Serine racemase (SR, EC 5.1.1.18) is the first racemase enzyme in human biology to be identified. This enzyme converts L-serine to its enantiomer form, D-serine. D-serine acts as a neuronal signaling molecule by activating NMDA receptors in the brain.
Since NMDA receptors Dysfunction has been suggested as one of the promising hypotheses for the pathophysiology of schizophrenia, it has been shown that underexpression of this enzyme is an indicator, especially for the paranoid subtype.[5] Treatment of schizophrenia with D-serine has been shown to play some role in ameliorating some symptoms.[6]
In humans, the serine racemase protein is encoded by the SRR gene.[7] Serine racemase may have evolved from L-thre-hydroxyaspartate (L-THA) eliminase and served as the precursor to aspartate racemase.[8]
Mammalian serine racemase is a pyridoxal 5'-phosphate dependent enzyme that catalyzes both the racemization of L-serine to D-serine and also the elimination of water from L-serine, generating pyruvate and ammonia through the β-elimination of L-serine.[9] This makes serine a known bifurcating enzyme. The β-elimination pathway is thought to serve as a bleed valve that allows local stores of L-serine to be diverted away from D-serine as a means of muting the D-serine signaling pathway. The canonical tetraglycine loop that serves as a PLP phosphate binding pocket includes the active residues being F55, K56, G185, G186, G187, G188, and S313.[8]
The enzyme is physiologically stimulated by divalent cations (e.g., magnesium) and is allosterically activated by the magnesium/ATP complex, associated with a conformational change upon nucleotide binding that depends upon interactions with Q89. The canonical coordination sphere of the divalent cation interaction site includes the active residues E210 and D216 within 2.1 angstroms of the ion.[8]
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References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000167720 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001323 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Morita, Yukitaka; Ujike, Hiroshi; Tanaka, Yuji; Otani, Kyohei; Kishimoto, Makiko; Morio, Akiko; Kotaka, Tatsuya; Okahisa, Yuko; Matsushita, Masayuki; Morikawa, Akiko; Hamase, Kenji (May 2007). "A Genetic Variant of the Serine Racemase Gene Is Associated with Schizophrenia". Biological Psychiatry. 61 (10): 1200–1203. doi:10.1016/j.biopsych.2006.07.025. PMID 17067558. S2CID 8142062.
- ^ Fujii, K; Maeda, K; Hikida, T; Mustafa, A K; Balkissoon, R; Xia, J; Yamada, T; Ozeki, Y; Kawahara, R; Okawa, M; Huganir, R L (2006-02-01). "Serine racemase binds to PICK1: potential relevance to schizophrenia". Molecular Psychiatry. 11 (2): 150–157. doi:10.1038/sj.mp.4001776. ISSN 1359-4184. PMID 16314870. S2CID 23387084.
- ^ De Miranda J, Santoro A, Engelender S, Wolosker H (Oct 2000). "Human serine racemase: moleular cloning, genomic organization and functional analysis". Gene. 256 (1–2): 183–8. doi:10.1016/S0378-1119(00)00356-5. PMID 11054547.
- ^ a b c Graham, Danielle L.; Beio, Matthew L.; Nelson, David L.; Berkowitz, David B. (2019-03-13). "Human Serine Racemase: Key Residues/Active Site Motifs and Their Relation to Enzyme Function". Frontiers in Molecular Biosciences. 6: 8. doi:10.3389/fmolb.2019.00008. ISSN 2296-889X. PMC 6424897. PMID 30918891.
- ^ De Miranda J, Panizzutti R, Foltyn VN, Wolosker H (Oct 2002). "Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14542–7. Bibcode:2002PNAS...9914542D. doi:10.1073/pnas.222421299. PMC 137919. PMID 12393813.
Further reading
- Morita Y, Ujike H, Tanaka Y, Otani K, Kishimoto M, Morio A, Kotaka T, Okahisa Y, Matsushita M, Morikawa A, Hamase K, Zaitsu K, Kuroda S (May 2007). "A genetic variant of the serine racemase gene is associated with schizophrenia". Biological Psychiatry. 61 (10): 1200–3. doi:10.1016/j.biopsych.2006.07.025. PMID 17067558. S2CID 8142062.
- Steffek AE, Haroutunian V, Meador-Woodruff JH (Jul 2006). "Serine racemase protein expression in cortex and hippocampus in schizophrenia". NeuroReport. 17 (11): 1181–5. doi:10.1097/01.wnr.0000230512.01339.72. PMID 16837850. S2CID 35663584.
- Fujii K, Maeda K, Hikida T, Mustafa AK, Balkissoon R, Xia J, Yamada T, Ozeki Y, Kawahara R, Okawa M, Huganir RL, Ujike H, Snyder SH, Sawa A (Feb 2006). "Serine racemase binds to PICK1: potential relevance to schizophrenia". Molecular Psychiatry. 11 (2): 150–7. doi:10.1038/sj.mp.4001776. PMID 16314870. S2CID 23387084.
- Dumin E, Bendikov I, Foltyn VN, Misumi Y, Ikehara Y, Kartvelishvily E, Wolosker H (Jul 2006). "Modulation of D-serine levels via ubiquitin-dependent proteasomal degradation of serine racemase". The Journal of Biological Chemistry. 281 (29): 20291–302. doi:10.1074/jbc.M601971200. PMID 16714286.
- Strísovský K, Jirásková J, Barinka C, Majer P, Rojas C, Slusher BS, Konvalinka J (Jan 2003). "Mouse brain serine racemase catalyzes specific elimination of L-serine to pyruvate". FEBS Letters. 535 (1–3): 44–8. doi:10.1016/s0014-5793(02)03855-3. PMID 12560076. S2CID 43772379.
- Hoffman HE, Jirásková J, Ingr M, Zvelebil M, Konvalinka J (Jan 2009). "Recombinant human serine racemase: enzymologic characterization and comparison with its mouse ortholog". Protein Expression and Purification. 63 (1): 62–7. doi:10.1016/j.pep.2008.09.003. PMID 18812225.
- Sarras H, Semeralul MO, Fadel MP, Feldcamp LA, Labrie V, Wong AH (Jul 2010). "Elevated PICK1 mRNA in schizophrenia increased SRR mRNA in suicide". Schizophrenia Research. 120 (1–3): 236–7. doi:10.1016/j.schres.2010.03.002. PMID 20385472. S2CID 21820692.
- Yamada K, Ohnishi T, Hashimoto K, Ohba H, Iwayama-Shigeno Y, Toyoshima M, Okuno A, Takao H, Toyota T, Minabe Y, Nakamura K, Shimizu E, Itokawa M, Mori N, Iyo M, Yoshikawa T (Jun 2005). "Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels". Biological Psychiatry. 57 (12): 1493–503. doi:10.1016/j.biopsych.2005.03.018. PMID 15953485. S2CID 22811942.
- Xia M, Liu Y, Figueroa DJ, Chiu CS, Wei N, Lawlor AM, Lu P, Sur C, Koblan KS, Connolly TM (Jun 2004). "Characterization and localization of a human serine racemase". Brain Research. Molecular Brain Research. 125 (1–2): 96–104. doi:10.1016/j.molbrainres.2004.03.007. PMID 15193426.
External links
- Serine+racemase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: Q9GZT4 (Serine racemase) at the PDBe-KB.
This page was last edited on 24 December 2023, at 03:49