2.0 2012-05-31 14:20:46 -0600 2015-06-03 17:19:02 -0600 ECMDB12149 M2MDB000823 2-Isopropyl-3-oxosuccinate 2-Isopropyl-3-oxosuccinate is an intermediate in leucine biosynthesis and can be generated from (2R,3S)-3-Isopropylmalate. It is the third step in leucine biosynthesis after the fork from valine synthesis. It is an oxidative decarboxylation. Leucine biosynthesis involves a five-step conversion process starting with the valine precursor 2-keto-isovalerate. The final step in this pathway is catalyzed by two transaminases of broad specificity, Branched-chain amino acid transferase (IlvE) and Tyrosine aminotransferase (TyrB). In this pathway 2-Isopropyl-3-oxosuccinate is converted to 4-Methyl-2-oxopentanoate via spontaneous reaction.(BioCyc) (2S)-2-(1-methylethyl)-3-oxobutanedioate (2S)-2-(1-methylethyl)-3-oxobutanedioic acid (2S)-2-Isopropyl-3-oxosuccinate (2S)-2-isopropyl-3-oxosuccinic acid (2S)-3-oxo-2-(propan-2-yl)butanedioate (2S)-3-oxo-2-(propan-2-yl)butanedioic acid 2-isopropyl-3-oxosuccinate 2-Isopropyl-3-oxosuccinic acid 2-Oxo-4-methyl-3-carboxypentanoate 2-Oxo-4-methyl-3-carboxypentanoic acid 3-Carboxy-4-methyl-2-oxopentanoate 3-Carboxy-4-methyl-2-oxopentanoic acid C7H10O5 174.1513 174.05282343 (3S)-2-oxo-3-(propan-2-yl)butanedioic acid (2S)-2-isopropyl-3-oxobutanedioic acid CC(C)[C@H](C(O)=O)C(=O)C(O)=O InChI=1S/C7H10O5/c1-3(2)4(6(9)10)5(8)7(11)12/h3-4H,1-2H3,(H,9,10)(H,11,12)/t4-/m0/s1 HIIZAGQWABAMRR-BYPYZUCNSA-N Solid Cytosol logp 0.43 ALOGPS logs -1.39 ALOGPS solubility 7.02e+00 g/l ALOGPS logp 1.23 ChemAxon pka_strongest_acidic 2.93 ChemAxon pka_strongest_basic -10 ChemAxon iupac (3S)-2-oxo-3-(propan-2-yl)butanedioic acid ChemAxon average_mass 174.1513 ChemAxon mono_mass 174.05282343 ChemAxon smiles CC(C)[C@H](C(O)=O)C(=O)C(O)=O ChemAxon formula C7H10O5 ChemAxon inchi InChI=1S/C7H10O5/c1-3(2)4(6(9)10)5(8)7(11)12/h3-4H,1-2H3,(H,9,10)(H,11,12)/t4-/m0/s1 ChemAxon inchikey HIIZAGQWABAMRR-BYPYZUCNSA-N ChemAxon polar_surface_area 91.67 ChemAxon refractivity 38.06 ChemAxon polarizability 15.83 ChemAxon rotatable_bond_count 4 ChemAxon acceptor_count 5 ChemAxon donor_count 2 ChemAxon physiological_charge -2 ChemAxon formal_charge 0 ChemAxon Valine, leucine and isoleucine biosynthesis ec00290 C5-Branched dibasic acid metabolism ec00660 Metabolic pathways eco01100 Leucine Biosynthesis Leucine biosynthesis involves a five-step conversion process starting with the valine precursor 2-keto-isovalerate interacting with acetyl-CoA and water through a 2-isopropylmalate synthase resulting in Coenzyme A, hydrogen Ion and 2-isopropylmalic acid. The latter compound reacts with isopropylmalate isomerase which dehydrates the compound resulting in a Isopropylmaleate. This compound reacts with water through a isopropylmalate isomerase resulting in 3-isopropylmalate. This compound interacts with a NAD-driven D-malate / 3-isopropylmalate dehydrogenase results in 2-isopropyl-3-oxosuccinate. This compound interacts spontaneously with hydrogen resulting in the release of carbon dioxide and ketoleucine. Ketoleucine interacts in a reversible reaction with L-glutamic acid through a branched-chain amino-acid aminotransferase resulting in Oxoglutaric acid and L-leucine L-leucine can then be exported outside the cytoplasm through a transporter: L-amino acid efflux transporter. The final step in this pathway is catalyzed by two transaminases of broad specificity, IlvE and TyrB. Both the first enzyme in the pathway, 2-isopropylmalate synthase, and the terminal transaminase TyrB are suppressed by leucine. TyrB is subject to inhibition by the pathway's starting compound, 2-keto-isovalerate, and by one of its off-pathway products, tyrosine. One consequence of this inhibition by 2-keto-isovalerate is that in the absence of IlvE activity, mutations in earlier steps in the pathway cannot be compensated for by any alternate method of introducing 2-ketoisocaproate for conversion to leucine. PW000811 Metabolic Secondary Metabolite: Leucine biosynthesis Leucine biosynthesis involves a five-step conversion process starting with a 3-methyl-2-oxovaleric acid interacting with acetyl-CoA and a water molecule through a 2-isopropylmalate synthase resulting in Coenzyme A, hydrogen Ion and 2-isopropylmalic acid. The latter compound reacts with isopropylmalate isomerase which dehydrates the compound resulting in a Isopropylmaleate. This compound reacts with water through a isopropylmalate isomerase resulting in 3-isopropylmalate. This compound interacts with a NAD-driven D-malate / 3-isopropylmalate dehydrogenase results in 2-isopropyl-3-oxosuccinate. This compound interacts spontaneously with hydrogen resulting in the release of carbon dioxide and ketoleucine. Ketoleucine interacts in a reversible reaction with L-glutamic acid through a branched-chain amino-acid aminotransferase resulting in Oxoglutaric acid and L-leucine Both the first enzyme in the pathway, 2-isopropylmalate synthase, and the terminal transaminase TyrB are suppressed by leucine. TyrB is subject to inhibition by the pathway's starting compound, 2-keto-isovalerate, and by one of its off-pathway products, tyrosine. One consequence of this inhibition by 2-keto-isovalerate is that in the absence of IlvE activity, mutations in earlier steps in the pathway cannot be compensated for by any alternate method of introducing 2-ketoisocaproate for conversion to leucine. PW000980 Metabolic Secondary Metabolites: Valine and I-leucine biosynthesis from pyruvate The biosynthesis of Valine and L-leucine from pyruvic acid starts with pyruvic acid interacting with a hydrogen ion through a acetolactate synthase / acetohydroxybutanoate synthase resulting in a release of a carbon dioxide, a (S)-2-acetolactate. The latter compound then interacts with a hydrogen ion through a NADPH-driven acetohydroxy acid isomeroreductase resulting in the release of a NADP, a (R) 2,3-dihydroxy-3-methylvalerate. The latter compound is then dehydrated by a dihydroxy acid dehydratase resulting in the release of a water molecule an 3-methyl-2-oxovaleric acid. The 3-methyl-2-oxovaleric acid can produce an L-valine by interacting with a L-glutamic acid through a Valine Transaminase resulting in the release of a Oxoglutaric acid and a L-valine. The 3-methyl-2-oxovaleric acid then interacts with an acetyl-CoA and a water molecule through a 2-isopropylmalate synthase resulting in the release of a hydrogen ion, a Coenzyme A and a 2-Isopropylmalic acid. The isopropylimalic acid is then hydrated by interacting with a isopropylmalate isomerase resulting in a 3-isopropylmalate. This compound then interacts with an NAD driven 3-isopropylmalate dehydrogenase resulting in a NADH, a hydrogen ion and a 2-isopropyl-3-oxosuccinate. The latter compound then interacts with hydrogen ion spontaneously resulting in a carbon dioxide and a ketoleucine. The ketoleucine then interacts with a L-glutamic acid through a branched-chain amino-acid aminotransferase resulting in the oxoglutaric acid and L-leucine. PW000978 Metabolic isoleucine biosynthesis I (from threonine) LEUSYN-PWY Specdb::CMs 2539 Specdb::CMs 39833 Specdb::CMs 136309 Specdb::CMs 144043 Specdb::NmrOneD 151270 Specdb::NmrOneD 151271 Specdb::NmrOneD 151272 Specdb::NmrOneD 151273 Specdb::NmrOneD 151274 Specdb::NmrOneD 151275 Specdb::NmrOneD 151276 Specdb::NmrOneD 151277 Specdb::NmrOneD 151278 Specdb::NmrOneD 151279 Specdb::NmrOneD 151280 Specdb::NmrOneD 151281 Specdb::NmrOneD 151282 Specdb::NmrOneD 151283 Specdb::NmrOneD 151284 Specdb::NmrOneD 151285 Specdb::NmrOneD 151286 Specdb::NmrOneD 151287 Specdb::NmrOneD 151288 Specdb::NmrOneD 151289 Specdb::MsMs 28559 Specdb::MsMs 28560 Specdb::MsMs 28561 Specdb::MsMs 35117 Specdb::MsMs 35118 Specdb::MsMs 35119 Specdb::MsMs 2261260 Specdb::MsMs 2261261 Specdb::MsMs 2261262 Specdb::MsMs 3077016 Specdb::MsMs 3077017 Specdb::MsMs 3077018 HMDB12149 5462259 4575347 C04236 1467 CPD-7100 Keseler, 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. 21097882 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 3-isopropylmalate dehydrogenase P30125 LEU3_ECOLI leuB http://ecmdb.ca/proteins/P30125.xml D-malate dehydrogenase [decarboxylating] P76251 DMLA_ECOLI dmlA http://ecmdb.ca/proteins/P76251.xml 3-Isopropylmalate + NAD > 2-Isopropyl-3-oxosuccinate + Hydrogen ion + NADH R04426 3-ISOPROPYLMALDEHYDROG-RXN 2-Isopropyl-3-oxosuccinate + Hydrogen ion > Ketoleucine + Carbon dioxide RXN-7800 3-Isopropylmalate + NAD <> 2-Isopropyl-3-oxosuccinate + NADH + Hydrogen ion R04426 3-Isopropylmalate + NAD + 2-Isopropyl-3-oxosuccinate <> Ketoleucine + Carbon dioxide + NADH + Hydrogen ion R10052 3 3-Isopropylmalate + NAD >2 2-Isopropyl-3-oxosuccinate + Hydrogen ion + NADH 3 3-Isopropylmalate + NAD >2 2-Isopropyl-3-oxosuccinate + Hydrogen ion + NADH