Towards a structural basis for the relationship between blood group and the severity of El Tor cholera.

Towards a structural basis for the relationship between blood group and the severity of El Tor cholera.
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DOI:
10.1002/anie.201109068
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发表时间:
2012-05-21
影响因子:
16.6
通讯作者:
Turnbull, W. Bruce
Turnbull, W. Bruce
中科院分区:
化学1区
文献类型:
--
作者:
Mandal, Pintu K.;Branson, Thomas R.;Hayes, Edward D.;Ross, James F.;Gavin, Jose A.;Daranas, Antonio H.;Turnbull, W. Bruce

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霍乱弧菌和产肠毒素E.大肠杆菌(ETEC)每年导致数百万人死亡。[1]由这些细菌产生的蛋白质毒素是80%相同的,并且包含与B亚基的五聚体相关的单个毒性A亚基。[2]B-五聚体通过首先与神经节苷脂GM 1糖脂1结合使毒素能够进入细胞(图1a、B)。[2,3]因此,这种结合事件的抑制剂是潜在的抗真菌药物。[4]由埃尔托生物型霍乱弧菌引起的霍乱的严重程度已知是血型依赖性的;[5] O型血的人比A型或B型血的人受到的影响更严重。[6]相比之下,霍乱弧菌O 1经典生物型没有明显的血型依赖性,[7]并且ETEC相关腹泻的任何类似相关性都是一个争议问题。[8]A、B和O血型的区别在于细胞表面存在的碳水化合物。[9]例如,血型O的特征在于以2-O-岩藻糖基-半乳糖结构(例如5)终止的寡糖,即所谓的H-抗原。在A和B血型中,H抗原分别进一步被α-半乳糖胺或半乳糖残基取代(如3a和4)。有几份报告称霍乱毒素B亚基(CT B)不与血型寡糖结合;[10]然而,大多数结合研究似乎是使用经典生物型CT B,而不是El Tor CT B进行的。相反,据报道,热不稳定毒素B亚基(LTBh)以相似的亲和力结合血型A和B寡糖,但不结合H抗原寡糖。[10a,B]血型A低聚糖3 B已结晶-
Diarrheal diseases caused by Vibrio cholerae and enterotoxigenic E. coli (ETEC) lead to millions of deaths each year.[1] The protein toxins produced by these bacteria are 80% identical and comprise a single toxic A-subunit associated with a pentamer of B-subunits.[2] The B-pentamer enables the toxin to enter cells by first binding to the ganglioside GM1 glycolipid 1 (Figure 1 a, b).[2, 3] Inhibitors of this binding event are therefore potential anti-diarrheal drugs.[4] The severity of cholera caused by the El Tor biotype of V. cholerae is known to be blood-group dependent;[5] people in blood group O are affected more severely than those in blood groups A or B.[6] In contrast, there is no clear blood-group dependence for the V. cholerae O1 classical biotype,[7] and any similar correlation for ETEC-related diarrhoea is a matter of dispute.[8] The A, B and O blood groups are distinguished by carbohydrates present on the surface of cells.[9] For example, blood group O is characterized by oligosaccharides terminating in a 2-O-fucosyl-galactose structure (eg 5), the so-called H-antigen. In blood groups A and B, the H-antigen is further substituted by an α-galactosamine or galactose residue, respectively (eg, 3a and 4).There have been several reports that the cholera toxin B-subunit (CTB) does not bind to blood group oligosaccharides;[10] however, most binding studies appear to have been undertaken using classical biotype CTB, rather than El Tor CTB. In contrast, the heat-labile toxin B-subunit (LTBh) is reported to bind to both blood group A and B oligosaccharides with similar affinity, but not to H-antigen oligosaccharides.[10a, b] Blood group A oligosaccharide 3b has been crystal-
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