Cancer biomarker AKR1B10 and carbonyl metabolism.
Cancer biomarker AKR1B10 and carbonyl metabolism.
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癌症生物标志物AKR1B10和羰基代谢。
DOI：
10.1016/j.cbi.2008.10.044
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发表时间：
2009-03-16
影响因子：
5.1
通讯作者：
Maser E
中科院分区：
文献类型：
--
作者：
Balendiran GK;Martin HJ;El-Hawari Y;Maser E
醛酮还原酶 (AKR) 蛋白超家族的成员 AKR1B10 在人类肝癌以及许多因吸烟引起的腺癌病例中过度表达。 AKR1B10 也在子宫癌患者的宫颈癌和子宫内膜癌病例中检测到。此外，通过生物信息学和临床分析相结合，AKR1B10 已被确定为非小细胞肺癌的生物标志物。此外，在乳腺癌细胞中，脂肪酸生物合成受 AKR1B10 调节。 AKR1B10 包含 316 个残基，与醛糖还原酶 (AKR1B1) 具有 70% 的序列同一性，并在 299 位具有保守的 Cys 残基。一些抗癌药物和 dl-甘油醛中的羰基可被 AKR1B10 转化为相应的醇。目前用于临床治疗多种癌症的抗癌药物柔红霉素，被AKR1B10转化为柔红霉素，Km和kcat分别为1.1±0.18 mM和1.4±0.16min−1。 AKR1B10 的这种羰基还原活性会降低柔红霉素的抗癌效果。类似地，野生型 AKR1B10 还原 dl-甘油醛的动力学参数 Km 和 kcat（NADPH、DL-甘油醛）分别为 2.2±0.2mM 和 0.71±0.05sec−1。 AKR1B10 中残基 299 从 Cys 突变为 Ser，降低了蛋白质对 dl-甘油醛的亲和力，增强了 AKR1B10 的催化活性，但总体催化效率降低。对于 Cys299Ser 突变体 AKR1B10 催化的 dl-甘油醛还原，Km 为 15.8±1.0mM，kcat（NADPH，DL-甘油醛）为 2.8±0.2sec−1。这意味着 AKR1B10 的底物特异性受到残基 299 从 Cys 突变为 Ser 的极大影响。在本文中，我们利用 AKR1B10 中的这种突变来表征化合物库，了解它们对野生型和 Cys299Ser 突变体 AKR1B10 的羰基还原活性的不同抑制效力。
A member of the aldo-keto reductase (AKR) protein superfamily, AKR1B10, is overexpressed in human liver cancers as well as in many adenocarcinoma cases due to smoking. AKR1B10 is also detected in instances of cervical and endometrial cancer in uterine cancer patients. In addition, AKR1B10 has been identifiedasabiomarkerfornon-small-celllungcancerbyacombinedbioinformaticsandclinicalanalysis. Furthermore, in breast cancer cells, fatty acid biosynthesis is regulated by AKR1B10. AKR1B10 contains 316 residues, shares 70% sequence identity with aldose reductase (AKR1B1) and has the conserved Cys residue at position 299. Carbonyl groups in some anticancer drugs and dl-glyceraldehyde are converted by AKR1B10 to their corresponding alcohols. The anticancer drug daunorubicin, which is currently used in the clinical treatment of various forms of cancer, is converted by AKR1B10 to daunorubicinol with a Km and kcat of 1.1±0.18 mM and 1.4±0.16min−1, respectively. This carbonyl reducing activity of AKR1B10 decreases the anticancer effectiveness of daunorubicin. Similarly, kinetic parameters Km and kcat (NADPH, DL-glyceraldehyde) for the reduction of dl-glyceraldehyde by wild-type AKR1B10 are 2.2±0.2mM and 0.71±0.05sec−1, respectively. Mutation of residue 299 from Cys to Ser in AKR1B10 reduces the protein affinity for dl-glyceraldehyde and enhances AKR1B10’s catalytic activity but overall catalytic efficiency is reduced. For dl-glyceraldehyde reduction that is catalyzed by the Cys299Ser mutant AKR1B10, Km is 15.8±1.0mM and kcat (NADPH, DL-glyceraldehyde) is 2.8±0.2sec−1. This implies that the substrate specificity of AKR1B10 is drastically affected by mutation of residue 299 from Cys to Ser. In the present paper, we use this mutation in AKR1B10 to characterize a library of compounds regarding their different inhibitory potency on the carbonyl reducing activity of wild-type and the Cys299Ser mutant AKR1B10.
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影响因子：
4.8
作者：
Kaiserova, Karin;Srivastava, Sanjay;Bhatnagar, Aruni
通讯作者：
Bhatnagar, Aruni
影响因子：
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作者：
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Wanders, RJA
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Aburatani, H
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5.8
作者：
SATO, S;KADOR, PF
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