title: Inhibition of serine and proline racemases by substrate-product analogues.
abstract: d-Amino acids can play important roles as specific biosynthetic building blocks required by organisms or act as regulatory molecules. Consequently, amino acid racemases that catalyze the formation of d-amino acids are potential therapeutic targets. Serine racemase catalyzes the reversible formation of d-serine (a modulator of neurotransmission) from l-serine, while proline racemase (an essential enzymatic and mitogenic protein in trypanosomes) catalyzes the reversible conversion of l-proline to d-proline. We show the substrate-product analogue α-(hydroxymethyl)serine is a modest, linear mixed-type inhibitor of serine racemase from Schizosaccharomyces pombe (Ki=167±21mM, Ki'=661±81mM, cf. Km=19±2mM). The bicyclic substrate-product analogue of proline, 7-azabicyclo[2.2.1]heptan-7-ium-1-carboxylate is a weak inhibitor of proline racemase from Clostridium sticklandii, giving only 29% inhibition at 142.5mM. However, the more flexible bicyclic substrate-product analogue tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate is a noncompetitive inhibitor of proline racemase from C. sticklandii (Ki=111±15mM, cf. Km=5.7±0.5mM). These results suggest that substrate-product analogue inhibitors of racemases may only be effective when the active site is capacious and/or plastic, or when the inhibitor is sufficiently flexible.
authors: Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors: Matthew
authors: M
authors: Harty
authors: Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors: Mitesh
authors: M
authors: Nagar
authors: Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors: Logan
authors: L
authors: Atkinson
authors: Department of Chemistry, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, Canada.
authors: Christina M
authors: CM
authors: Legay
authors: Department of Chemistry, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, Canada. Electronic address: dderksen@stfx.ca.
authors: Darren J
authors: DJ
authors: Derksen
authors: Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada; Department of Chemistry, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada. Electronic address: sbearne@dal.ca.
authors: Stephen L
authors: SL
authors: Bearne
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047991:Acetoanaerobium sticklandii / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology; D012694:Serine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099300:Serine Racemase
chemical_list: D000591:Amino Acid Isomerases; D004791:Enzyme Inhibitors; D011392:Proline; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase; C588121:alpha-(hydroxymethyl)serine; C022451:proline racemase
keywords: Inhibition; Racemases; Substrate-product analogues; d-Proline; d-Serine