2.0 2012-05-31 10:26:35 -0600 2015-09-13 12:56:08 -0600 ECMDB00402 M2MDB000135 2-Isopropylmalic acid 2-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 acid 2-D-Threo-hydroxy-3-carboxy-isocaproate 2-D-Threo-hydroxy-3-carboxy-isocaproic acid 2-Hydroxy-2-isopropylsuccinate 2-Hydroxy-2-isopropylsuccinic acid 2-Isopropyl-2-hydroxybutanedioate 2-Isopropyl-2-hydroxybutanedioic acid 2-Isopropyl-Malate 2-Isopropyl-Malic acid 2-Isopropylmalate 2-Isopropylmalic acid 3-Carboxy-2-hydroxy-4-methylpentanoate 3-Carboxy-2-hydroxy-4-methylpentanoic acid 3-Carboxy-3-hydroxyisocaproate 3-Carboxy-3-hydroxyisocaproic acid 3-Isopropylmalate 3-Isopropylmalic acid A-Isopropylmalate A-Isopropylmalic acid Alpha-Isopropylmalate Alpha-Isopropylmalic acid b-Isopropylmalate b-Isopropylmalic acid Beta-Isopropylmalate Beta-Isopropylmalic acid α-Isopropylmalate α-Isopropylmalic acid β-Isopropylmalate β-Isopropylmalic acid C7H12O5 176.1672 176.068473494 (2S)-2-hydroxy-2-(propan-2-yl)butanedioic acid 2-isopropyl-malic acid 3237-44-3 CC(C)[C@@](O)(CC(O)=O)C(O)=O InChI=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/s1 BITYXLXUCSKTJS-ZETCQYMHSA-N Solid Cytosol Cytosol logp -0.29 ALOGPS logs 0.01 ALOGPS solubility 1.81e+02 g/l ALOGPS melting_point 144-146 oC logp 0.21 ChemAxon pka_strongest_acidic 3.63 ChemAxon pka_strongest_basic -4.1 ChemAxon iupac (2S)-2-hydroxy-2-(propan-2-yl)butanedioic acid ChemAxon average_mass 176.1672 ChemAxon mono_mass 176.068473494 ChemAxon smiles CC(C)[C@@](O)(CC(O)=O)C(O)=O ChemAxon formula C7H12O5 ChemAxon inchi InChI=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/s1 ChemAxon inchikey BITYXLXUCSKTJS-ZETCQYMHSA-N ChemAxon polar_surface_area 94.83 ChemAxon refractivity 38.58 ChemAxon polarizability 16.37 ChemAxon rotatable_bond_count 4 ChemAxon acceptor_count 5 ChemAxon donor_count 3 ChemAxon physiological_charge -2 ChemAxon formal_charge 0 ChemAxon Pyruvate metabolism ec00620 Valine, leucine and isoleucine biosynthesis ec00290 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 2903 Specdb::CMs 37502 Specdb::CMs 151413 Specdb::CMs 1060692 Specdb::CMs 1060694 Specdb::CMs 1060695 Specdb::CMs 1060697 Specdb::CMs 1060699 Specdb::CMs 1060701 Specdb::CMs 1060703 Specdb::CMs 1060704 Specdb::CMs 1060706 Specdb::CMs 1060708 Specdb::CMs 1060710 Specdb::CMs 1060712 Specdb::CMs 1060714 Specdb::NmrOneD 1356 Specdb::NmrOneD 143730 Specdb::NmrOneD 143731 Specdb::NmrOneD 143732 Specdb::NmrOneD 143733 Specdb::NmrOneD 143734 Specdb::NmrOneD 143735 Specdb::NmrOneD 143736 Specdb::NmrOneD 143737 Specdb::NmrOneD 143738 Specdb::NmrOneD 143739 Specdb::NmrOneD 143740 Specdb::NmrOneD 143741 Specdb::NmrOneD 143742 Specdb::NmrOneD 143743 Specdb::NmrOneD 143744 Specdb::NmrOneD 143745 Specdb::NmrOneD 143746 Specdb::NmrOneD 143747 Specdb::NmrOneD 143748 Specdb::NmrOneD 143749 Specdb::MsMs 609 Specdb::MsMs 610 Specdb::MsMs 611 Specdb::MsMs 179085 Specdb::MsMs 179086 Specdb::MsMs 179087 Specdb::MsMs 181410 Specdb::MsMs 181411 Specdb::MsMs 181412 Specdb::MsMs 2255126 Specdb::MsMs 2255436 Specdb::MsMs 2257079 Specdb::MsMs 2257527 Specdb::MsMs 2259078 Specdb::MsMs 2259470 Specdb::MsMs 2459287 Specdb::MsMs 2459288 Specdb::MsMs 2459289 Specdb::MsMs 2475479 Specdb::MsMs 2475480 Specdb::MsMs 2475481 Specdb::NmrTwoD 1299 HMDB00402 5280523 4444155 C02504 28635 Keseler, I. 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Methods in enzymology (1988), 166 92-6. http://hmdb.ca/system/metabolites/msds/000/000/321/original/HMDB00402.pdf?1358461633 2-isopropylmalate synthase P09151 LEU1_ECOLI leuA http://ecmdb.ca/proteins/P09151.xml 3-isopropylmalate dehydratase large subunit P0A6A6 LEUC_ECOLI leuC http://ecmdb.ca/proteins/P0A6A6.xml 3-isopropylmalate dehydratase small subunit P30126 LEUD_ECOLI leuD http://ecmdb.ca/proteins/P30126.xml Isopropylmaleate + Water <> 2-Isopropylmalic acid R03968 alpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <> 2-Isopropylmalic acid + Coenzyme A + Hydrogen ion R01213 2-Isopropylmalic acid + Coenzyme A <> Acetyl-CoA + alpha-Ketoisovaleric acid + Water R01213 2-Isopropylmalic acid <> Isopropylmaleate + Water R03968 Acetyl-CoA + a-Ketoisovaleric acid + Water > 2-Isopropylmalic acid + CoA Isopropylmaleate + Water > 2-Isopropylmalic acid 3-Isopropylmalate + Isopropylmaleate + Water <> 2-Isopropylmalic acid R10170 3-Methyl-2-oxovaleric acid + Water + Acetyl-CoA + 3-Methyl-2-oxovaleric acid > Coenzyme A + Hydrogen ion + 2-Isopropylmalic acid PW_R002875 2-Isopropylmalic acid > Water + Isopropylmaleate PW_R002876 alpha-Ketoisovaleric acid + Acetyl-CoA + Water + a-Ketoisovaleric acid <>2 2-Isopropylmalic acid + Coenzyme A + Hydrogen ion