Involvement of subdomain II in the recognition of acetyl‐CoA revealed by the crystal structure of homocitrate synthase from Sulfolobus acidocaldarius

Homocitrate synthase (HCS) catalyzes the aldol condensation of α‐ketoglutarate and acetyl coenzyme A to form homocitrate, which is the first committed step of lysine biosynthesis through the α‐aminoadipate pathway in yeast, fungi, and some prokaryotes. We determined the crystal structure of a truncated form of HCS from a hyperthermophilic acidophilic archaeon, Sulfolobus acidocaldarius, which lacks the RAM (Regulation of amino acid metabolism) domain at the C terminus serving as the regulatory domain for the feedback inhibition by lysine, in complex with α‐ketoglutarate, Mg2+, and CoA. This structure coupled with mutational analysis revealed that a subdomain, subdomain II, connecting the N‐terminal catalytic domain and C‐terminal RAM domain is involved in the recognition of acetyl‐CoA. This is the first structural evidence of the function of subdomain II in the related enzyme family, which will lead to a better understanding of the catalytic mechanism of HCS. Databases Structural data are available in the RCSB PDB database under the accession number 6KTQ. Homocitrate synthase (HCS) catalyzes the aldol condensation of α‐ketoglutarate and acetyl CoA to form homocitrate, which is the first committed step of lysine biosynthesis through α‐aminoadipate pathway in yeast, fungi, and some prokaryotes. We determined the crystal structure of HCS from Sulfolobus acidocaldarius (SaHCS) lacking the RAM domain and revealed that the subdomain II of SaHCS is involved in the recognition of acetyl‐CoA.