2-isopropylmalate synthase

The enzyme belongs to the family of [[transferase]]s, specifically those [[acyltransferases]] that convert acyl groups into alkyl groups on transfer. The [[List of enzymes|systematic name]] of this enzyme class is ''acetyl-CoA:3-methyl-2-oxobutanoate C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming)''. Other names in common use include ''3-carboxy-3-hydroxy-4-methylpentanoate 3-methyl-2-oxobutanoate-lyase'', ''(CoA-acetylating)'', ''alpha-isopropylmalate synthetase'', ''alpha-isopropylmalate synthase'', ''alpha-isopropylmalic synthetase'', ''isopropylmalate synthase'', and ''isopropylmalate synthetase''. This enzyme participates in biosynthesis of <small>L</small>-[[leucine]] and [[pyruvate metabolism]]. Monovalent and divalent cation activation have been reported for enzymes from different sources.<ref>{{cite journal |vauthors=Cole FE, Kalyanpur MG, Stevens CM | date = 1973 | title = Absolute configuration of alpha isopropylmalate and the mechanism of its conversion to beta isopropylmalate in the biosynthesis of leucine | journal = Biochemistry | volume = 12 | pages = 3346&ndash;50 | pmid = 4270046 | doi = 10.1021/bi00741a031 | issue = 17 }}</ref><ref>{{cite journal |vauthors=Kohlhaw G, Leary TR, Umbarger HE | date = 1969 | title = Alpha-isopropylmalate synthase from Salmonella typhimurium Purification and properties | journal = J. Biol. Chem. | volume = 244 | pages = 2218&ndash;25 | pmid = 4976555 | issue = 8 | doi = 10.1016/S0021-9258(18)97789-6 | doi-access = free }}</ref><ref>{{cite journal |author1=Webster RE |author2=Gross, SR | date = 1965 | title = The alpha-isopropylmalate synthetase of Neurospora. I. The kinetics and end product control of alpha-isopropylmalate synthetase function | journal = Biochemistry | volume = 4 | pages = 2309&ndash;2327 | doi = 10.1021/bi00887a008 | issue = 11 }}</ref>

The enzyme belongs to the family of [[transferase]]s, specifically those [[acyltransferases]] that convert acyl groups into alkyl groups on transfer. The [[List of enzymes|systematic name]] of this enzyme class is ''acetyl-CoA:3-methyl-2-oxobutanoate C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming)''. Other names in common use include ''3-carboxy-3-hydroxy-4-methylpentanoate 3-methyl-2-oxobutanoate-lyase'', ''(CoA-acetylating)'', ''alpha-isopropylmalate synthetase'', ''alpha-isopropylmalate synthase'', ''alpha-isopropylmalic synthetase'', ''isopropylmalate synthase'', and ''isopropylmalate synthetase''. This enzyme participates in biosynthesis of <small>L</small>-[[leucine]] and [[pyruvate metabolism]]. Monovalent and divalent cation activation have been reported for enzymes from different sources.<ref>{{cite journal |vauthors=Cole FE, Kalyanpur MG, Stevens CM | date = 1973 | title = Absolute configuration of alpha isopropylmalate and the mechanism of its conversion to beta isopropylmalate in the biosynthesis of leucine | journal = Biochemistry | volume = 12 | pages = 3346&ndash;50 | pmid = 4270046 | doi = 10.1021/bi00741a031 | issue = 17 }}</ref><ref>{{cite journal |vauthors=Kohlhaw G, Leary TR, Umbarger HE | date = 1969 | title = Alpha-isopropylmalate synthase from Salmonella typhimurium Purification and properties | journal = J. Biol. Chem. | volume = 244 | pages = 2218&ndash;25 | pmid = 4976555 | issue = 8 | doi = 10.1016/S0021-9258(18)97789-6 | doi-access = free }}</ref><ref>{{cite journal |author1=Webster RE |author2=Gross, SR | date = 1965 | title = The alpha-isopropylmalate synthetase of Neurospora. I. The kinetics and end product control of alpha-isopropylmalate synthetase function | journal = Biochemistry | volume = 4 | pages = 2309&ndash;2327 | doi = 10.1021/bi00887a008 | issue = 11 }}</ref>

''[[Mycobacterium tuberculosis]]'' α-isopropylmalate synthase requires a divalent metal ion, of which Mg²⁺ and Mn²⁺ give highest activity, and a monovalent cation, with K⁺ as the best activator.<ref>{{cite journal |vauthors=Carvalho LP, Blanchard, JS | date = 2006 | title = Kinetic and Chemical Mechanism of alpha-Isopropylmalate Synthase from Mycobacterium tuberculosis | journal = Biochemistry | volume = 45 | pages = 8988&ndash;99 | pmid = 16846242 | doi = 10.1021/bi0606602 | issue = 29 | pmc = 2507874 }}</ref><ref>{{cite journal |vauthors=Carvalho LP, Blanchard, JS | date = 2006 | title = Kinetic analysis of the effects of monovalent cations and divalent metals on the activity of Mycobacterium tuberculosis alpha-isopropylmalate synthase | journal = Archives of Biochemistry and Biophysics | volume = 451 | pages = 141&ndash;48 | pmid = 16684501 | doi = 10.1016/j.abb.2006.03.030 | issue = 2 }}</ref> Zn²⁺ was shown to be an inhibitor, contrary to what was assumed from the structural data. Another feature of the ''M. tuberculosis'' homolog is that <small>L</small>-leucine, the feedback inhibitor, inhibits the enzyme in a time-dependent fashion. This was the first demonstration of a feedback inhibitor that displays slow-onset inhibition.<ref>{{cite journal |vauthors=Carvalho LP, Argyrou A, Blanchard, JS | date = 2005 | title = Slow-onset Feedback Inhibition: Inhibition of Mycobacterium tuberculosis alpha-Isopropylmalate Synthase by L-Leucine | journal = Journal of the American Chemical Society | volume = 127 | pages = 10004&ndash;5 | pmid = 16011356 | doi = 10.1021/ja052513h | issue = 28 }}</ref>

''[[Mycobacterium tuberculosis]]'' α-isopropylmalate synthase requires a divalent metal ion, of which Mg²⁺ and Mn²⁺ give highest activity, and a monovalent cation, with K⁺ as the best activator.<ref>{{cite journal |vauthors=Carvalho LP, Blanchard, JS | date = 2006 | title = Kinetic and Chemical Mechanism of alpha-Isopropylmalate Synthase from Mycobacterium tuberculosis | journal = Biochemistry | volume = 45 | pages = 8988&ndash;99 | pmid = 16846242 | doi = 10.1021/bi0606602 | issue = 29 | pmc = 2507874 }}</ref><ref>{{cite journal |vauthors=Carvalho LP, Blanchard, JS | date = 2006 | title = Kinetic analysis of the effects of monovalent cations and divalent metals on the activity of Mycobacterium tuberculosis alpha-isopropylmalate synthase | journal = Archives of Biochemistry and Biophysics | volume = 451 | pages = 141&ndash;48 | pmid = 16684501 | doi = 10.1016/j.abb.2006.03.030 | issue = 2 }}</ref> Zn²⁺ was shown to be an inhibitor, contrary to what was assumed from the structural data. Another feature of the ''M. tuberculosis'' homolog is that <small>L</small>-leucine, the feedback inhibitor, inhibits the enzyme in a time-dependent fashion. This was the first demonstration of a feedback inhibitor that displays slow-onset inhibition.<ref>{{cite journal |vauthors=Carvalho LP, Argyrou A, Blanchard, JS | date = 2005 | title = Slow-onset Feedback Inhibition: Inhibition of Mycobacterium tuberculosis alpha-Isopropylmalate Synthase by L-Leucine | journal = Journal of the American Chemical Society | volume = 127 | pages = 10004&ndash;5 | pmid = 16011356 | doi = 10.1021/ja052513h | issue = 28 | bibcode = 2005JAChS.12710004D }}</ref>

==Tertiary structure==

==Tertiary structure==