Inhibition of serine and proline racemases by substrate-product analogues

• Published in: Bioorganic & medicinal chemistry letters 2014-01, Vol.24 (1), p.390-393
• Main Authors: Harty, Matthew, Nagar, Mitesh, Atkinson, Logan, Legay, Christina M, Derksen, Darren J, Bearne, Stephen L
• Format: Article
• Language: English
• Subjects: Amino Acid Isomerases - antagonists & inhibitors; Amino Acid Isomerases - metabolism; Amino acids; Clostridium sticklandii; Clostridium sticklandii - enzymology; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Models, Molecular; Molecular Structure; Proline - analogs & derivatives; Proline - chemistry; Proline - pharmacology; Racemases and Epimerases - antagonists & inhibitors; Racemases and Epimerases - metabolism; Schizosaccharomyces - enzymology; Serine - analogs & derivatives; Serine - chemical synthesis; Serine - chemistry; Serine - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.10.061

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.