The Catalytic Machinery of a Key Enzyme in Amino Acid Biosynthesis

Abstract

The aspartate pathway of amino acid biosynthesis is essential for all microbial life but is absent in mammals. Characterizing the enzyme-catalyzed reactions in this pathway can identify new protein targets for the development of antibiotics with unique modes of action. The enzyme aspartate β-semialdehyde dehydrogenase (ASADH) catalyzes an early branch point reaction in the aspartate pathway. Kinetic, mutagenic, and structural studies of ASADH from various microbial species have been used to elucidate mechanistic details and to identify essential amino acids involved in substrate binding, catalysis, and enzyme regulation. Important structural and functional differences have been found between ASADHs isolated from these bacterial and fungal organisms, opening the possibility for developing species-specific antimicrobial agents that target this family of enzymes.

Structural Basis for a Bispecific NADP+ and CoA Binding Site in an Archaeal Malonyl-Coenzyme A Reductase

“…1). The presented structural data support this proposal and revealed a remarkable relationship between the active sites of MCR and ASD that allows a direct application of the wealth of structural and mechanistic data available for ASD (13). This high degree of conservation, despite substantial differences of the substrates used, becomes comprehensible when considering similarities between the aspartate and malonate/ succinate and the CoA and NADP ϩ structures as well as between the catalyzed reactions.…”

“…glyceraldehyde-3-phosphate dehydrogenase; however, the physiological role is not known (11,12). An x-ray structure was so far not reported for MCR but for homologous enzymes, with the most related being the well characterized aspartate-␤-semialdehyde dehydrogenase (ASD) (13). However, MCR catalyzes a different reaction, which might implicate significant differences in the active site architecture and the enzymatic mechanism.…”

Systematic Analysis of Intracellular-targeting Antimicrobial Peptides, Bactenecin 7, Hybrid of Pleurocidin and Dermaseptin, Proline–Arginine-rich Peptide, and Lactoferricin B, by Using Escherichia coli Proteome Microarrays

“…Although this process is essential in microorganisms, it is absent in mammals. Thus, this could possibly aid in the development of antibiotics targeting the proteins of the aspartate family amino acid metabolic processes (38,39). The KEGG analysis indicated that the overlapping protein hits of Bac7 and PR-39 were overrepresented in fructose and mannose metabolism and in terpenoid backbone biosynthesis.…”

Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

“…1). 6 It catalyzes the conversion of L-homoserine to O-acetyl-L-homoserine (OAHS) by transfer of an acetyl group from Acetyl-CoA to the γ -hydroxyl of homoserine. This transfer uses a doubledisplacement mechanism facilitated by a Ser-His-Asp catalytic triad.…”