2.0 2012-05-31 09:55:21 -0600 2015-10-02 02:25:48 -0600 ECMDB00019 M2MDB000004 a-Ketoisovaleric acid a-Ketoisovaleric acid is a precursor of valine, leucine and pantothenate. It can be synthesized in E. coli. anabolically (via dihydroxyacid dehydrase) and catabolically (branched-chain amino acid transaminase and alanine-valine transaminase) (PMID: 7040341) 2-Keto-3-Methylbutyrate 2-Keto-3-Methylbutyric acid 2-Ketoisovalerate 2-Ketoisovaleric acid 2-Oxo-3-methylbutanoate 2-Oxo-3-methylbutanoic acid 2-Oxo-3-methylbutyrate 2-Oxo-3-methylbutyric acid 2-Oxoisovalerate 2-Oxoisovaleric acid 3-Methyl-2-oxo-Butanoate 3-Methyl-2-oxo-Butanoic acid 3-Methyl-2-oxo-Butyrate 3-Methyl-2-oxo-Butyric acid 3-Methyl-2-oxobutanoate 3-Methyl-2-oxobutanoic acid 3-Methyl-2-oxobutyrate 3-Methyl-2-oxobutyric acid A-Keto-b-Methylbutyrate a-Keto-b-Methylbutyric acid A-Keto-Isovalerate a-Keto-Isovaleric acid A-Ketoisovalerate A-Oxo-b-methylbutyrate a-Oxo-b-methylbutyric acid A-Oxoisovalerate a-Oxoisovaleric acid alpha-Ketoisovalerate alpha-Ketoisovaleric acid Dimethylpyruvate Dimethylpyruvic acid Isopropylglyoxylate Isopropylglyoxylic acid Ketovaline α-Ketoisovalerate α-Ketoisovaleric acid C5H8O3 116.1152 116.047344122 3-methyl-2-oxobutanoic acid α-ketoisovalerate 759-05-7 CC(C)C(=O)C(O)=O InChI=1S/C5H8O3/c1-3(2)4(6)5(7)8/h3H,1-2H3,(H,7,8) QHKABHOOEWYVLI-UHFFFAOYSA-N Solid Cytosol logp 0.49 ALOGPS logs -0.59 ALOGPS solubility 3.02e+01 g/l ALOGPS melting_point 31.5 oC logp 1.31 ChemAxon pka_strongest_acidic 3.37 ChemAxon pka_strongest_basic -9.7 ChemAxon iupac 3-methyl-2-oxobutanoic acid ChemAxon average_mass 116.1152 ChemAxon mono_mass 116.047344122 ChemAxon smiles CC(C)C(=O)C(O)=O ChemAxon formula C5H8O3 ChemAxon inchi InChI=1S/C5H8O3/c1-3(2)4(6)5(7)8/h3H,1-2H3,(H,7,8) ChemAxon inchikey QHKABHOOEWYVLI-UHFFFAOYSA-N ChemAxon polar_surface_area 54.37 ChemAxon refractivity 27.19 ChemAxon polarizability 11.04 ChemAxon rotatable_bond_count 2 ChemAxon acceptor_count 3 ChemAxon donor_count 1 ChemAxon physiological_charge -1 ChemAxon formal_charge 0 ChemAxon Alanine, aspartate and glutamate metabolism ec00250 Pyruvate metabolism ec00620 Valine, leucine and isoleucine biosynthesis ec00290 Pantothenate and CoA biosynthesis The 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]. PW000828 ec00770 Metabolic Valine, leucine and isoleucine degradation ec00280 Metabolic pathways eco01100 L-alanine metabolism L-alanine is an essential component of proteins and peptidoglycan. The latter also contains about three molecules of D-alanine for every L-alanine. Only about 10 percent of the total alanine synthesized flows into peptidoglycan. There are at least 3 ways to begin the biosynthesis of alanine. The first method for alanine biosynthesis begins with L-cysteine produced from L-cysteine biosynthesis pathway. L-cysteine reacts with an [L-cysteine desulfurase] L-cysteine persulfide through a cysteine desulfurase resulting in a release of [L-cysteine desulfurase] l-cysteine persulfide and L-alanine. The second method starts with pyruvic acid reacting with L-glutamic acid through a glutamate-pyruvate aminotransferase resulting in a oxoglutaric acid and L-alanine. The third method starts with L-glutamic acid interacting with Alpha-ketoisovaleric acid through a valine transaminase resulting in an oxoglutaric acid and L-valine. L-valine reacts with pyruvic acid through a valine-pyruvate aminotransferase resulting Alpha-ketoisovaleric acid and L-alanine. This first step of the pathway, which can be catalyzed by either of two racemases( biosynthetic or catabolic), also serves an essential role in biosynthesis because its product, D-alanine, is an essential component of cell wall peptidoglycan (murein). D-alanine is metabolized by an ATP driven D-alanine ligase A and B resulting in D-alanyl-D-alanine. This product is incorporated into the peptidoglycan biosynthesis. L-alanine is metabolized with alanine racemase, either catabolic or metabolic resulting in a D-alanine. This compound reacts with water and a quinone through a D-amino acid dehydrogenase resulting in Pyruvic acid, hydroquinone and ammonium, thus entering the central metabolism and thereby can serve as a total source of carbon and energy. This pathway is unique among those through which L-amino acids are degraded, in that the L form must first be converted to the D form. D-alanine, is an essential component of cell wall peptidoglycan (murein). The role of the alr racemase is predominately biosynthetic: it is produced constitutively in small amounts. The role of the dadX racemase is degradative: it is induced to high levels by alanine and is subject to catabolite repression. PW000788 Metabolic Specdb::CMs 282 Specdb::CMs 283 Specdb::CMs 938 Specdb::CMs 966 Specdb::CMs 2985 Specdb::CMs 30050 Specdb::CMs 30051 Specdb::CMs 30583 Specdb::CMs 30584 Specdb::CMs 30953 Specdb::CMs 30954 Specdb::CMs 31977 Specdb::CMs 31978 Specdb::CMs 37247 Specdb::CMs 137030 Specdb::CMs 144764 Specdb::CMs 1047012 Specdb::CMs 1047014 Specdb::CMs 1047015 Specdb::NmrOneD 1033 Specdb::NmrOneD 4866 Specdb::NmrOneD 4867 Specdb::NmrOneD 5352 Specdb::NmrOneD 5353 Specdb::NmrOneD 5354 Specdb::NmrOneD 5355 Specdb::NmrOneD 5356 Specdb::NmrOneD 5357 Specdb::NmrOneD 5358 Specdb::NmrOneD 5359 Specdb::NmrOneD 5360 Specdb::NmrOneD 5361 Specdb::NmrOneD 5362 Specdb::NmrOneD 5363 Specdb::NmrOneD 5364 Specdb::NmrOneD 5365 Specdb::NmrOneD 5366 Specdb::NmrOneD 5367 Specdb::NmrOneD 5368 Specdb::NmrOneD 5369 Specdb::NmrOneD 5370 Specdb::NmrOneD 5371 Specdb::NmrOneD 166590 Specdb::MsMs 31 Specdb::MsMs 32 Specdb::MsMs 2549 Specdb::MsMs 2550 Specdb::MsMs 2551 Specdb::MsMs 2552 Specdb::MsMs 7013 Specdb::MsMs 7014 Specdb::MsMs 7015 Specdb::MsMs 13685 Specdb::MsMs 13686 Specdb::MsMs 13687 Specdb::MsMs 438056 Specdb::MsMs 438057 Specdb::MsMs 438058 Specdb::MsMs 438059 Specdb::MsMs 438656 Specdb::MsMs 2231662 Specdb::MsMs 2232510 Specdb::MsMs 2234104 Specdb::MsMs 2234852 Specdb::MsMs 3043420 Specdb::MsMs 3043421 Specdb::MsMs 3043422 Specdb::MsMs 3099565 Specdb::NmrTwoD 926 Specdb::NmrTwoD 935 HMDB00019 48 C00141 16530 KIV Kanehisa, 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. 22080510 Winder, 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. 18331064 Yurtsever D. (2007). Fatty acid methyl ester profiling of Enterococcus and Esherichia coli for microbial source tracking. M.sc. Thesis. Villanova University: U.S.A Schaefer K, von Herrath D, Erley CM, Asmus G: Calcium ketovaline as new therapy for uremic hyperphosphatemia. Miner Electrolyte Metab. 1990;16(6):362-4. 2089249 Shoemaker 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. 2026685 Livesey G, Lund P: Binding of branched-chain 2-oxo acids to bovine serum albumin. Biochem J. 1982 Apr 15;204(1):265-72. 7115325 Shigematsu 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. 6422161 Chuang 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. 6895847 Lee 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. 9869358 Gallina DL, Dominguez JM, Hoschoian JC, Barrio JR: Maintenance of nitrogen balance in a young woman by substitution of -ketoisovaleric acid for valine. J Nutr. 1971 Sep;101(9):1165-7. 5096137 Schauder P, Schroder K, Langenbeck U: Serum branched-chain amino and keto acid response to a protein-rich meal in man. Ann Nutr Metab. 1984;28(6):350-6. 6393856 Tsuchiya H, Hashizume I, Tokunaga T, Tatsumi M, Takagi N, Hayashi T: High-performance liquid chromatography of alpha-keto acids in human saliva. Arch Oral Biol. 1983;28(11):989-92. 6581765 Bouveault, L. etal., Bull. Soc. Chim. Fr., 1901, 1031; Singh, J. etal., Org. Prep. Proced. Int., 1989, 21, 501; Hata, H. etal., Synthesis, 1991, 289 http://hmdb.ca/system/metabolites/msds/000/000/012/original/HMDB00019.pdf?1358461321 Dihydroxy-acid dehydratase P05791 ILVD_ECOLI ilvD http://ecmdb.ca/proteins/P05791.xml Valine--pyruvate aminotransferase P09053 AVTA_ECOLI avtA http://ecmdb.ca/proteins/P09053.xml 2-isopropylmalate synthase P09151 LEU1_ECOLI leuA http://ecmdb.ca/proteins/P09151.xml 3-methyl-2-oxobutanoate hydroxymethyltransferase P31057 PANB_ECOLI panB http://ecmdb.ca/proteins/P31057.xml Uncharacterized aminotransferase yfbQ P0A959 YFBQ_ECOLI yfbQ http://ecmdb.ca/proteins/P0A959.xml Branched-chain-amino-acid aminotransferase P0AB80 ILVE_ECOLI ilvE http://ecmdb.ca/proteins/P0AB80.xml L-Valine + Pyruvic acid > a-Ketoisovaleric acid + L-Alanine 2,3-Dihydroxyisovaleric acid > a-Ketoisovaleric acid + Water L-Valine + Oxoglutaric acid > a-Ketoisovaleric acid + L-Glutamate Acetyl-CoA + a-Ketoisovaleric acid + Water > 2-Isopropylmalic acid + CoA 5,10-Methylene-THF + a-Ketoisovaleric acid + Water > Tetrahydrofolic acid + 2-Dehydropantoate 2,3-Dihydroxyisovaleric acid <> alpha-Ketoisovaleric acid + Water + a-Ketoisovaleric acid R01209 alpha-Ketoisovaleric acid + L-Alanine <> Pyruvic acid + L-Valine + a-Ketoisovaleric acid R01215 VALINE-PYRUVATE-AMINOTRANSFER-RXN alpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <> 2-Isopropylmalic acid + Coenzyme A + Hydrogen ion R01213 alpha-Ketoisovaleric acid + Water + 5,10-Methylene-THF + a-Ketoisovaleric acid <> 2-Dehydropantoate + Tetrahydrofolic acid R01226 3-CH3-2-OXOBUTANOATE-OH-CH3-XFER-RXN L-Valine + Pyruvic acid + L-Valine > L-Alanine + a-Ketoisovaleric acid + L-Alanine PW_R002662 a-Ketoisovaleric acid + L-Glutamic acid + L-Glutamate > Oxoglutaric acid + L-Valine + L-Valine PW_R002663 a-Ketoisovaleric acid + 5,10-Methylene-THF + Water + 5,10-Methylene-THF > Tetrahydrofolic acid + 2-dehydropantoate + Tetrahydrofolic acid + 2-Dehydropantoate PW_R002999 2,3-Dihydroxyisovaleric acid <>2 a-Ketoisovaleric acid + Water PW_R005525 alpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <>2 2-Isopropylmalic acid + Coenzyme A + Hydrogen ion alpha-Ketoisovaleric acid + Water + 5 5,10-Methylene-THF + a-Ketoisovaleric acid <>2 2-Dehydropantoate + Tetrahydrofolic acid