霍亂毒素

霍亂毒素（英語：Cholera toxin，又稱為英語：choleragen，有時簡稱為CTX、Ctx 或 CT）是霍亂弧菌分泌的AB₅多聚體蛋白質複合體。^[1]^[2]霍亂毒素是造成霍亂感染特有的大量水瀉的原因。^[3]它是耐熱腸毒素家族（英語：Heat-labile enterotoxin family）的成員。

歷史

羅伯特·科赫是一位德國醫生和微生物學家，他是第一個提出霍亂毒素存在的人。1886年，科赫提出霍亂弧菌會分泌一種導致霍亂症狀的物質。^[4]科赫的推測被印度微生物學家 Sambhu Nath De 證實是正確的，他在1951年研究並記錄了用熱殺霍亂弧菌注射兔子的效果。^[5]他從這個實驗中得出結論：細菌分解時釋放出來的內毒素是導致霍亂症狀的原因。^[5]1959年，De 進行了另一項實驗，這次他使用無菌的霍亂弧菌培養濾液注入兔子的小腸。^[6]結果腸內積液確實證明了毒素的存在。^[7]

結構

完整的毒素是由一份A亞基（A部分，酶，UniProt P01555）和五份B亞基（B部分，受體結合，UniProt P01556）組成的六聚體，表示為AB₅。B亞基結合，而A亞基則活化 G蛋白，進而活化腺苷酸環化酶。該毒素的三維結構是由 Zhang 等人在1995年使用X射線晶體學測定的。^[8]

五個各重11 kDa的B亞基構成一個五元環。28 kDa的A亞基有兩個重要的區段。A1部分的鏈 (CTA1) 是球狀的酶載荷，可二磷酸腺苷核糖基化化G蛋白，而A2鏈 (CTA2) 則形成延伸的α螺旋，緊貼在B亞基環的中央孔隙中。^[9]

這種結構在形狀、機制和序列上與大腸桿菌某些菌株所分泌的耐熱腸毒素家族（英語：Heat-labile enterotoxin family）類似。

致病機制

霍亂毒素的作用機制如下：首先，霍亂毒素的B亞基環與目標細胞表面的GM1 神經節苷脂結合。如果細胞缺乏GM1，毒素很可能會與其他類型的聚糖結合，例如附著在蛋白質上的Lewis Y和Lewis X，而不是脂質。^[10]^[11]^[12] 一旦結合，整個毒素複合物會被細胞內吞，二硫橋的還原會釋放霍亂毒素A1 (CTA1) 鏈。胞內體被移動到高爾基體，在那裡A1蛋白被內質網 (ER) 分子伴侶蛋白二硫異構酶（protein disulfide-isomerase）識別。A1鏈隨後展開並被送到膜上，在膜上，Ero1觸發蛋白質二硫化異構酶複合物氧化，釋放A1蛋白。^[13]當A1蛋白透過Sec61通道從內質網移動到細胞質時，它會重新折疊，避免因泛素化而失去活性。

參見

參考資料

^ Ryan KJ; Ray CG (編). Sherris Medical Microbiology 4th. McGraw Hill. 2004: 375. ISBN 978-0-8385-8529-0.
^ Faruque, Shah M; Nair, G. Balakrish (編). 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 （英語）.
^ 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.

外部鏈接

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. （原始內容存檔於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. （原始內容存檔於October 25, 2011）.
醫學主題詞表（MeSH）：Cholera+Toxin
PDB中UniProt可用的所有結構信息之概述：P01555 (Cholera enterotoxin subunit A) 在PDBe-KB（英語：PDBe-KB）。
PDB中UniProt可用的所有結構信息之概述：P01556 (Cholera enterotoxin subunit B) 在PDBe-KB（英語：PDBe-KB）。

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

[FaruqueNair-2] Faruque, Shah M; Nair, G. Balakrish (編). 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 （英語）.

[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.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]