2.02012-05-31 10:26:35 -06002015-09-13 12:56:08 -0600ECMDB00402M2MDB0001352-Isopropylmalic acid2-Isopropylmalic acid is involved in valine, leucine and isoleucine biosynthesis and pyruvate metabolism pathways. In pyruvate metabolism, 2-isopropylmalate synthase (EC:2.3.3.13) catalyzes the formation of 2-Isopropylmalic acid from acetyl-CoA. (KEGG)(2S)-2-Isopropylmalate(2S)-2-Isopropylmalic acid2-D-Threo-hydroxy-3-carboxy-isocaproate2-D-Threo-hydroxy-3-carboxy-isocaproic acid2-Hydroxy-2-isopropylsuccinate2-Hydroxy-2-isopropylsuccinic acid2-Isopropyl-2-hydroxybutanedioate2-Isopropyl-2-hydroxybutanedioic acid2-Isopropyl-Malate2-Isopropyl-Malic acid2-Isopropylmalate2-Isopropylmalic acid3-Carboxy-2-hydroxy-4-methylpentanoate3-Carboxy-2-hydroxy-4-methylpentanoic acid3-Carboxy-3-hydroxyisocaproate3-Carboxy-3-hydroxyisocaproic acid3-Isopropylmalate3-Isopropylmalic acidA-IsopropylmalateA-Isopropylmalic acidAlpha-IsopropylmalateAlpha-Isopropylmalic acidb-Isopropylmalateb-Isopropylmalic acidBeta-IsopropylmalateBeta-Isopropylmalic acidα-Isopropylmalateα-Isopropylmalic acidβ-Isopropylmalateβ-Isopropylmalic acidC7H12O5176.1672176.068473494(2S)-2-hydroxy-2-(propan-2-yl)butanedioic acid2-isopropyl-malic acid3237-44-3CC(C)[C@@](O)(CC(O)=O)C(O)=OInChI=1S/C7H12O5/c1-4(2)7(12,6(10)11)3-5(8)9/h4,12H,3H2,1-2H3,(H,8,9)(H,10,11)/t7-/m0/s1BITYXLXUCSKTJS-ZETCQYMHSA-NSolidCytosolCytosollogp-0.29logs0.01solubility1.81e+02 g/lmelting_point144-146 oClogp0.21pka_strongest_acidic3.63pka_strongest_basic-4.1iupac(2S)-2-hydroxy-2-(propan-2-yl)butanedioic acidaverage_mass176.1672mono_mass176.068473494smilesCC(C)[C@@](O)(CC(O)=O)C(O)=OformulaC7H12O5inchiInChI=1S/C7H12O5/c1-4(2)7(12,6(10)11)3-5(8)9/h4,12H,3H2,1-2H3,(H,8,9)(H,10,11)/t7-/m0/s1inchikeyBITYXLXUCSKTJS-ZETCQYMHSA-Npolar_surface_area94.83refractivity38.58polarizability16.37rotatable_bond_count4acceptor_count5donor_count3physiological_charge-2formal_charge0Pyruvate metabolismec00620Valine, leucine and isoleucine biosynthesisec00290Metabolic 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::CMs2903Specdb::CMs37502Specdb::CMs151413Specdb::CMs1060692Specdb::CMs1060694Specdb::CMs1060695Specdb::CMs1060697Specdb::CMs1060699Specdb::CMs1060701Specdb::CMs1060703Specdb::CMs1060704Specdb::CMs1060706Specdb::CMs1060708Specdb::CMs1060710Specdb::CMs1060712Specdb::CMs1060714Specdb::NmrOneD1356Specdb::NmrOneD143730Specdb::NmrOneD143731Specdb::NmrOneD143732Specdb::NmrOneD143733Specdb::NmrOneD143734Specdb::NmrOneD143735Specdb::NmrOneD143736Specdb::NmrOneD143737Specdb::NmrOneD143738Specdb::NmrOneD143739Specdb::NmrOneD143740Specdb::NmrOneD143741Specdb::NmrOneD143742Specdb::NmrOneD143743Specdb::NmrOneD143744Specdb::NmrOneD143745Specdb::NmrOneD143746Specdb::NmrOneD143747Specdb::NmrOneD143748Specdb::NmrOneD143749Specdb::MsMs609Specdb::MsMs610Specdb::MsMs611Specdb::MsMs179085Specdb::MsMs179086Specdb::MsMs179087Specdb::MsMs181410Specdb::MsMs181411Specdb::MsMs181412Specdb::MsMs2255126Specdb::MsMs2255436Specdb::MsMs2257079Specdb::MsMs2257527Specdb::MsMs2259078Specdb::MsMs2259470Specdb::MsMs2459287Specdb::MsMs2459288Specdb::MsMs2459289Specdb::MsMs2475479Specdb::MsMs2475480Specdb::MsMs2475481Specdb::NmrTwoD1299HMDB0040252805234444155C0250428635Keseler, 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-D114.22080510Vijayendran, C., Barsch, A., Friehs, K., Niehaus, K., Becker, A., Flaschel, E. (2008). "Perceiving molecular evolution processes in Escherichia coli by comprehensive metabolite and gene expression profiling." Genome Biol 9:R72.18402659van 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 80:2939-2948.18331064Verhaeghe BJ, Van Bocxlaer JF, De Leenheer AP: Gas chromatographic/mass spectrometric identification of 3-hydroxydicarboxylic acids in urine. Biol Mass Spectrom. 1992 Jan;21(1):27-32.1591279Pinkston D, Spiteller G, Von Henning H, Matthaei D: High resolution gas chromatography mass spectrometry of the methyl esters of organic acids from uremic hemofiltrates. J Chromatogr. 1981 Apr 10;223(1):1-19.7251751Schloss J V; Magolda R; Emptage M Synthesis of alpha-isopropylmalate, beta-isopropylmalate, and dimethylcitraconate. Methods in enzymology (1988), 166 92-6. http://hmdb.ca/system/metabolites/msds/000/000/321/original/HMDB00402.pdf?13584616332-isopropylmalate synthaseP09151LEU1_ECOLIleuAhttp://ecmdb.ca/proteins/P09151.xml3-isopropylmalate dehydratase large subunitP0A6A6LEUC_ECOLIleuChttp://ecmdb.ca/proteins/P0A6A6.xml3-isopropylmalate dehydratase small subunitP30126LEUD_ECOLIleuDhttp://ecmdb.ca/proteins/P30126.xmlIsopropylmaleate + Water <> 2-Isopropylmalic acidR03968alpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <> 2-Isopropylmalic acid + Coenzyme A + Hydrogen ionR012132-Isopropylmalic acid + Coenzyme A <> Acetyl-CoA + alpha-Ketoisovaleric acid + WaterR012132-Isopropylmalic acid <> Isopropylmaleate + WaterR03968Acetyl-CoA + a-Ketoisovaleric acid + Water > 2-Isopropylmalic acid + CoAIsopropylmaleate + Water > 2-Isopropylmalic acid3-Isopropylmalate + Isopropylmaleate + Water <> 2-Isopropylmalic acidR10170 3-Methyl-2-oxovaleric acid + Water + Acetyl-CoA + 3-Methyl-2-oxovaleric acid > Coenzyme A + Hydrogen ion + 2-Isopropylmalic acidPW_R0028752-Isopropylmalic acid > Water + IsopropylmaleatePW_R002876alpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <>2 2-Isopropylmalic acid + Coenzyme A + Hydrogen ion