InterPro domain: IPR005671

The branched-chain amino acids are synthesised by a common pathway that leads from pyruvate and alpha-ketobutyrate to valine and isoleucine, and a branch that leads from the immediate precursor of valine, alpha-ketoisovalerate, to leucine [ 1 ]. This pathway operates in archaea, bacteria, fungi and plants, but not mammals, making the enzymes suitable targets for the development of novel antibiotics and herbicides.

Isopropylmalate synthase is the enzyme responsible for the the first committed step in the leucine branch of this biosynthetic pathway, the conversion of alpha-ketoisovalerate to alpha-isopropylmalate. It is either dimeric or tetrameric, depending on the organism, with a monomer molecular mass of 60-70kDa, a dependence on divalent metal ions for activity, and an alkaline pH optimum [ 2 , 3 , 4 , 5 ]. Like many other biosynthetic enzymes it is subject to feedback inhibition by the end product of the pathway, leucine.

This entry represents the isopropylmalate synthase most commonly found in bacteria. A related form of this enzyme is found mainly in eukaryotes and some other bacteria ( IPR005668 ). A homologous family in archaea may represent isozymes and/or related enzymes ( IPR005675 ).

1. Leucine biosynthesis in fungi: entering metabolism through the back door. Microbiol. Mol. Biol. Rev. 67, 1-15, table of contents
2. -isopropylmalate synthase from Salmonella typhimurium. Analysis of the guaternary structure and its relation to function. J. Biol. Chem. 247, 1089-95
3. Leucine synthesis in Corynebacterium glutamicum: enzyme activities, structure of leuA, and effect of leuA inactivation on lysine synthesis. Appl. Environ. Microbiol. 60, 133-40
4. End-product control of enzymes of branched-chain amino acid biosynthesis in Streptomyces coelicolor. Microbiology (Reading, Engl.) 142 ( Pt 8), 1945-52
5. Crystal structure of LeuA from Mycobacterium tuberculosis, a key enzyme in leucine biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 101, 8295-300