Mechanism of substrate recognition and insight into feedback inhibition of homocitrate synthase from thermus thermophilus

摘要: Homocitrate synthase (HCS) catalyzes aldol-type condensation of acetyl coenzyme A (acetyl-CoA) and α-ketoglutarate (α-KG) to synthesize homocitrate (HC), which is the first committed step in lysine biosynthetic pathway through α-aminoadipate. As known most enzymes catalyzing reactions amino acid pathways, HCS regulated via feedback inhibition by end product, lysine. Here, we determined crystal structures from Thermus thermophilus complexed with α-KG, HC, or In HC complex, C1-carboxyl group derived acetyl-CoA, hydrogen-bonded His-292* another subunit (indicated asterisk), indicating direct involvement this residue catalytic mechanism HCS. The structure showed that bound active site rearrangement residues substrate-binding site, accounts for competitive α-KG. Comparison between suggests His-72, conserved lysine-sensitive HCSs binds C5-carboxyl serves as a switch conformational change. Replacement His-72 leucine made resistant inhibition, demonstrating regulatory role residue.