| Structural highlights
Function
SRR_HUMAN Catalyzes the synthesis of D-serine from L-serine. D-serine is a key coagonist with glutamate at NMDA receptors. Has dehydratase activity towards both L-serine and D-serine.[1] [2]
Publication Abstract from PubMed
Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR. Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR.
Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase.,Takahara S, Nakagawa K, Uchiyama T, Yoshida T, Matsumoto K, Kawasumi Y, Mizuguchi M, Obita T, Watanabe Y, Hayakawa D, Gouda H, Mori H, Toyooka N Bioorg Med Chem Lett. 2017 Dec 13. pii: S0960-894X(17)31180-0. doi:, 10.1016/j.bmcl.2017.12.021. PMID:29277459[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ De Miranda J, Santoro A, Engelender S, Wolosker H. Human serine racemase: moleular cloning, genomic organization and functional analysis. Gene. 2000 Oct 3;256(1-2):183-8. PMID:11054547
- ↑ Smith MA, Mack V, Ebneth A, Moraes I, Felicetti B, Wood M, Schonfeld D, Mather O, Cesura A, Barker J. The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding. J Biol Chem. 2010 Apr 23;285(17):12873-81. Epub 2010 Jan 27. PMID:20106978 doi:10.1074/jbc.M109.050062
- ↑ Takahara S, Nakagawa K, Uchiyama T, Yoshida T, Matsumoto K, Kawasumi Y, Mizuguchi M, Obita T, Watanabe Y, Hayakawa D, Gouda H, Mori H, Toyooka N. Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase. Bioorg Med Chem Lett. 2017 Dec 13. pii: S0960-894X(17)31180-0. doi:, 10.1016/j.bmcl.2017.12.021. PMID:29277459 doi:http://dx.doi.org/10.1016/j.bmcl.2017.12.021
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