%0 Journal Article
%T The Catalytic Machinery of a Key Enzyme in Amino Acid Biosynthesis
%A Ronald E. Viola
%A Christopher R. Faehnle
%A Julio Blanco
%A Roger A. Moore
%A Xuying Liu
%A Buenafe T. Arachea
%A Alexander G. Pavlovsky
%J Journal of Amino Acids
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/352538
%X 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 ¦Â-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. 1. Introduction Enzyme-catalyzed reactions organized into sequential pathways are responsible for producing the molecules needed to sustain life. While many essential metabolic pathways are present in all known life forms, there are also significant differences between microbial and mammalian metabolism. Most microbial species can synthesize all of their important metabolic building block molecules, while mammals must acquire many of these from dietary sources. These metabolic differences provide a substantial number of potential protein targets to be examined for the development of selective antimicrobial agents. There is a growing need to identify effective new antibiotics that function against new targets to combat the expanding threat from pathogenic species that are becoming increasingly resistant to existing antibiotics [1, 2]. There are, however, fundamental problems that must be resolved for effective biocides to be developed against metabolic enzyme targets. Infectious microorganisms often use their host as a source of essential metabolites, thus bypassing inhibitors designed to block key steps in microbial metabolism. In many instances microorganisms have developed alternative routes for the production of important metabolites that can readily bypass inhibited enzyme reactions [3]. Essential enzymatic pathways can also be altered in response to an antibiotic threat. Although these microbial pathways may not exist in mammals, related enzymes with similar active site geometries or substrate binding motifs can potentially interact with even the most carefully designed inhibitors. The structure and mechanism of a bacterial metabolic enzyme must be thoroughly characterized before a potential
%U http://www.hindawi.com/journals/jaa/2011/352538/