The Enzyme Database

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EC 1.2.1.25     
Accepted name: branched-chain α-keto acid dehydrogenase system
Reaction: 3-methyl-2-oxobutanoate + CoA + NAD+ = 2-methylpropanoyl-CoA + CO2 + NADH
Other name(s): branched-chain α-keto acid dehydrogenase complex; 2-oxoisovalerate dehydrogenase; α-ketoisovalerate dehydrogenase; 2-oxoisovalerate dehydrogenase (acylating)
Systematic name: 3-methyl-2-oxobutanoate:NAD+ 2-oxidoreductase (CoA-methylpropanoylating)
Comments: This enzyme system catalyses the oxidative decarboxylation of branched-chain α-keto acids derived from L-leucine, L-isoleucine, and L-valine to branched-chain acyl-CoAs. It belongs to the 2-oxoacid dehydrogenase system family, which also includes EC 1.2.1.104, pyruvate dehydrogenase system, EC 1.2.1.105, 2-oxoglutarate dehydrogenase system, EC 1.4.1.27, glycine cleavage system, and EC 2.3.1.190, acetoin dehydrogenase system. With the exception of the glycine cleavage system, which contains 4 components, the 2-oxoacid dehydrogenase systems share a common structure, consisting of three main components, namely a 2-oxoacid dehydrogenase (E1), a dihydrolipoamide acyltransferase (E2), and dihydrolipoamide dehydrogenase (E3). The reaction catalysed by this system is the sum of three activities: EC 1.2.4.4, 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), EC 2.3.1.168, dihydrolipoyllysine-residue (2-methylpropanoyl)transferase, and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The system also acts on (S)-3-methyl-2-oxopentanoate and 4-methyl-2-oxopentanoate.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 37211-61-3
References:
1.  Namba, Y., Yoshizawa, K., Ejima, A., Hayashi, T. and Kaneda, T. Coenzyme A- and nicotinamide adenine dinucleotide-dependent branched chain α-keto acid dehydrogenase. I. Purification and properties of the enzyme from Bacillus subtilis. J. Biol. Chem. 244 (1969) 4437–4447. [PMID: 4308861]
2.  Pettit, F.H., Yeaman, S.J. and Reed, L.J. Purification and characterization of branched chain α-keto acid dehydrogenase complex of bovine kidney. Proc. Natl. Acad. Sci. USA 75 (1978) 4881–4885. [DOI] [PMID: 283398]
3.  Harris, R.A., Hawes, J.W., Popov, K.M., Zhao, Y., Shimomura, Y., Sato, J., Jaskiewicz, J. and Hurley, T.D. Studies on the regulation of the mitochondrial α-ketoacid dehydrogenase complexes and their kinases. Adv. Enzyme Regul. 37 (1997) 271–293. [DOI] [PMID: 9381974]
4.  Evarsson, A., Chuang, J.L., Wynn, R.M., Turley, S., Chuang, D.T. and Hol, W.G. Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Structure 8 (2000) 277–291. [PMID: 10745006]
5.  Reed, L.J. A trail of research from lipoic acid to α-keto acid dehydrogenase complexes. J. Biol. Chem. 276 (2001) 38329–38336. [DOI] [PMID: 11477096]
[EC 1.2.1.25 created 1972, modified 2019, modified 2020]
 
 
EC 1.3.99.12      
Transferred entry: 2-methylacyl-CoA dehydrogenase. Now classified as EC 1.3.8.5, 2-methyl-branched-chain-enoyl-CoA reductase.
[EC 1.3.99.12 created 1986, deleted 2020]
 
 
EC 2.3.1.168     
Accepted name: dihydrolipoyllysine-residue (2-methylpropanoyl)transferase
Reaction: 2-methylpropanoyl-CoA + enzyme N6-(dihydrolipoyl)lysine = CoA + enzyme N6-(S-[2-methylpropanoyl]dihydrolipoyl)lysine
For diagram of oxo-acid-dehydrogenase complexes, click here
Glossary: dihydrolipoyl group
Other name(s): dihydrolipoyl transacylase; enzyme-dihydrolipoyllysine:2-methylpropanoyl-CoA S-(2-methylpropanoyl)transferase; 2-methylpropanoyl-CoA:enzyme-6-N-(dihydrolipoyl)lysine S-(2-methylpropanoyl)transferase
Systematic name: 2-methylpropanoyl-CoA:enzyme-N6-(dihydrolipoyl)lysine S-(2-methylpropanoyl)transferase
Comments: A multimer (24-mer) of this enzyme forms the core of the multienzyme 3-methyl-2-oxobutanoate dehydrogenase complex, and binds tightly both EC 1.2.4.4, 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively 2-methylpropanoylated by EC 1.2.4.4, and the only observed direction catalysed by EC 2.3.1.168 is that where this 2-methylpropanoyl is passed to coenzyme A. In addition to the 2-methylpropanoyl group, formed when EC 1.2.4.4 acts on the oxoacid that corresponds with valine, this enzyme also transfers the 3-methylbutanoyl and S-2-methylbutanoyl groups, donated to it when EC 1.2.4.4 acts on the oxo acids corresponding with leucine and isoleucine.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 102784-26-9
References:
1.  Massey, L.K., Sokatch, J.R. and Conrad, R.S. Branched-chain amino acid catabolism in bacteria. Bacteriol. Rev. 40 (1976) 42–54. [PMID: 773366]
2.  Chuang, D.T., Hu, C.C., Ku, L.S., Niu, W.L., Myers, D.E. and Cox, R.P. Catalytic and structural properties of the dihydrolipoyl transacylase component of bovine branched-chain α-keto acid dehydrogenase. J. Biol. Chem. 259 (1984) 9277–9284. [PMID: 6746648]
3.  Wynn, R.M., Davie, J.R., Zhi, W., Cox, R.P. and Chuang, D.T. In vitro reconstitution of the 24-meric E2 inner core of bovine mitochondrial branched-chain α-keto acid dehydrogenase complex: requirement for chaperonins GroEL and GroES. Biochemistry 33 (1994) 8962–8968. [PMID: 7913832]
4.  Perham, R.N. Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu. Rev. Biochem. 69 (2000) 961–1004. [DOI] [PMID: 10966480]
[EC 2.3.1.168 created 2003]
 
 
EC 2.3.1.300     
Accepted name: branched-chain β-ketoacyl-[acyl-carrier-protein] synthase
Reaction: (1) 3-methylbutanoyl-CoA + a malonyl-[acyl-carrier protein] = a 5-methyl-3-oxohexanoyl-[acyl-carrier-protein] + CoA + CO2
(2) 2-methylpropanoyl-CoA + a malonyl-[acyl-carrier protein] = a 4-methyl-3-oxopentanoyl-[acyl-carrier-protein] + CoA + CO2
(3) (2S)-2-methylbutanoyl-CoA + a malonyl-[acyl-carrier protein] = a (4S)-4-methyl-3-oxohexanoyl-[acyl-carrier-protein] + CoA + CO2
Glossary: 3-methylbutanoyl-CoA = isovaleryl-CoA
2-methylpropanoyl-CoA = isobutanoyl-CoA = isobutyryl-CoA
Systematic name: 3-methylbutanoyl-CoA:malonyl-[acyl-carrier protein] C-acyltransferase
Comments: The enzyme is responsible for initiating branched-chain fatty acid biosynthesis by the dissociated (or type II) fatty-acid biosynthesis system (FAS-II) in some bacteria, using molecules derived from degradation of the branched-chain amino acids L-leucine, L-valine, and L-isoleucine to form the starting molecules for elongation by the FAS-II system. In some organisms the enzyme is also able to use acetyl-CoA, leading to production of a mix of branched-chain and straight-chain fatty acids [3] (cf. EC 2.3.1.180, β-ketoacyl-[acyl-carrier-protein] synthase III).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Han, L., Lobo, S. and Reynolds, K.A. Characterization of β-ketoacyl-acyl carrier protein synthase III from Streptomyces glaucescens and its role in initiation of fatty acid biosynthesis. J. Bacteriol. 180 (1998) 4481–4486. [DOI] [PMID: 9721286]
2.  Choi, K.H., Heath, R.J. and Rock, C.O. β-ketoacyl-acyl carrier protein synthase III (FabH) is a determining factor in branched-chain fatty acid biosynthesis. J. Bacteriol. 182 (2000) 365–370. [DOI] [PMID: 10629181]
3.  Khandekar, S.S., Gentry, D.R., Van Aller, G.S., Warren, P., Xiang, H., Silverman, C., Doyle, M.L., Chambers, P.A., Konstantinidis, A.K., Brandt, M., Daines, R.A. and Lonsdale, J.T. Identification, substrate specificity, and inhibition of the Streptococcus pneumoniae β-ketoacyl-acyl carrier protein synthase III (FabH). J. Biol. Chem. 276 (2001) 30024–30030. [DOI] [PMID: 11375394]
4.  Singh, A.K., Zhang, Y.M., Zhu, K., Subramanian, C., Li, Z., Jayaswal, R.K., Gatto, C., Rock, C.O. and Wilkinson, B.J. FabH selectivity for anteiso branched-chain fatty acid precursors in low-temperature adaptation in Listeria monocytogenes. FEMS Microbiol. Lett. 301 (2009) 188–192. [DOI] [PMID: 19863661]
5.  Yu, Y.H., Hu, Z., Dong, H.J., Ma, J.C. and Wang, H.H. Xanthomonas campestris FabH is required for branched-chain fatty acid and DSF-family quorum sensing signal biosynthesis. Sci. Rep. 6:32811 (2016). [DOI] [PMID: 27595587]
[EC 2.3.1.300 created 2021]
 
 
EC 3.1.2.4     
Accepted name: 3-hydroxyisobutyryl-CoA hydrolase
Reaction: 3-hydroxy-2-methylpropanoyl-CoA + H2O = CoA + 3-hydroxy-2-methylpropanoate
Other name(s): 3-hydroxy-isobutyryl CoA hydrolase; HIB CoA deacylase
Systematic name: 3-hydroxy-2-methylpropanoyl-CoA hydrolase
Comments: Also hydrolyses 3-hydroxypropanoyl-CoA.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9025-88-1
References:
1.  Rendina, G. and Coon, M.J. Enzymatic hydrolysis of the coenzyme A thiol esters of β-hydroxypropionic and β-hydroxyisobutyric acids. J. Biol. Chem. 225 (1957) 523–534. [PMID: 13457352]
[EC 3.1.2.4 created 1961]
 
 
EC 5.4.99.13     
Accepted name: isobutyryl-CoA mutase
Reaction: 2-methylpropanoyl-CoA = butanoyl-CoA
Glossary: pivalate = 2,2-dimethylpropanoate
Other name(s): isobutyryl coenzyme A mutase; butyryl-CoA:isobutyryl-CoA mutase; icmA (gene name); icmB (gene name); icmF (gene name)
Systematic name: 2-methylpropanoyl-CoA CoA-carbonylmutase
Comments: This bacterial enzyme utilizes 5′-deoxyadenosylcobalamin as a cofactor. Following substrate binding, the enzyme catalyses the homolytic cleavage of the cobalt-carbon bond of AdoCbl, yielding cob(II)alamin and a 5′-deoxyadenosyl radical, which initiates the the carbon skeleton rearrangement reaction by hydrogen atom abstraction from the substrate. At the end of each catalytic cycle the 5′-deoxyadenosyl radical and cob(II)alamin recombine, regenerating the resting form of the cofactor. The enzyme is prone to inactivation resulting from occassional loss of the 5′-deoxyadenosyl molecule. Inactivated enzymes are repaired by the action of EC 2.5.1.17, cob(I)yrinic acid a,c-diamide adenosyltransferase, and a G-protein chaperone, which restore cob(II)alamin (which is first reduced to cob(I)alamin by an unidentified reductase) to 5′-deoxyadenosylcobalamin and load it back on the mutase. Some mutases are fused with their G-protein chaperone. These enzyme can also catalyse the interconversion of isovaleryl-CoA with pivalyl-CoA.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 116405-23-3
References:
1.  Brendelberger, G., Rétey, J., Ashworth, D.M., Reynolds, K., Willenbrock, F. and Robinson, J.A. The enzymic interconversion of isobutyryl and N-butyrylcarba(dethia)-coenzyme-A - a coenzyme-B12-dependent carbon skeleton rearrangement. Angew. Chem. Int. Ed. Engl. 27 (1988) 1089–1091.
2.  Ratnatilleke, A., Vrijbloed, J.W. and Robinson, J.A. Cloning and sequencing of the coenzyme B12-binding domain of isobutyryl-CoA mutase from Streptomyces cinnamonensis, reconstitution of mutase activity, and characterization of the recombinant enzyme produced in Escherichia coli. J. Biol. Chem. 274 (1999) 31679–31685. [DOI] [PMID: 10531377]
3.  Cracan, V., Padovani, D. and Banerjee, R. IcmF is a fusion between the radical B12 enzyme isobutyryl-CoA mutase and its G-protein chaperone. J. Biol. Chem. 285 (2010) 655–666. [DOI] [PMID: 19864421]
4.  Cracan, V. and Banerjee, R. Novel coenzyme B12-dependent interconversion of isovaleryl-CoA and pivalyl-CoA. J. Biol. Chem. 287 (2012) 3723–3732. [DOI] [PMID: 22167181]
5.  Jost, M., Born, D.A., Cracan, V., Banerjee, R. and Drennan, C.L. Structural basis for substrate specificity in adenosylcobalamin-dependent isobutyryl-CoA mutase and related acyl-CoA mutases. J. Biol. Chem. 290 (2015) 26882–26898. [DOI] [PMID: 26318610]
6.  Li, Z., Kitanishi, K., Twahir, U.T., Cracan, V., Chapman, D., Warncke, K. and Banerjee, R. Cofactor editing by the G-protein metallochaperone domain regulates the radical B12 enzyme IcmF. J. Biol. Chem. 292 (2017) 3977–3987. [DOI] [PMID: 28130442]
[EC 5.4.99.13 created 1992, revised 2017]
 
 
EC 5.4.99.64     
Accepted name: 2-hydroxyisobutanoyl-CoA mutase
Reaction: 2-hydroxy-2-methylpropanoyl-CoA = (S)-3-hydroxybutanoyl-CoA
Glossary: 2-hydroxy-2-methylpropanoyl-CoA = 2-hydroxyisobutanoyl-CoA
Other name(s): hcmAB (gene names)
Systematic name: 2-hydroxy-2-methylpropanoyl-CoA mutase
Comments: The enzyme, characterized from the bacterium Aquincola tertiaricarbonis, uses radical chemistry to rearrange the positions of both a methyl group and a hydroxyl group. It consists of two subunits, the smaller one containing a cobalamin cofactor. It plays a central role in the degradation of assorted substrates containing a tert-butyl moiety.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Yaneva, N., Schuster, J., Schafer, F., Lede, V., Przybylski, D., Paproth, T., Harms, H., Muller, R.H. and Rohwerder, T. Bacterial acyl-CoA mutase specifically catalyzes coenzyme B12-dependent isomerization of 2-hydroxyisobutyryl-CoA and (S)-3-hydroxybutyryl-CoA. J. Biol. Chem. 287 (2012) 15502–15511. [DOI] [PMID: 22433853]
2.  Kurteva-Yaneva, N., Zahn, M., Weichler, M.T., Starke, R., Harms, H., Muller, R.H., Strater, N. and Rohwerder, T. Structural basis of the stereospecificity of bacterial B12-dependent 2-hydroxyisobutyryl-CoA mutase. J. Biol. Chem. 290 (2015) 9727–9737. [DOI] [PMID: 25720495]
[EC 5.4.99.64 created 2016 as EC 5.3.3.20, transferred 2017 to EC 5.4.99.64]
 
 


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