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Bioorg Med Chem Lett. 2014 Jan 1;24(1):390-3. doi: 10.1016/j.bmcl.2013.10.061. Epub 2013 Nov 4.

Inhibition of serine and proline racemases by substrate-product analogues.

Author information

1
Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
2
Department of Chemistry, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, Canada.
3
Department of Chemistry, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, Canada. Electronic address: dderksen@stfx.ca.
4
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.

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.

KEYWORDS:

Inhibition; Racemases; Substrate-product analogues; d-Proline; d-Serine

PMID:
24314397
DOI:
10.1016/j.bmcl.2013.10.061
[Indexed for MEDLINE]

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