霍乱毒素

霍乱毒素（英语：Cholera toxin，又称为英语：choleragen，有时简称为CTX、Ctx 或 CT）是霍乱弧菌分泌的AB₅多聚体蛋白质复合体。^[1]^[2]霍乱毒素是造成霍乱感染特有的大量水泻的原因。^[3]它是耐热肠毒素家族（英语：Heat-labile enterotoxin family）的成员。

历史

罗伯特·科赫是一位德国医生和微生物学家，他是第一个提出霍乱毒素存在的人。1886年，科赫提出霍乱弧菌会分泌一种导致霍乱症状的物质。^[4]科赫的推测被印度微生物学家 Sambhu Nath De 证实是正确的，他在1951年研究并记录了用热杀霍乱弧菌注射兔子的效果。^[5]他从这个实验中得出结论：细菌分解时释放出来的内毒素是导致霍乱症状的原因。^[5]1959年，De 进行了另一项实验，这次他使用无菌的霍乱弧菌培养滤液注入兔子的小肠。^[6]结果肠内积液确实证明了毒素的存在。^[7]

结构

完整的毒素是由一份A亚基（A部分，酶，UniProt P01555）和五份B亚基（B部分，受体结合，UniProt P01556）组成的六聚体，表示为AB₅。B亚基结合，而A亚基则活化 G蛋白，进而活化腺苷酸环化酶。该毒素的三维结构是由 Zhang 等人在1995年使用X射线晶体学测定的。^[8]

五个各重11 kDa的B亚基构成一个五元环。28 kDa的A亚基有两个重要的区段。A1部分的链 (CTA1) 是球状的酶载荷，可二磷酸腺苷核糖基化化G蛋白，而A2链 (CTA2) 则形成延伸的α螺旋，紧贴在B亚基环的中央孔隙中。^[9]

这种结构在形状、机制和序列上与大肠杆菌某些菌株所分泌的耐热肠毒素家族（英语：Heat-labile enterotoxin family）类似。

致病机制

霍乱毒素的作用机制如下：首先，霍乱毒素的B亚基环与目标细胞表面的GM1 神经节苷脂结合。如果细胞缺乏GM1，毒素很可能会与其他类型的聚糖结合，例如附着在蛋白质上的Lewis Y和Lewis X，而不是脂质。^[10]^[11]^[12] 一旦结合，整个毒素复合物会被细胞内吞，二硫桥的还原会释放霍乱毒素A1 (CTA1) 链。胞内体被移动到高尔基体，在那里A1蛋白被内质网 (ER) 分子伴侣蛋白二硫异构酶（protein disulfide-isomerase）识别。A1链随后展开并被送到膜上，在膜上，Ero1触发蛋白质二硫化异构酶复合物氧化，释放A1蛋白。^[13]当A1蛋白透过Sec61通道从内质网移动到细胞质时，它会重新折叠，避免因泛素化而失去活性。

参见

参考资料

^ Ryan KJ; Ray CG (编). Sherris Medical Microbiology 4th. McGraw Hill. 2004: 375. ISBN 978-0-8385-8529-0.
^ Faruque, Shah M; Nair, G. Balakrish (编). Vibrio cholerae: Genomics and Molecular Biology. Caister Academic Press. July 2008. ISBN 978-1-904455-33-2.
^ Aizpurua-Olaizola, Oier; Sastre Torano, Javier; Pukin, Aliaksei; Fu, Ou; Boons, Geert Jan; de Jong, Gerhardus J.; Pieters, Roland J. Affinity capillary electrophoresis for the assessment of binding affinity of carbohydrate-based cholera toxin inhibitors. Electrophoresis. 2018, 39 (2): 344–347. ISSN 1522-2683. PMID 28905402. S2CID 33657660. doi:10.1002/elps.201700207 （英语）.
^ Bharati, Kaushik; Ganguly, Nirmal K. Cholera toxin: A paradigm of a multifunctional protein. The Indian Journal of Medical Research. February 2011, 133 (2): 179–187. ISSN 0971-5916. PMC 3089049 . PMID 21415492.
^ ^5.0 ^5.1 De, S. N.; Sarkar, J. K.; Tribedi, B. P. An experimental study of the action of cholera toxin. The Journal of Pathology and Bacteriology. 1951, 63 (4): 707–717. PMID 14898376. doi:10.1002/path.1700630417.
^ De, S. N. Enterotoxicity of bacteria-free culture-filtrate of Vibrio cholerae. Nature. 1959-05-30, 183 (4674): 1533–1534. ISSN 0028-0836. PMID 13666809. doi:10.1038/1831533a0.
^ Bharati, Kaushik; Ganguly, Nirmal K. Cholera toxin: A paradigm of a multifunctional protein. The Indian Journal of Medical Research. February 2011, 133 (2): 179–187. ISSN 0971-5916. PMC 3089049 . PMID 21415492.
^ Zhang R, Scott D, Westbrook M, Nance S, Spangler B, Shipley G, Westbrook E. The three-dimensional crystal structure of cholera toxin. J Mol Biol. 1995, 251 (4): 563–73. PMID 7658473. doi:10.1006/jmbi.1995.0456 .
^ De Haan L, Hirst TR. Cholera toxin: a paradigm for multi-functional engagement of cellular mechanisms (Review). Mol. Membr. Biol. 2004, 21 (2): 77–92. PMID 15204437. S2CID 22270979. doi:10.1080/09687680410001663267 .
^ Amberlyn M Wands; Akiko Fujita. Fucosylation and protein glycosylation create functional receptors for Cholera toxin. eLife. October 2015, 4: e09545. PMC 4686427 . PMID 26512888. doi:10.7554/eLife.09545 .
^ Cervin J, Wands AM, Casselbrant A, Wu H, Krishnamurthy S, Cvjetkovic A, et al. GM1 ganglioside-independent intoxication by Cholera toxin. PLOS Pathogens. 2018, 14 (2): e1006862. PMC 5825173 . PMID 29432456. doi:10.1371/journal.ppat.1006862 .
^ Wands AM, Cervin J, Huang H, Zhang Y, Youn G, Brautigam CA, Matson Dzebo M, Björklund P, Wallenius V, Bright DK, Bennett CS, Wittung-Stafshede P, Sampson NS, Yrlid U, Kohler JJ. Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells. ACS Infectious Diseases. February 7, 2018, 4 (5): 758–770. PMC 5948155 . PMID 29411974. doi:10.1021/acsinfecdis.7b00085.
^ Tsai, Billy; Rapoport, Tom A. Unfolded cholera toxin is transferred to the ER membrane and released from protein disulfide isomerase upon oxidation by Ero1. Journal of Cell Biology. 2002, 159 (2): 207–216. PMC 2173060 . PMID 12403808. S2CID 3111310. doi:10.1083/jcb.200207120.

外部链接

De, Sambhu Nath. Enterotoxicity of bacteria-free culture filtrate of Vibrio cholerae. Nature. 30 May 1959. 183:1533–4.
McDowall, Jennifer. Cholera toxin. Protein of the Month (POTM). Protein Data Bank in Europe (PDBe). Sep 2005. （原始内容存档于April 27, 2019）.
Goodsell, David. Cholera Toxin. RCSB Protein Data Bank. Molecule of the Month (MOTM) (Protein Data Bank (PDB)). Sep 2005. doi:10.2210/rcsb_pdb/mom_2005_9. （原始内容存档于October 25, 2011）.
医学主题词表（MeSH）：Cholera+Toxin
PDB中UniProt可用的所有结构信息之概述：P01555 (Cholera enterotoxin subunit A) 在PDBe-KB（英语：PDBe-KB）。
PDB中UniProt可用的所有结构信息之概述：P01556 (Cholera enterotoxin subunit B) 在PDBe-KB（英语：PDBe-KB）。

[Sherris-1] Ryan KJ; Ray CG (编). Sherris Medical Microbiology 4th. McGraw Hill. 2004: 375. ISBN 978-0-8385-8529-0.

[FaruqueNair-2] Faruque, Shah M; Nair, G. Balakrish (编). Vibrio cholerae: Genomics and Molecular Biology. Caister Academic Press. July 2008. ISBN 978-1-904455-33-2.

[3] Aizpurua-Olaizola, Oier; Sastre Torano, Javier; Pukin, Aliaksei; Fu, Ou; Boons, Geert Jan; de Jong, Gerhardus J.; Pieters, Roland J. Affinity capillary electrophoresis for the assessment of binding affinity of carbohydrate-based cholera toxin inhibitors. Electrophoresis. 2018, 39 (2): 344–347. ISSN 1522-2683. PMID 28905402. S2CID 33657660. doi:10.1002/elps.201700207 （英语）.

[4] Bharati, Kaushik; Ganguly, Nirmal K. Cholera toxin: A paradigm of a multifunctional protein. The Indian Journal of Medical Research. February 2011, 133 (2): 179–187. ISSN 0971-5916. PMC 3089049 . PMID 21415492.

[:2-5] 5.0 ^5.1 De, S. N.; Sarkar, J. K.; Tribedi, B. P. An experimental study of the action of cholera toxin. The Journal of Pathology and Bacteriology. 1951, 63 (4): 707–717. PMID 14898376. doi:10.1002/path.1700630417.

[6] De, S. N. Enterotoxicity of bacteria-free culture-filtrate of Vibrio cholerae. Nature. 1959-05-30, 183 (4674): 1533–1534. ISSN 0028-0836. PMID 13666809. doi:10.1038/1831533a0.

[7] Bharati, Kaushik; Ganguly, Nirmal K. Cholera toxin: A paradigm of a multifunctional protein. The Indian Journal of Medical Research. February 2011, 133 (2): 179–187. ISSN 0971-5916. PMC 3089049 . PMID 21415492.

[Zhang_1995-8] Zhang R, Scott D, Westbrook M, Nance S, Spangler B, Shipley G, Westbrook E. The three-dimensional crystal structure of cholera toxin. J Mol Biol. 1995, 251 (4): 563–73. PMID 7658473. doi:10.1006/jmbi.1995.0456 .

[9] De Haan L, Hirst TR. Cholera toxin: a paradigm for multi-functional engagement of cellular mechanisms (Review). Mol. Membr. Biol. 2004, 21 (2): 77–92. PMID 15204437. S2CID 22270979. doi:10.1080/09687680410001663267 .

[10] Amberlyn M Wands; Akiko Fujita. Fucosylation and protein glycosylation create functional receptors for Cholera toxin. eLife. October 2015, 4: e09545. PMC 4686427 . PMID 26512888. doi:10.7554/eLife.09545 .

[11] Cervin J, Wands AM, Casselbrant A, Wu H, Krishnamurthy S, Cvjetkovic A, et al. GM1 ganglioside-independent intoxication by Cholera toxin. PLOS Pathogens. 2018, 14 (2): e1006862. PMC 5825173 . PMID 29432456. doi:10.1371/journal.ppat.1006862 .

[12] Wands AM, Cervin J, Huang H, Zhang Y, Youn G, Brautigam CA, Matson Dzebo M, Björklund P, Wallenius V, Bright DK, Bennett CS, Wittung-Stafshede P, Sampson NS, Yrlid U, Kohler JJ. Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells. ACS Infectious Diseases. February 7, 2018, 4 (5): 758–770. PMC 5948155 . PMID 29411974. doi:10.1021/acsinfecdis.7b00085.

[13] Tsai, Billy; Rapoport, Tom A. Unfolded cholera toxin is transferred to the ER membrane and released from protein disulfide isomerase upon oxidation by Ero1. Journal of Cell Biology. 2002, 159 (2): 207–216. PMC 2173060 . PMID 12403808. S2CID 3111310. doi:10.1083/jcb.200207120.

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