2-isopropylmalate synthase

{{Short description|InterPro Family}}

{{infobox enzyme

| Name = 2-isopropylmalate synthase

| EC_number = 2.3.3.13

| CAS_number = 9030-98-2

| GO_code = 0003852

| image =

| width =

| caption =

}}

In enzymology, a 2-isopropylmalate synthase ({{EC number|2.3.3.13}}) is an enzyme that catalyzes the chemical reaction

:acetyl-CoA + 3-methyl-2-oxobutanoate + H₂O $\backslash rightleftharpoons$ (2S)-2-isopropylmalate + CoA

The three substrates of this enzyme are acetyl-CoA, 3-methyl-2-oxobutanoate, and H₂O, and its products are (2S)-2-isopropylmalate and CoA.

The enzyme belongs to the family of transferases, specifically those acyltransferases that convert acyl groups into alkyl groups on transfer. The 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 L-leucine and pyruvate metabolism. Monovalent and divalent cation activation have been reported for enzymes from different sources.{{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 = 3346–50 | pmid = 4270046 | doi = 10.1021/bi00741a031 | issue = 17 }}{{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 = 2218–25 | pmid = 4976555 | issue = 8 | doi = 10.1016/S0021-9258(18)97789-6 | doi-access = free }}{{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 = 2309–2327 | doi = 10.1021/bi00887a008 | issue = 11 }}

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.{{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 = 8988–99 | pmid = 16846242 | doi = 10.1021/bi0606602 | issue = 29 | pmc = 2507874 }}{{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 = 141–48 | pmid = 16684501 | doi = 10.1016/j.abb.2006.03.030 | issue = 2 }} 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 L-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.{{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 = 10004–5 | pmid = 16011356 | doi = 10.1021/ja052513h | issue = 28 }}