A side reaction of alanine racemase: transamination of cycloserine.

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Fenn TD, Stamper GF, Morollo AA, Ringe D

A side reaction of alanine racemase: transamination of cycloserine.

Biochemistry. 2003 May 20;42(19):5775-83.

PubMed ID

12741835 [ View in PubMed

]

Abstract

Alanine racemase (EC 5.1.1.1) catalyzes the interconversion of alanine enantiomers, and thus represents the first committed step involved in bacterial cell wall biosynthesis. Cycloserine acts as a suicide inhibitor of alanine racemase and as such, serves as an antimicrobial agent. The chemical means by which cycloserine inhibits alanine racemase is unknown. Through spectroscopic assays, we show here evidence of a pyridoxal derivative (arising from either isomer of cycloserine) saturated at the C4' carbon position. We additionally report the L- and D-cycloserine inactivated crystal structures of Bacillus stearothermophilus alanine racemase, which corroborates the spectroscopy via evidence of a 3-hydroxyisoxazole pyridoxamine derivative. Upon the basis of the kinetic and structural properties of both the L- and D-isomers of the inhibitor, we propose a mechanism of alanine racemase inactivation by cycloserine. This pathway involves an initial transamination step followed by tautomerization to form a stable aromatic adduct, a scheme similar to that seen in cycloserine inactivation of aminotransferases.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cycloserine	Alanine racemase	Protein	Mycobacterium avium	Yes	Inhibitor	Details

Polypeptides

Name	UniProt ID
Alanine racemase	P10724	Details