Bioinformatics and function of SR and DAO in schizophrenia
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摘要:
目的 D-ser作为一种重要的神经胶质细胞递质,其合成与代谢依赖于丝氨酸消旋酶(SR)和D构象氨基酸氧化酶(DAO),SR及DAO基因与精神分裂症密切相关,本研究目的为阐明精神分裂症患者SR及DAO结构与功能的关系。 方法 从精神分裂症血液中克隆到SR及DAO基因,对其进行生物信息学分析。 结果 序列分析结果表明,SR及DAO基因分别编码340个和347个氨基酸的多肽,与健康人、猿、猴的同源性在96%以上;预测SR及DAO蛋白质的相对分子质量分别为36.57 KDa和39.47 KDa,理论等电点分别为6.11和6.36。亚细胞定位分析结果发现,SR蛋白主要定位于细胞的线粒体中,DAO蛋白主要定位于线粒体和过氧化物酶体中,提示此两种蛋白在细胞中主要发挥合成与代谢作用。结构与功能分析发现,SR蛋白有1个结构域,DAO蛋白含有2个结构域和一个链接区。 结论 推测SR及DAO在真核细胞的蛋白质合成与代谢等过程中发挥重要功能。 Abstract:Objective To explore the relationship between structure and function of SR and DAO in schizophrenia. Methods SR and DAO gene were cloned from blood of patients with schizophrenia with bioinformatics analysis. Results The SR and DAO genes encoded 340 and 347 amino acids, respectively. It had more than 96% homology with healthy humans, apes and monkeys. The relative molecular mass of SR and DAO proteins were predicted to be 36.57 KDa and 39.47 KDa, respectively. The isoelectric point were 6.11 and 6.36. SR distribution was involved in chondriosome. DAO distribution was involved in chondriosome and peroxysome. It indicated that SR and DAO played a mayor role in synthesis and metabolism of cells.Three-dimensional measurement revealed that SR protein was composed of a structural domains and DAO protein was composed of two structural domains and one link region. Conclution SR and DAO can promote protein synthesis and metabolism in eukaryotic cells. -
Key words:
- schizophrenia /
- SR /
- DAO /
- structure prediction /
- sequence analysis
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表 1 SR蛋白功能预测结果
功能分类 产物 概率 氨基酸生物合成 0.224 10.174 脂肪酸代谢 0.070 5.397 转化 0.151 3.438 辅酶因子的生物合成 0.231 3.203 能量代谢 0.258 2.866 中间产物代谢 0.096 1.520 表 2 DAO蛋白功能预测结果
功能分类 产物 概率 氨基酸生物合成 0.185 8.432 细胞膜 0.333 5.466 中间产物代谢 0.341 5.407 辅酶因子的生物合成 0.273 3.789 能量代谢 0.317 3.525 脂肪酸代谢 0.026 2.004 -
[1] O'donovan MC, Craddock N, Norton NA, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up[J]. Nat Genet, 2008, 40(9): 1053-5. doi: 10.1038/ng.201 [2] Hashimoto A, Nishikawa T, Hayashi T, et al. The presence of free D-serine in rat brain[J]. FEBS Lett, 1992, 296(1): 33-6. doi: 10.1016/0014-5793(92)80397-Y [3] Burnet PW, Hutchinson L, von Hesling M, et al. Expression of D-serine and glycine transporters in the prefrontal cortex and cerebellum in schizophrenia[J]. Schizophr Res, 2008, 102(1/3): 283-94. [4] de Miranda J, Santoro A, Engelender S, et al. Human serine racemase: moleular cloning, genomic organization and functional analysis[J]. Gene, 2000, 256(1/2): 183-8. [5] Mustafa AK, Kumar M, Selvakumar B, et al. Nitric oxide S-nitrosylates serine racemase, mediating feedback inhibition of D-serine formation[J]. Proc Natl Acad Sci U S A, 2007, 104(8): 2950-5. doi: 10.1073/pnas.0611620104 [6] 阳洪波, 袁建刚, 彭小忠. D构象丝氨酸在中枢神经系统中的功能研究进展[J]. 生物化学与生物物理进展, 2003, 30(6): 852-4. http://www.cnki.com.cn/Article/CJFDTOTAL-SHSW200306005.htm [7] Billard JM. D-serine signalling as a prominent determinant of neuronal-glial dialogue in the healthy and diseased brain[J]. J Cell Mol Med, 2008, 12(5B): 1872-84. doi: 10.1111/j.1582-4934.2008.00315.x [8] Wu SZ, Bodles AM, Porter MM, et al. Induction of serine racemase expression and D-serine release from microglia by amyloid beta-paptide[J]. J Neuroinflammation, 2004, 1(1): 1-11. doi: 10.1186/1742-2094-1-1 [9] Nadri C, Amar S, Bendikov I, et al. A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia[J]. Proc Natl Acad Sci U S A, 2006, 9(1): S222-3. [10] Morita Y, Ujike H, Tanaka Y, et al. A genetic variant of the serine racemase gene is associated with schizophrenia[J]. Biol Psychiatry, 2007, 61(10): 1200-3. doi: 10.1016/j.biopsych.2006.07.025 [11] Balu DT, Li Y, Puhl MD, et al. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction[J]. Proc Natl Acad Sci USA, 2013, 110(26): E2400-9. doi: 10.1073/pnas.1304308110 [12] Balu DT, Basu AC, Corradi JP, et al. The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex[J]. Neurobiol Dis, 2012, 45(2): 671-82. doi: 10.1016/j.nbd.2011.10.006 [13] Devito LM, Balu DT, Kanter BR, et al. Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology[J]. Genes Brain Behav, 2011, 10(2): 210-22. doi: 10.1111/gbb.2011.10.issue-2 [14] Labrie V, Fukumura R, Rastogi A, et al. Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model[J]. Hum Mol Genet, 2009, 18(17): 3227-43. doi: 10.1093/hmg/ddp261 [15] 李 悦, 陈元堂, 胡 江, 等. D-氨基酸氧化酶基因多态性与精神分裂症的关联研究[J]. 南方医科大学学报, 2010, 30(9): 2142-4, 2147. http://www.cnki.com.cn/Article/CJFDTOTAL-DYJD201009033.htm [16] Ohnuma T, Shibata N, Maeshima H, et al. Association analysis of glycine- and serine-related genes in a Japanese population of patients with schizophrenia[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2009, 33(3): 511-8. doi: 10.1016/j.pnpbp.2009.02.004 [17] Corvin A, Mcghee KA, Murphy K, et al. Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample[J]. Am J Med Genet B Neuropsychiatr Genet, 2007, 144B(7): 949-53. doi: 10.1002/(ISSN)1552-485X [18] 胡建平, 柯国涛, 常 珊, 等. HIV-1病毒DNA与整合酶结合后的构象变化[J]. 物理化学学报, 2008, 24(10): 1803-10. doi: 10.3866/PKU.WHXB20081012 [19] 陈元堂, 高成阁. α7-烟碱样乙酰胆碱受体基因多态性与精神分裂症的关联研究[J]. 四川精神卫生, 2008, 21(1): 1-4. http://www.cnki.com.cn/Article/CJFDTOTAL-WANT200801000.htm [20] Schizophrenia working group of the psychiatric genomics consorting. Biological insights from 108 schizophrenia-associated genetic loci[J]. Nature, 2014, 23(511): 421-7.