Structural characterization of the aspartate semialdehyde dehydrogenase family of enzymes

Microorganisms utilize aspartic acid as a precursor for the biosynthesis of the essential amino acids lysine, methionine, isoleucine and threonine. Additionally, upstream metabolic intermediates play critical roles in the microorganisms’ survival. Aspartate‐β‐semialdehyde dehydrogenase (ASADH) catalyzes the first branch point of this pathway, the conversion of β‐aspartyl phosphate to aspartate‐β‐semialdehyde. Inhibition of ASADH would shut down the downstream synthesis of these essential products with lethal consequences to infectious bacteria. Since the gene that encodes for ASADH is not present in humans, potent inhibitors could serve as novel antimicrobial compounds with a high degree of selectivity. We have extended our exploration of the diversity in the ASADH family through solved structures of the enzyme from the hyperthermophilic archaea Methanococcus jannaschii ( mj ASADH) and the gram‐positive human pathogen Streptococcus pneumoniae ( sp ASADH). The mj ASADH structure has a similar overall fold to the gram‐negative ASADHs despite a number of insertions and deletions. The entire repertoire of functionally important active site amino acids are conserved, suggesting an identical catalytic mechanism but with lower catalytic efficiency. A new coenzyme binding conformation, dual NAD/NADP coenzyme specificity and an altered intersubunit communication channel further distinguishes the archaeal branch of this enzyme family.