2.02012-05-31 14:20:46 -06002015-06-03 17:19:02 -0600ECMDB12149M2MDB0008232-Isopropyl-3-oxosuccinate2-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 acid2-isopropyl-3-oxosuccinate2-Isopropyl-3-oxosuccinic acid2-Oxo-4-methyl-3-carboxypentanoate2-Oxo-4-methyl-3-carboxypentanoic acid3-Carboxy-4-methyl-2-oxopentanoate3-Carboxy-4-methyl-2-oxopentanoic acidC7H10O5174.1513174.05282343(3S)-2-oxo-3-(propan-2-yl)butanedioic acid(2S)-2-isopropyl-3-oxobutanedioic acidCC(C)[C@H](C(O)=O)C(=O)C(O)=OInChI=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/s1HIIZAGQWABAMRR-BYPYZUCNSA-NSolidCytosollogp0.43logs-1.39solubility7.02e+00 g/llogp1.23pka_strongest_acidic2.93pka_strongest_basic-10iupac(3S)-2-oxo-3-(propan-2-yl)butanedioic acidaverage_mass174.1513mono_mass174.05282343smilesCC(C)[C@H](C(O)=O)C(=O)C(O)=OformulaC7H10O5inchiInChI=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/s1inchikeyHIIZAGQWABAMRR-BYPYZUCNSA-Npolar_surface_area91.67refractivity38.06polarizability15.83rotatable_bond_count4acceptor_count5donor_count2physiological_charge-2formal_charge0Valine, leucine and isoleucine biosynthesisec00290C5-Branched dibasic acid metabolismec00660Metabolic pathwayseco01100Leucine BiosynthesisLeucine 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. PW000811MetabolicSecondary Metabolite: Leucine biosynthesisLeucine 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. PW000980MetabolicSecondary Metabolites: Valine and I-leucine biosynthesis from pyruvateThe 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.PW000978Metabolicisoleucine biosynthesis I (from threonine)LEUSYN-PWYSpecdb::CMs2539Specdb::CMs39833Specdb::CMs136309Specdb::CMs144043Specdb::NmrOneD151270Specdb::NmrOneD151271Specdb::NmrOneD151272Specdb::NmrOneD151273Specdb::NmrOneD151274Specdb::NmrOneD151275Specdb::NmrOneD151276Specdb::NmrOneD151277Specdb::NmrOneD151278Specdb::NmrOneD151279Specdb::NmrOneD151280Specdb::NmrOneD151281Specdb::NmrOneD151282Specdb::NmrOneD151283Specdb::NmrOneD151284Specdb::NmrOneD151285Specdb::NmrOneD151286Specdb::NmrOneD151287Specdb::NmrOneD151288Specdb::NmrOneD151289Specdb::MsMs28559Specdb::MsMs28560Specdb::MsMs28561Specdb::MsMs35117Specdb::MsMs35118Specdb::MsMs35119Specdb::MsMs2261260Specdb::MsMs2261261Specdb::MsMs2261262Specdb::MsMs3077016Specdb::MsMs3077017Specdb::MsMs3077018HMDB1214954622594575347C042361467CPD-7100Keseler, 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-D114.220805103-isopropylmalate dehydrogenaseP30125LEU3_ECOLIleuBhttp://ecmdb.ca/proteins/P30125.xmlD-malate dehydrogenase [decarboxylating]P76251DMLA_ECOLIdmlAhttp://ecmdb.ca/proteins/P76251.xml3-Isopropylmalate + NAD > 2-Isopropyl-3-oxosuccinate + Hydrogen ion + NADHR044263-ISOPROPYLMALDEHYDROG-RXN2-Isopropyl-3-oxosuccinate + Hydrogen ion > Ketoleucine + Carbon dioxideRXN-78003-Isopropylmalate + NAD <> 2-Isopropyl-3-oxosuccinate + NADH + Hydrogen ionR044263-Isopropylmalate + NAD + 2-Isopropyl-3-oxosuccinate <> Ketoleucine + Carbon dioxide + NADH + Hydrogen ionR10052 3 3-Isopropylmalate + NAD >2 2-Isopropyl-3-oxosuccinate + Hydrogen ion + NADH3 3-Isopropylmalate + NAD >2 2-Isopropyl-3-oxosuccinate + Hydrogen ion + NADH