<br>肿瘤标志物 AKR1B10 的高全反式视黄醛还原酶活性的结构基础。,Proceedings of the National Academy of Sciences of the United States of America

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肿瘤标志物 AKR1B10 的高全反式视黄醛还原酶活性的结构基础。
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2007 Dec 26 , DOI: 10.1073/pnas.0705659105
Oriol Gallego ₁ , F Xavier Ruiz , Albert Ardèvol , Marta Domínguez , Rosana Alvarez , Angel R de Lera , Carme Rovira , Jaume Farrés , Ignacio Fita , Xavier Parés

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AKR1B10 是一种人醛酮还原酶 (AKR)，被发现在多种癌症类型和癌前病变中升高。在体外，AKR1B10 表现出比任何其他人类 AKR（包括 AKR1B1（醛糖还原酶））更高的视黄醛还原酶活性。我们在此证明 AKR1B10 在体内也可充当视黄醛还原酶。该活性可能与控制视黄酸合成的第一步有关。 AKR1B10 上调导致视黄酸消耗，可能导致细胞增殖。 AKR1B10 的体外和体内活性均被 tolrestat 抑制，tolrestat 是一种为糖尿病治疗而开发的 AKR1B1 抑制剂。以 1.25-A 分辨率测定了三元复合物 AKR1B10-NADP(+)-tolrestat 的晶体结构。具有视黄醛异构体和定点诱变的 AKR1B10 和 AKR1B1 的分子动力学模型表明，类视黄醇结合位点入口处（尤其是第 125 位）的细微差异是 AKR1B10 的全反式视黄醛特异性的决定因素。视黄醛环己烯环中的取代也影响特异性。这些结构特征应有助于特定抑制剂的设计，并有可能用于癌症和糖尿病的治疗。

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Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10.

AKR1B10 is a human aldo-keto reductase (AKR) found to be elevated in several cancer types and in precancerous lesions. In vitro, AKR1B10 exhibits a much higher retinaldehyde reductase activity than any other human AKR, including AKR1B1 (aldose reductase). We here demonstrate that AKR1B10 also acts as a retinaldehyde reductase in vivo. This activity may be relevant in controlling the first step of retinoic acid synthesis. Up-regulation of AKR1B10, resulting in retinoic acid depletion, may lead to cellular proliferation. Both in vitro and in vivo activities of AKR1B10 were inhibited by tolrestat, an AKR1B1 inhibitor developed for diabetes treatment. The crystal structure of the ternary complex AKR1B10-NADP(+)-tolrestat was determined at 1.25-A resolution. Molecular dynamics models of AKR1B10 and AKR1B1 with retinaldehyde isomers and site-directed mutagenesis show that subtle differences at the entrance of the retinoid-binding site, especially at position 125, are determinant for the all-trans-retinaldehyde specificity of AKR1B10. Substitutions in the retinaldehyde cyclohexene ring also influence the specificity. These structural features should facilitate the design of specific inhibitors, with potential use in cancer and diabetes treatments.

更新日期：2017-01-31

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