克洛素(Klotho,或译可罗素)是一种由人类KL基因编码而成的酵素[5]

克洛素
识别号
别名KL;, entrez:9365, klotho, HFTC3, KLA
外部IDOMIM604824 MGI1101771 HomoloGene68415 GeneCardsKL
基因位置(人类
13号染色体
染色体13号染色体[1]
13号染色体
克洛素的基因位置
克洛素的基因位置
基因座13q13.1起始33,016,423 bp[1]
终止33,066,143 bp[1]
直系同源
物种人类小鼠
Entrez
Ensembl
UniProt
mRNA​序列

​NM_004795
​NM_153683

NM_013823

蛋白序列

NP_004786

NP_038851

基因位置​(UCSC)Chr 13: 33.02 – 33.07 MbChr 5: 150.88 – 150.92 Mb
PubMed​查找[3][4]
维基数据
查看/编辑人类查看/编辑小鼠

该基因属于第一型跨膜蛋白,且具有β-葡萄糖醛酸苷酶英语beta-glucuronidase活性。慢性肾衰竭患者体内的可罗素制造会减少,这也可能是造成慢性肾衰后一连串并发症的原因(如动脉硬化、骨质疏松、以及皮肤松弛等等)。该编码基因的突变也与老化、骨质流失有关[6][7]。过度表现可罗素的小鼠,寿命会较野生型小鼠长[8]

功能

克洛素为一种跨膜蛋白,会调控生物体对于胰岛素的敏感性,且可能也与老化有关。本蛋白最早由黑尾诚等人于1997年发现[9],该蛋白命名自希腊神话命运三女神中的克洛托(Klotho)。

克洛素具有β-葡萄糖醛酸苷酶英语beta-glucuronidase活性,可以水解β-葡萄糖醛酸英语glucuronide,与人类老化有关[10][11]血浆中的循环克洛素会随年纪逐渐减少[12]。β-克洛素会与FGF受体行程协同受体英语co-receptor,可与FGF19、FGF20、FGF23等成纤维细胞生长因子(FGF)结合进行作用[13][14]

克洛素缺乏的小鼠会出现类似人类早衰的症状,并加速动脉血管硬化的进程,同时也会损伤血管新生内皮调控血管扩张的能力。推论克洛素可能可以透过内皮源性一氧化氮释放来保护心血管系统。

过度表现克洛素的小鼠,平均寿命会较一般小数多出19%至31%[8]。克洛速基因的某些变异还与长寿和增进认知功能相关[15]

克洛素的作用机转迄今未明,目前已知可以透过提升TRPV5英语TRPV5和降低TRPC6英语TRPC6的表达调控细胞的钙平衡[16]。此外,克洛素也会增加内向整流离子通道ROMK英语ROMK的表达[16]。克洛素缺乏的小鼠会会增加维他命D的制造[17][18][19][20]

参考文献

  1. ^ 1.0 1.1 1.2 GRCh38: Ensembl release 89: ENSG00000133116 - Ensembl, May 2017
  2. ^ 2.0 2.1 2.2 GRCm38: Ensembl release 89: ENSMUSG00000058488 - Ensembl, May 2017
  3. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  4. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochemical and Biophysical Research Communications. Jan 1998, 242 (3): 626–30. PMID 9464267. doi:10.1006/bbrc.1997.8019. 
  6. ^ Entrez Gene: klotho. 
  7. ^ Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, et al. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proceedings of the National Academy of Sciences of the United States of America. 2016, 113 (50): 14372–14377. PMC 5167198 . PMID 27911795. doi:10.1073/pnas.1611243113. 
  8. ^ 8.0 8.1 Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M. Suppression of aging in mice by the hormone Klotho. Science. Sep 2005, 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. PMC 2536606 . PMID 16123266. doi:10.1126/science.1112766. 
  9. ^ Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. Nov 1997, 390 (6655): 45–51. Bibcode:1997Natur.390...45K. PMID 9363890. doi:10.1038/36285. 
  10. ^ Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proceedings of the National Academy of Sciences of the United States of America. Jan 2002, 99 (2): 856–61. Bibcode:2002PNAS...99..856A. PMC 117395 . PMID 11792841. doi:10.1073/pnas.022484299. 
  11. ^ Rodriguez T. Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy. Journal of Molecular Biology Research. 2015, 5 (1): 11. doi:10.5539/jmbr.v5n1p11. 
  12. ^ Xiao NM, Zhang YM, Zheng Q, Gu J. Klotho is a serum factor related to human aging. Chinese Medical Journal. May 2004, 117 (5): 742–7. PMID 15161545. [永久失效链接]
  13. ^ Helsten T, Schwaederle M, Kurzrock R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Reviews. 2015, 34 (3): 479–96. PMC 4573649 . PMID 26224133. doi:10.1007/s10555-015-9579-8. 
  14. ^ Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA. FGF21 Regulates Sweet and Alcohol Preference. Cell Metabolism. February 2016, 23 (2): 344–9. PMC 4749404 . PMID 26724861. doi:10.1016/j.cmet.2015.12.008. 
  15. ^ Dena B. Dubal et al., Life Extension Factor Klotho Enhances Cognition, Cell Reports, 2014, DOI: 10.1016/j.celrep.2014.03.076 (open access)
  16. ^ 16.0 16.1 Huang CL. Regulation of ion channels by secreted Klotho: mechanisms and implications. Kidney International. May 2010, 77 (10): 855–60. PMID 20375979. doi:10.1038/ki.2010.73. 
  17. ^ Kuro-o M. Klotho and aging. Biochimica et Biophysica Acta. Oct 2009, 1790 (10): 1049–58. PMC 2743784 . PMID 19230844. doi:10.1016/j.bbagen.2009.02.005. 
  18. ^ Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. The Journal of Cell Biology. Aug 2008, 182 (3): 459–65. PMC 2500132 . PMID 18678710. doi:10.1083/jcb.200803024. 
  19. ^ Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Molecular Endocrinology. Dec 2003, 17 (12): 2393–403. PMID 14528024. doi:10.1210/me.2003-0048. 
  20. ^ Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y. alpha-Klotho as a regulator of calcium homeostasis. Science. Jun 2007, 316 (5831): 1615–8. Bibcode:2007Sci...316.1615I. PMID 17569864. doi:10.1126/science.1135901. 

延伸阅读

外部链接


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