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首页> 外文OA文献 >Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
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Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase

机译：醛基酮还原酶1B15的底物特异性，抑制剂选择性和结构功能关系：一种新型的人类视醛醛还原酶。

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摘要

Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 is a well characterized enzyme with high retinaldehyde reductase activity, involved in the development of several cancer types, the enzymatic activity and physiological role of AKR1B15 are still poorly known. Here, the purified recombinant enzyme has been subjected to substrate specificity characterization, kinetic analysis and inhibitor screening, combined with structural modeling. AKR1B15 is active towards a variety of carbonyl substrates, including retinoids, with lower kcat and Km values than AKR1B10. In contrast to AKR1B10, which strongly prefers all-trans-retinaldehyde, AKR1B15 exhibits superior catalytic efficiency with 9-cis-retinaldehyde, the best substrate found for this enzyme. With ketone and dicarbonyl substrates, AKR1B15 also shows higher catalytic activity than AKR1B10. Several typical AKR inhibitors do not significantly affect AKR1B15 activity. Amino acid substitutions clustered in loops A and C result in a smaller, more hydrophobic and more rigid active site in AKR1B15 compared with the AKR1B10 pocket, consistent with distinct substrate specificity and narrower inhibitor selectivity for AKR1B15.
机译：人醛基酮还原酶1B15（AKR1B15）是一种新发现的酶，与AKR1B10具有92％的氨基酸序列同一性。虽然AKR1B10是一种具有良好的视黄醛还原酶活性的酶，具有很好的表征，但参与了几种癌症的发展，但AKR1B15的酶活性和生理作用仍然鲜为人知。在此，对纯化的重组酶进行了底物特异性表征，动力学分析和抑制剂筛选，并结合了结构建模。 AKR1B15对各种羰基底物（包括类视色素）具有活性，其kcat和Km值均低于AKR1B10。与强烈偏爱全反式维甲酸的AKR1B10相比，AKR1B15具有9-顺式-维甲酸的最佳催化效果，后者是该酶的最佳底物。对于酮和二羰基底物，AKR1B15还显示出比AKR1B10更高的催化活性。几种典型的AKR抑制剂不会显着影响AKR1B15活性。与AKR1B10口袋相比，聚集在环A和C中的氨基酸取代在AKR1B15中产生了更小，更疏水和更刚性的活性位点，这与独特的底物特异性和更窄的AKR1B15抑制剂选择性相符。

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