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Mammalian Serine Racemase as a Pharmaceutical Terget
Vaníčková, Jana ; Konvalinka, Jan (advisor) ; Kotora, Martin (referee) ; Křen, Vladimír (referee)
PH.D. DISSERTATION Mammalian Serine Racemase as a Pharmaceutical Target Jana Jirásková Supervisor: Jan Konvalinka Department of Biochemistry Faculty of Science Charles University Institute of Organic Chemistry and Biochemistry Gilead Sciences & IOCB Research Centre Academy of Sciences of the Czech Republic Praha 2010 Introduction Serine racemase is a pyridoxal-5'-phosphate (PLP) -dependent enzyme that is responsible for D- serine production. D-serine is a neurotransmitter that acts, together with L-glutamate, as agonist of ionotropic N-methyl-D-aspartate (NMDA) receptors, which are important for neuronal tissue signalization. Recent serine racemase knock-out mouse studies revealed that SR produces approximately 90% of brain D-serine. SR was first isolated from a pool of rat brains about a decade ago. Its orthologs are present in mammals as well as plants and yeast. Mammalian SRs share high sequence identity, about 90%. Mouse and human SRs are similar enzymatically, suggesting that mouse SR and mouse model are suitable to shed light on human SR. SR forms homodimers in solution and has a molecular weight of approximately 37 kDa per monomer. In addition to pyridoxal-5'-phosphate, the enzyme requires divalent cations such as Ca2+ or Mg2+ , nucleotides such as ATP, and reducing agents for full activity. The...
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