayre syndrome presenting as 2-oxoadipic aciduria.
Molecular genetics and metabolism 69, 64-68 [PubMed:10655159]
[show Abstract]
A patient with 2-oxoadipic aciduria and 2-aminoadipic aciduria presented at 2 years of age with manifestations typical of organic acidemia, episodes of ketosis and acidosis, progressive to coma. This resolved and the key metabolites disappeared from the urine and blood. At 9 years of age she developed typical Kearns-Sayre syndrome with complete heart block, retinopathy, and ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome. | Lee SH, Kim SO, Chung BC (1998)
Gas chromatographic-mass spectrometric determination of urinary oxoacids using O-(2,3,4,5,6-pentafluorobenzyl)oxime-trimethylsilyl ester derivatization and cation-exchange chromatography.
Journal of chromatography. B, Biomedical sciences and applications 719, 1-7 [PubMed:9869358]
[show Abstract]
We introduced a new combined method to isolate, purify and quantify oxoacids in human urine. Preparation of O-(2,3,4,5,6-pentafluorobenzyl) oximes of oxoacids at pH 2 to 3 was followed by cation-exchange column chromatography for removing the biological interferences. The effluent with water was extracted with ethyl acetate and the oxoacids were quantitatively converted into their trimethylsilyl derivatives for detection by gas chromatography-mass spectrometry. Good quality control data were obtained through precision and accuracy tests. Analytical recoveries (53.5-99.8%) were quantitative for a wide variety of oxoacids. This method was used for the measurement of 18 oxoacids in the urine of healthy volunteers. | Guneral F, Bachmann C (1994)
Age-related reference values for urinary organic acids in a healthy Turkish pediatric population.
Clinical chemistry 40, 862-866 [PubMed:8087979]
[show Abstract]
Organic acid concentrations were quantified by gas chromatography and the individual acids identified by mass spectrometry in urine specimens from a healthy Turkish pediatric population of ages 2 days to 16 years, subdivided into five age groups. We quantified 69 organic acids (32 major and 37 minor components) and report here the median values and percentiles for each compound, adjusted for creatinine content, for the five groups. Concentrations of most of the organic acids tend to decrease with age but display substantial differences between age groups. This emphasizes the importance of comparing patients' data with age-matched reference data. Correlations between the excretion of organic acids and protein or caloric intake were significant for several compounds. | Bunik VI, Pavlova OG (1993)
Inactivation of alpha-ketoglutarate dehydrogenase during oxidative decarboxylation of alpha-ketoadipic acid.
FEBS letters 323, 166-170 [PubMed:8495733]
[show Abstract]
alpha-Ketoglutarate dehydrogenase was inactivated irreversibly and completely during oxidation of alpha-ketoadipic acid. The inactivation was revealed both in the model system with ferricyanide and in the overall reaction catalyzed by the alpha-ketoglutarate dehydrogenase complex. Neither substrate depletion nor product accumulation induced the inactivation. The results obtained were compared with recent data on the enzyme inactivation during oxidation of alpha-ketoglutaric acid. The differences in the inactivation kinetics observed with the two substrates of the enzyme were analyzed. They seem not to reflect the different mechanisms of the inactivation, but, rather, depend on the changes in the rates of the individual stages of the process. | Strassman M, Ceci LN (1965)
Enzymatic formation of alpha-ketoadipic acid from homoisocitric acid.
The Journal of biological chemistry 240, 4357-4361 [PubMed:4284830] | WEBER MA, HOAGLAND AN, KLEIN J, LEWIS K (1964)
BIOSYNTHESIS OF ALPHA-KETOADIPIC ACID BY EXTRACTS OF BAKER'S YEAST.
Archives of biochemistry and biophysics 104, 257-266 [PubMed:14163891] | Strassman M, Ceci LN, Silverman BE (1964)
Enzymatic conversion of homoisocitric acid into alpha-ketoadipic acid.
Biochemical and biophysical research communications 14, 268-271 [PubMed:5836515] | Broquist HP, Stiffey AV, Albrecht AM (1961)
Biosynthesis of Lysine from alpha-Ketoadipic Acid and alpha-Aminoadipic Acid in Yeast.
Applied microbiology 9, 1-5 [PubMed:16349595] |
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