2.02012-05-31 14:04:48 -06002015-06-03 15:54:43 -0600ECMDB04092M2MDB000606alpha-Ketoisovaleric acidAlpha-ketoisovaleric acid is a branched chain organic acid which is a precursor to leucine and valine synthesis. It is also a degradation product from valine. The enzyme dihydroxy-acid dehydratase catalyzes the fourth step in the biosynthesis of isoleucine and valine, through the dehydration of 2, 3-dihydroxy-isovaleic acid into alpha-ketoisovaleric acid.α-keto-isovalerateα-keto-isovaleric acidα-keto-valineα-ketoisopentanoateα-ketoisopentanoic acidα-ketovalineα-oxoisovalerateα-oxoisovaleric acid2-Keto-3-Methylbutyrate2-Keto-3-Methylbutyric acid2-Keto-isovalerate2-Keto-isovaleric acid2-Ketoisovalerate2-Ketoisovaleric acid2-Ketoisvalerate2-ketoisvaleric acid2-Ketovaline2-KIV2-Oxo-3-methyl-butyrate2-oxo-3-Methyl-butyric acid2-Oxo-3-methylbutanoate2-Oxo-3-methylbutanoic acid2-Oxo-3-methylbutyrate2-Oxo-3-methylbutyric acid2-Oxoisopentanoate2-Oxoisopentanoic acid2-Oxoisovalerate2-Oxoisovaleric acid3-Methyl-2-oxo-Butanoate3-Methyl-2-oxo-Butanoic acid3-Methyl-2-oxo-Butyrate3-Methyl-2-oxo-Butyric acid3-Methyl-2-oxobutanoate3-Methyl-2-oxobutanoic acid3-Methyl-2-oxobutinoate3-Methyl-2-oxobutinoic acid3-Methyl-2-oxobutyrate3-Methyl-2-oxobutyric acidA-Keto-b-MethylbutyrateA-Keto-b-Methylbutyric acidA-Keto-IsovalerateA-Keto-Isovaleric acida-keto-Valinea-Ketoisopentanoatea-Ketoisopentanoic acida-Ketoisovaleratea-Ketoisovaleric acida-KetovalineA-Oxo-b-methylbutyrateA-Oxo-b-methylbutyric acidA-OxoisovalerateA-Oxoisovaleric acidAlpha-Keto-beta-MethylbutyrateAlpha-Keto-beta-Methylbutyric acidAlpha-Keto-IsovalerateAlpha-Keto-Isovaleric acidAlpha-Keto-valineAlpha-KetoisopentanoateAlpha-Ketoisopentanoic acidAlpha-KetoisovalerateAlpha-Ketoisovaleric acidAlpha-KetovalineAlpha-Oxo-beta-methylbutyrateAlpha-Oxo-beta-methylbutyric acidAlpha-OxoisovalerateAlpha-Oxoisovaleric acidDimethylpyruvateDimethylpyruvic acidIsopropylglyoxylateIsopropylglyoxylic acidKetovalineα-keto-Isovalerateα-keto-Isovaleric acidα-keto-Valineα-keto-β-Methylbutyrateα-keto-β-Methylbutyric acidα-Ketoisopentanoateα-Ketoisopentanoic acidα-Ketoisovalerateα-Ketoisovaleric acidα-Ketovalineα-oxo-β-Methylbutyrateα-oxo-β-Methylbutyric acidα-Oxoisovalerateα-Oxoisovaleric acidC5H8O3116.1152116.0473441223-methyl-2-oxobutanoic acidα-ketoisovalerate759-05-7CC(C)C(=O)C(O)=OInChI=1S/C5H8O3/c1-3(2)4(6)5(7)8/h3H,1-2H3,(H,7,8)QHKABHOOEWYVLI-UHFFFAOYSA-NSolidOuter membraneInner membranelogp0.49logs-0.59solubility3.02e+01 g/lmelting_point31.5 oClogp1.31pka_strongest_acidic3.37pka_strongest_basic-9.7iupac3-methyl-2-oxobutanoic acidaverage_mass116.1152mono_mass116.047344122smilesCC(C)C(=O)C(O)=OformulaC5H8O3inchiInChI=1S/C5H8O3/c1-3(2)4(6)5(7)8/h3H,1-2H3,(H,7,8)inchikeyQHKABHOOEWYVLI-UHFFFAOYSA-Npolar_surface_area54.37refractivity27.19polarizability11.04rotatable_bond_count2acceptor_count3donor_count1physiological_charge-1formal_charge0Valine, leucine and isoleucine biosynthesisec00290Pantothenate and CoA biosynthesisThe CoA biosynthesis requires compounds from two other pathways: aspartate metabolism and valine biosynthesis. It requires a Beta-Alanine and R-pantoate.
The compound (R)-pantoate is generated in two reactions, as shown by the interaction of alpha-ketoisovaleric acid, 5,10 methylene-THF and water through a 3-methyl-2-oxobutanoate hydroxymethyltransferase resulting in a tetrahydrofolic acid and a 2-dehydropantoate. This compound interacts with hydrogen through a NADPH driven acetohydroxy acid isomeroreductase resulting in the release of NADP and R-pantoate.
On the other hand L-aspartic acid interacts with a hydrogen ion and gets decarboxylated through an Aspartate 1- decarboxylase resulting in a carbon dioxide and a Beta-alanine.
Beta-alanine and R-pantoate interact with an ATP driven pantothenate synthetase resulting in pyrophosphate, AMP, hydrogen ion and pantothenic acid.
Pantothenic acid is phosphorylated through a ATP-driven pantothenate kinase resulting in a ADP, a hydrogen ion and D-4'-Phosphopantothenate. This compound interacts with a CTP and a L-cysteine resulting in a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a hydrogen ion, a pyrophosphate, a CMP and 4-phosphopantothenoylcysteine.
The latter compound interacts with a hydrogen ion through a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a carbon dioxide release and a 4-phosphopantetheine. This compound interacts with an ATP, hydrogen ion and an phosphopantetheine adenylyltransferase resulting in a release of pyrophosphate, and dephospho-CoA.
Dephospho-CoA reacts with an ATP driven dephospho-CoA kinase resulting in a ADP , a hydrogen ion and a Coenzyme A.
. The latter is converted into (R)-4'-phosphopantothenate is two steps, involving a β-alanine ligase and a kinase. In most organsims the ligase acts before the kinase (EC 6.3.2.1, pantoate—β-alanine ligase (AMP-forming) followed by EC 2.7.1.33, pantothenate kinase, as described in phosphopantothenate biosynthesis I and phosphopantothenate biosynthesis II. However, in archaea the order is reversed, and EC 2.7.1.169, pantoate kinase acts before EC 6.3.2.36, 4-phosphopantoate—β-alanine ligase, as described in phosphopantothenate biosynthesis III.
The kinases are feedback inhibited by CoA itself, accounting for the primary regulatory mechanism of CoA biosynthesis. The addition of L-cysteine to (R)-4'-phosphopantothenate, resulting in the formation of R-4'-phosphopantothenoyl-L-cysteine (PPC), is followed by decarboxylation of PPC to 4'-phosphopantetheine. The ultimate reaction is catalyzed by EC 2.7.1.24, dephospho-CoA kinase, which converts 4'-phosphopantetheine to CoA. All enzymes of this pathway are essential for growth.
The reactions in the biosynthetic route towards CoA are identical in most organisms, although there are differences in the functionality of the involved enzymes. In plants every step is catalyzed by single monofunctional enzymes, whereas in bacteria and mammals bifunctional enzymes are often employed [Rubio06].PW000828ec00770MetabolicValine, leucine and isoleucine degradationec00280phosphopantothenate biosynthesis IPANTO-PWYisoleucine biosynthesis I (from threonine)LEUSYN-PWYalanine biosynthesis IALANINE-VALINESYN-PWYvaline biosynthesisVALSYN-PWYSpecdb::CMs282Specdb::CMs283Specdb::CMs938Specdb::CMs966Specdb::CMs2985Specdb::CMs30050Specdb::CMs30051Specdb::CMs30583Specdb::CMs30584Specdb::CMs30953Specdb::CMs30954Specdb::CMs31977Specdb::CMs31978Specdb::CMs37247Specdb::CMs137030Specdb::CMs144764Specdb::CMs1047012Specdb::CMs1047014Specdb::CMs1047015Specdb::NmrOneD1033Specdb::NmrOneD4866Specdb::NmrOneD4867Specdb::NmrOneD5352Specdb::NmrOneD5353Specdb::NmrOneD5354Specdb::NmrOneD5355Specdb::NmrOneD5356Specdb::NmrOneD5357Specdb::NmrOneD5358Specdb::NmrOneD5359Specdb::NmrOneD5360Specdb::NmrOneD5361Specdb::NmrOneD5362Specdb::NmrOneD5363Specdb::NmrOneD5364Specdb::NmrOneD5365Specdb::NmrOneD5366Specdb::NmrOneD5367Specdb::NmrOneD5368Specdb::NmrOneD5369Specdb::NmrOneD5370Specdb::NmrOneD5371Specdb::NmrOneD166590Specdb::MsMs31Specdb::MsMs32Specdb::MsMs2549Specdb::MsMs2550Specdb::MsMs2551Specdb::MsMs2552Specdb::MsMs7013Specdb::MsMs7014Specdb::MsMs7015Specdb::MsMs13685Specdb::MsMs13686Specdb::MsMs13687Specdb::MsMs438056Specdb::MsMs438057Specdb::MsMs438058Specdb::MsMs438059Specdb::MsMs438656Specdb::MsMs2231662Specdb::MsMs2232510Specdb::MsMs2234104Specdb::MsMs2234852Specdb::MsMs3043420Specdb::MsMs3043421Specdb::MsMs3043422Specdb::MsMs3099565Specdb::NmrTwoD926Specdb::NmrTwoD935HMDB000194948C00141165302-KETO-ISOVALERATEKIVKeseler, I. M., Collado-Vides, J., Santos-Zavaleta, A., Peralta-Gil, M., Gama-Castro, S., Muniz-Rascado, L., Bonavides-Martinez, C., Paley, S., Krummenacker, M., Altman, T., Kaipa, P., Spaulding, A., Pacheco, J., Latendresse, M., Fulcher, C., Sarker, M., Shearer, A. G., Mackie, A., Paulsen, I., Gunsalus, R. P., Karp, P. D. (2011). "EcoCyc: a comprehensive database of Escherichia coli biology." Nucleic Acids Res 39:D583-D590.21097882Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., Tanabe, M. (2012). "KEGG for integration and interpretation of large-scale molecular data sets." Nucleic Acids Res 40:D109-D114.22080510van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L., Hankemeier, T. (2007). "Microbial metabolomics: toward a platform with full metabolome coverage." Anal Biochem 370:17-25.17765195Winder, C. L., Dunn, W. B., Schuler, S., Broadhurst, D., Jarvis, R., Stephens, G. M., Goodacre, R. (2008). "Global metabolic profiling of Escherichia coli cultures: an evaluation of methods for quenching and extraction of intracellular metabolites." Anal Chem 80:2939-2948.18331064Yurtsever D. (2007). Fatty acid methyl ester profiling of Enterococcus and Esherichia coli for microbial source tracking. M.sc. Thesis. Villanova University: U.S.ASchaefer K, von Herrath D, Erley CM, Asmus G: Calcium ketovaline as new therapy for uremic hyperphosphatemia. Miner Electrolyte Metab. 1990;16(6):362-4.2089249Shoemaker JD, Elliott WH: Automated screening of urine samples for carbohydrates, organic and amino acids after treatment with urease. J Chromatogr. 1991 Jan 2;562(1-2):125-38.2026685Livesey G, Lund P: Binding of branched-chain 2-oxo acids to bovine serum albumin. Biochem J. 1982 Apr 15;204(1):265-72.7115325Shigematsu Y, Kikuchi K, Momoi T, Sudo M, Kikawa Y, Nosaka K, Kuriyama M, Haruki S, Sanada K, Hamano N, et al.: Organic acids and branched-chain amino acids in body fluids before and after multiple exchange transfusions in maple syrup urine disease. J Inherit Metab Dis. 1983;6(4):183-9.6422161Chuang DT, Niu WL, Cox RP: Activities of branched-chain 2-oxo acid dehydrogenase and its components in skin fibroblasts from normal and classical-maple-syrup-urine-disease subjects. Biochem J. 1981 Oct 15;200(1):59-67.6895847Lee SH, Kim SO, Chung BC: Gas chromatographic-mass spectrometric determination of urinary oxoacids using O-(2,3,4,5,6-pentafluorobenzyl)oxime-trimethylsilyl ester derivatization and cation-exchange chromatography. J Chromatogr B Biomed Sci Appl. 1998 Nov 20;719(1-2):1-7.9869358Gallina DL, Dominguez JM, Hoschoian JC, Barrio JR: Maintenance of nitrogen balance in a young woman by substitution of -ketoisovaleric acid for valine. 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Dihydroxy-acid dehydrataseP05791ILVD_ECOLIilvDhttp://ecmdb.ca/proteins/P05791.xmlValine--pyruvate aminotransferaseP09053AVTA_ECOLIavtAhttp://ecmdb.ca/proteins/P09053.xml2-isopropylmalate synthaseP09151LEU1_ECOLIleuAhttp://ecmdb.ca/proteins/P09151.xml3-methyl-2-oxobutanoate hydroxymethyltransferaseP31057PANB_ECOLIpanBhttp://ecmdb.ca/proteins/P31057.xmlUncharacterized aminotransferase yfbQP0A959YFBQ_ECOLIyfbQhttp://ecmdb.ca/proteins/P0A959.xmlBranched-chain-amino-acid aminotransferaseP0AB80ILVE_ECOLIilvEhttp://ecmdb.ca/proteins/P0AB80.xmlalpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <> 2-Isopropylmalic acid + Coenzyme A + Hydrogen ionR01213alpha-Ketoisovaleric acid + Water + 5,10-Methylene-THF + a-Ketoisovaleric acid <> 2-Dehydropantoate + Tetrahydrofolic acidR012263-CH3-2-OXOBUTANOATE-OH-CH3-XFER-RXNalpha-Ketoisovaleric acid + L-Alanine <> Pyruvic acid + L-Valine + a-Ketoisovaleric acidR01215VALINE-PYRUVATE-AMINOTRANSFER-RXNalpha-Ketoglutarate + L-Valine <> alpha-Ketoisovaleric acid + L-GlutamateR01214(R)-2,3-Dihydroxy-isovalerate > alpha-Ketoisovaleric acid + WaterR04441DIHYDROXYISOVALDEHYDRAT-RXN2,3-Dihydroxyisovaleric acid <> alpha-Ketoisovaleric acid + Water + a-Ketoisovaleric acidR012092-Isopropylmalic acid + Coenzyme A <> Acetyl-CoA + alpha-Ketoisovaleric acid + WaterR01213L-Valine + Pyruvic acid <> alpha-Ketoisovaleric acid + L-AlanineR012155,10-Methylene-THF + alpha-Ketoisovaleric acid + Water <> Tetrahydrofolic acid + 2-DehydropantoateR01226(R)-2,3-Dihydroxy-isovalerate <> alpha-Ketoisovaleric acid + WaterR04441alpha-Ketoisovaleric acid + Acetyl-CoA + Water > Hydrogen ion + 3-Carboxy-3-hydroxy-isocaproate + Coenzyme A2-ISOPROPYLMALATESYN-RXNL-Valine + Oxoglutaric acid <> alpha-Ketoisovaleric acid + L-GlutamateBRANCHED-CHAINAMINOTRANSFERVAL-RXN(R)-2,3-Dihydroxy-isovalerate > alpha-Ketoisovaleric acid + Wateralpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <>2 2-Isopropylmalic acid + Coenzyme A + Hydrogen ionalpha-Ketoisovaleric acid + Water + 5 5,10-Methylene-THF + a-Ketoisovaleric acid <>2 2-Dehydropantoate + Tetrahydrofolic acid