Isopropylmalate

Isopropylmalate is a metabolic intermediate in the biosynthesis of the essential amino acid leucine in many bacteria, fungi, and plants. In the isopropylmalate pathway, acetyl-CoA condenses with α-ketoisovalerate under the action of isopropylmalate synthase to form 2-isopropylmalate. The molecule is then rearranged by isopropylmalate isomerase to yield 3-isopropylmalate, which is subsequently oxidatively decarboxylated by isopropylmalate dehydrogenase to α-ketoisocaproate. A transamination step then produces leucine. This sequence extends the carbon skeleton relative to α-ketoisovalerate, delivering the leucine backbone.

Genetics and regulation of the pathway are well characterized. The enzymes are encoded by leuA (isopropylmalate synthase), leuC and leuD (isopropylmalate isomerase), and leuB (isopropylmalate dehydrogenase). Leucine often exerts feedback inhibition on isopropylmalate synthase, providing regulatory control of the pathway in many organisms. The proteins are typically cytosolic in microbes and plants, reflecting their role in primary metabolism and amino acid production.

Relevance and applications include its use in studies of amino acid biosynthesis and in metabolic engineering to alter leucine production. Isopropylmalate and related intermediates are substrates and indicators in research on branched-chain amino acid metabolism, with flux through the pathway influencing overall carbon flow toward leucine.