Mycobacterium tuberculosis LeuA3 and related proteins, N-terminal catalytic TIM barrel domain
Alpha-isopropylmalate synthase (LeuA), a key enzyme in leucine biosynthesis, catalyzes the first committed step in the pathway, converting acetyl-CoA and alpha-ketoisovalerate to alpha-isopropyl malate and CoA. Although the reaction catalyzed by LeuA is similar to that of the Arabidopsis thaliana IPMS1 protein, the two fall into phylogenetically distinct families within the same superfamily. LeuA has and N-terminal TIM barrel catalytic domain, a helical linker domain, and a C-terminal regulatory domain. LeuA forms a homodimer in which the linker domain of one monomer sits over the catalytic domain of the other, inserting residues into the active site that may be important for catalysis. Homologs of LeuA are found in bacteria as well as fungi. This family includes alpha-isopropylmalate synthases I (LEU4) and II (LEU9) from Saccharomyces cerevisiae. This family belongs to the DRE-TIM metallolyase superfamily. DRE-TIM metallolyases include 2-isopropylmalate synthase (IPMS), alpha-isopropylmalate synthase (LeuA), 3-hydroxy-3-methylglutaryl-CoA lyase, homocitrate synthase, citramalate synthase, 4-hydroxy-2-oxovalerate aldolase, re-citrate synthase, transcarboxylase 5S, pyruvate carboxylase, AksA, and FrbC. These members all share a conserved triose-phosphate isomerase (TIM) barrel domain consisting of a core beta(8)-alpha(8) motif with the eight parallel beta strands forming an enclosed barrel surrounded by eight alpha helices. The domain has a catalytic center containing a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel. In addition, the catalytic site includes three invariant residues - an aspartate (D), an arginine (R), and a glutamate (E) - which is the basis for the domain name "DRE-TIM".
Jiyao W et al.(2023). "The conserved domain database in 2023.",