2.0 2012-05-31 13:00:31 -0600 2015-09-13 12:56:08 -0600 ECMDB00695 M2MDB000174 Ketoleucine Ketoleucine belongs to the class of Branched Fatty Acids. These are fatty acids containing a branched chain. (inferred from compound structure) Ketoleucine is also known by names such as 4-methyl-2-oxopentanoic acid and 2-Oxoisocaproic acid. (PubChem) In E. coli, the enzyme branched-chain amino acid aminotransferase (EC:2.6.1.42) catalyses the reversible conversion between ketoleucine and L-leucine. (KEGG) &alpha;-ketoisocaproate &alpha;-ketoisocaproic acid &alpha;-oxoisocaproate &alpha;-oxoisocaproic acid 2-Keto-4-methyl-pentanoate 2-Keto-4-methyl-pentanoic acid 2-Keto-4-Methylvalerate 2-Keto-4-Methylvaleric acid 2-Ketoisocaproate 2-Ketoisocaproic acid 2-Oxo-4-methylpentanoate 2-Oxo-4-methylpentanoic acid 2-Oxo-4-methylvalerate 2-Oxo-4-methylvaleric acid 2-Oxoisocaproate 2-Oxoisocaproic acid 2-Oxoleucine 2KICA 4-Methyl-2-oxo-Valerate 4-Methyl-2-oxo-Valeric acid 4-Methyl-2-oxopentanoate 4-Methyl-2-oxopentanoic acid a-keto-Isocaproate a-keto-Isocaproic acid A-Ketoisocaproate A-Ketoisocaproic acid A-Ketoisocapronate A-Ketoisocapronic acid A-Oxoisocaproate A-Oxoisocaproic acid Alpha-keto-isocaproate Alpha-keto-isocaproic acid alpha-Ketoisocaproate alpha-Ketoisocaproic acid Alpha-Ketoisocapronate Alpha-Ketoisocapronic acid alpha-Oxoisocaproate alpha-Oxoisocaproic acid Ketoisocaproate Ketoisocaproic acid Methyloxovalerate Methyloxovaleric acid Oxoisocaproate Oxoisocaproic acid α-keto-Isocaproate α-keto-Isocaproic acid α-Ketoisocaproate α-Ketoisocaproic acid α-Ketoisocapronate α-Ketoisocapronic acid α-Oxoisocaproate α-Oxoisocaproic acid C6H10O3 130.1418 130.062994186 4-methyl-2-oxopentanoic acid ketoisocaproate 816-66-0 CC(C)CC(=O)C(O)=O InChI=1S/C6H10O3/c1-4(2)3-5(7)6(8)9/h4H,3H2,1-2H3,(H,8,9) BKAJNAXTPSGJCU-UHFFFAOYSA-N Liquid Cytosol logp 0.82 ALOGPS logs -1.28 ALOGPS solubility 6.76e+00 g/l ALOGPS melting_point 8-10 oC logp 1.5 ChemAxon pka_strongest_acidic 3.53 ChemAxon pka_strongest_basic -9.7 ChemAxon iupac 4-methyl-2-oxopentanoic acid ChemAxon average_mass 130.1418 ChemAxon mono_mass 130.062994186 ChemAxon smiles CC(C)CC(=O)C(O)=O ChemAxon formula C6H10O3 ChemAxon inchi InChI=1S/C6H10O3/c1-4(2)3-5(7)6(8)9/h4H,3H2,1-2H3,(H,8,9) ChemAxon inchikey BKAJNAXTPSGJCU-UHFFFAOYSA-N ChemAxon polar_surface_area 54.37 ChemAxon refractivity 31.77 ChemAxon polarizability 13 ChemAxon rotatable_bond_count 3 ChemAxon acceptor_count 3 ChemAxon donor_count 1 ChemAxon physiological_charge -1 ChemAxon formal_charge 0 ChemAxon Valine, leucine and isoleucine biosynthesis ec00290 C5-Branched dibasic acid metabolism ec00660 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 Glucosinolate biosynthesis ec00966 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 612 Specdb::CMs 613 Specdb::CMs 614 Specdb::CMs 977 Specdb::CMs 981 Specdb::CMs 992 Specdb::CMs 3139 Specdb::CMs 30330 Specdb::CMs 30331 Specdb::CMs 30582 Specdb::CMs 31194 Specdb::CMs 31195 Specdb::CMs 31196 Specdb::CMs 31979 Specdb::CMs 31980 Specdb::CMs 37700 Specdb::CMs 133547 Specdb::CMs 141281 Specdb::CMs 1072489 Specdb::CMs 1072491 Specdb::CMs 1072493 Specdb::NmrOneD 1483 Specdb::NmrOneD 4878 Specdb::NmrOneD 4879 Specdb::NmrOneD 20582 Specdb::NmrOneD 20583 Specdb::NmrOneD 20584 Specdb::NmrOneD 20585 Specdb::NmrOneD 20586 Specdb::NmrOneD 20587 Specdb::NmrOneD 20588 Specdb::NmrOneD 20589 Specdb::NmrOneD 20590 Specdb::NmrOneD 20591 Specdb::NmrOneD 20592 Specdb::NmrOneD 20593 Specdb::NmrOneD 20594 Specdb::NmrOneD 20595 Specdb::NmrOneD 20596 Specdb::NmrOneD 20597 Specdb::NmrOneD 20598 Specdb::NmrOneD 20599 Specdb::NmrOneD 20600 Specdb::NmrOneD 20601 Specdb::MsMs 966 Specdb::MsMs 967 Specdb::MsMs 968 Specdb::MsMs 4433 Specdb::MsMs 4434 Specdb::MsMs 4435 Specdb::MsMs 4436 Specdb::MsMs 4437 Specdb::MsMs 20990 Specdb::MsMs 20991 Specdb::MsMs 20992 Specdb::MsMs 22541 Specdb::MsMs 22542 Specdb::MsMs 22543 Specdb::MsMs 438060 Specdb::MsMs 438061 Specdb::MsMs 438062 Specdb::MsMs 438063 Specdb::MsMs 438064 Specdb::MsMs 438620 Specdb::MsMs 438660 Specdb::MsMs 2226717 Specdb::MsMs 2227984 Specdb::MsMs 2229073 Specdb::MsMs 2230396 Specdb::NmrTwoD 1429 HMDB00695 70 69 C00233 48430 2K-4CH3-PENTANOATE COI Keseler, I. 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Anal Chem. 1991 May 1;63(9):919-23. 1858984 http://hmdb.ca/system/metabolites/msds/000/000/614/original/HMDB00695.pdf?1358461903 Aromatic-amino-acid aminotransferase P04693 TYRB_ECOLI tyrB http://ecmdb.ca/proteins/P04693.xml 3-isopropylmalate dehydrogenase P30125 LEU3_ECOLI leuB http://ecmdb.ca/proteins/P30125.xml Branched-chain-amino-acid aminotransferase P0AB80 ILVE_ECOLI ilvE http://ecmdb.ca/proteins/P0AB80.xml Ketoleucine + L-Glutamate > alpha-Ketoglutarate + L-Leucine 2-Isopropyl-3-oxosuccinate + Hydrogen ion > Ketoleucine + Carbon dioxide RXN-7800 L-Leucine + Oxoglutaric acid <> Ketoleucine + L-Glutamate BRANCHED-CHAINAMINOTRANSFERLEU-RXN L-Leucine + Oxoglutaric acid > Ketoleucine + L-Glutamate 3-Isopropylmalate + NAD > Ketoleucine + Carbon dioxide + NADH L-Leucine + alpha-Ketoglutarate <> 4-Methyl-2-oxopentanoate + L-Glutamate + Ketoleucine R01090 3-Isopropylmalate + NAD + 2-Isopropyl-3-oxosuccinate <> Ketoleucine + Carbon dioxide + NADH + Hydrogen ion R10052 Ketoleucine + L-Glutamic acid + L-Glutamate > Oxoglutaric acid + L-Leucine PW_R002881