Glutamate racemase as a target for drug discovery.
Bottom Line: Glutamate racemase, a member of the cofactor-independent, two-thiol-based family of amino acid racemases, has been implicated in the production and maintenance of sufficient d-glutamate pool levels required for growth.The subject of over four decades of research, it is now evident that the enzyme is conserved and essential for growth across the bacterial kingdom and has a conserved overall topology and active site architecture; however, several different mechanisms of regulation have been observed.These traits have recently been targeted in the discovery of both narrow and broad spectrum inhibitors.
Affiliation: Infection Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Stewart.Fisher@astrazeneca.comShow MeSH
Mentions: The Phase I portion of cell wall biosynthesis has relatively few clinically validated targets but has been the subject of intense discovery efforts over the past decade. Phase I biosynthesis includes the first committed step to peptidoglycan synthesis – conversion of glucosamine‐1‐phosphate to UDP‐N‐acetylglucosamine (UDP‐GlcNAc) – and culminates with the production of UDP‐N‐acetylmuramic acid‐pentapeptide (UDP‐MurNAc‐pentapeptide) (see Fig. 1). A key feature of the peptidoglycan is the incorporation of d‐amino acids, d‐glutamate by the ligase MurD and d‐alanine as a dipeptide formed by d‐ala‐d‐ala ligase, which is a substrate of the ligase MurF. It is presumed that these unusual residues provide a defence against hydrolysis of the bacterial capsule, as host proteases are unable to recognize sequences containing d‐amino acid residues. While there is some variation in the peptide composition of the pentapeptide intermediate, incorporation of d‐glutamate as the second amino acid is strictly conserved (van Heijenoort, 2001). Cellular pool levels of d‐glutamate are derived from l‐glutamate, which are transformed by glutamate racemase, the enzyme implicated in the production and maintenance of d‐glutamate in bacteria that produce a cell wall envelope.
Affiliation: Infection Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Stewart.Fisher@astrazeneca.com