کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2065200 1076910 2009 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
The effect of structural variation in 21 microcystins on their inhibition of PP2A and the effect of replacing cys269 with glycine
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیوشیمی، ژنتیک و زیست شناسی مولکولی (عمومی)
پیش نمایش صفحه اول مقاله
The effect of structural variation in 21 microcystins on their inhibition of PP2A and the effect of replacing cys269 with glycine
چکیده انگلیسی

Microcystins (MCs) are a group of cyclic heptapeptide hepatotoxins produced by Microcystis and several other genera of cyanobacteria. The representative MC, MC-LR, strongly inhibits protein phosphatase 2A (PP2A), while the inhibitory potencies of at least 60 MC analogs characterized from bloom samples and cultured strains have not been fully elucidated. In this study, we determined the IC50 values for 21 MC analogs for inhibiting the recombinant PP2A catalytic subunit (rPP2Ac). Of the 21 MC analogs, MC-LR was the strongest inhibitor of rPP2Ac. Comparison of the IC50 values indicates that demethylation of the amino acids at positions 3 or 7 leads to a greater reduction in activity than the substitution of l-amino acids at positions 2 and 4. To obtain further insight into the MC-PP2A interaction, we substituted cysteine at position 269 in PP2Ac with glycine. The mutant PP2Ac (C269G) was comparable to the wild-type PP2Ac in the hydrolysis of p-NPP, but was more resistant to MCs as indicated by the greater IC50 values. Our results indicate that cys269 in PP2Ac and N-methyldehydroalanine (Mdha) at position 7 in MCs play important roles in the enzyme-inhibitor interaction. We also determined the LC50 values of the MCs for cytotoxicity assay. Our results indicate that there is a weak correlation between the cytotoxicity and PP2A inhibiting activities of the MCs. The MCs and rPP2Ac used in this study were of high purity and the IC50 values were determined under the same experimental conditions, ensuring the quality of the data. The IC50 values are of practical importance because they enable the precise conversion of the amounts of various MCs detected using instrumental methods to MC-LR equivalents.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicon - Volume 54, Issue 4, 15 September 2009, Pages 539–544
نویسندگان
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