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首页> 外文期刊>RSC Advances >New findings about human dipeptidyl peptidase III based on mutations found in cancer
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New findings about human dipeptidyl peptidase III based on mutations found in cancer

机译：基于癌症中突变的人二肽基肽酶III的新发现

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Dipeptidyl peptidase III (DPP III) is a cytosolic enzyme belonging to the metallopeptidase family M49, involved in the final steps of protein catabolism. More than a hundred missense mutations can be found in the coding region of the human DPP3 gene when searching cBioPortal for Cancer Genomics. The role of two highly conserved residues in the family M49, whose mutations G313W and R510W were detected in human cancer, was investigated using combined experimental and computational approaches (substrate docking and MD simulations). Several mutants of human DPP III were expressed and purified as recombinant proteins, and their biochemical properties were determined. The conservative substitution of Arg510 with lysine mildly decreased enzyme activity activity for Arg-Arg-2-naphtylamide substrate, while the substitutions of Arg510 with glutamine and Gly313 with alanine substantially decreased enzyme activity, and tryptophan substitutions found in cancer, G313W and R510W, almost abolished enzyme activity. MD simulations showed that substitution of Gly313, and especially Arg510 with tryptophan, significantly increases the enzyme flexibility, particularly that of the binding site including the H450ELLGH455 motif, and influences the substrate interactions with the catalytic His568. The results clearly indicate that, besides the enzyme structure, its dynamics properties also significantly influence the human DPP III activity.
机译：二肽基肽酶III（DPP III）是属于金属肽酶家族M49的胞质酶，参与蛋白质分解代谢的最终步骤。搜索cBioPortal的Cancer Genomics时，在人DPP3基因的编码区中可以找到一百多个错义突变。使用组合的实验和计算方法（底物对接和MD模拟）研究了M49族中两个高度保守的残基（在人类癌症中检测到G313W和R510W突变）的作用。表达并纯化了人DPP III的几种突变体，作为重组蛋白，并确定了它们的生化特性。赖氨酸的保守取代Arg510轻微降低了Arg-Arg-2-萘酰胺底物的酶活性，而谷氨酰胺取代Arg510和丙氨酸取代Gly313则大大降低了酶活性，在癌症，G313W和R510W中发现的色氨酸取代几乎取消了酶活性。 MD模拟显示，用色氨酸取代Gly313，尤其是Arg510，可以显着提高酶的柔韧性，特别是结合位点的柔韧性，包括H 450 ELLGH 455 基序，并影响底物与催化His568的相互作用。结果清楚地表明，除酶结构外，其动力学性质还显着影响人DPP III的活性。

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