1NIU

ALANINE RACEMASE WITH BOUND INHIBITOR DERIVED FROM L-CYCLOSERINE

Summary for 1NIU

• Entry DOI: 10.2210/pdb1niu/pdb
• Related: 1BD0 1EPV 1SFT
• Descriptor: Alanine Racemase, D-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHYL]-N,O-CYCLOSERYLAMIDE (3 entities in total)
• Functional Keywords: tim barrel, plp-containing, isomerase
• Biological source: Geobacillus stearothermophilus
• Total number of polymer chains: 2
• Total formula weight: 88056.61

Authors

Fenn, T.D.,Stamper, G.F.,Morollo, A.A.,Ringe, D. (deposition date: 2002-12-26, release date: 2003-09-16, Last modification date: 2025-03-26)

Primary citation

Fenn, T.D.,Stamper, G.F.,Morollo, A.A.,Ringe, D.
A side reaction of alanine racemase: transamination of cycloserine.
Biochemistry, 42:5775-5783, 2003

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.

PubMed: 12741835
DOI: 10.1021/bi027022d

Experimental method

X-RAY DIFFRACTION (2.2 Å)