The aldo-keto reductases (AKRs): Overview.
The aldo-keto reductases (AKRs): Overview.
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DOI：
10.1016/j.cbi.2014.09.024
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发表时间：
2015-06-05
影响因子：
5.1
通讯作者：
Penning, Trevor M.
中科院分区：
文献类型：
--
作者：
Penning, Trevor M.
关键词：
醛酮还原酶（AKR）蛋白超家族包含超过190个成员，属于16个家族，并在所有门中发现。这些酶减少羰基底物，如：糖醛类;酮类固醇，酮-藜芦醇，视黄醇，醌，和脂质过氧化副产物。包括由AKR 1D酶（5种β-还原酶）催化的类固醇双键的还原;以及近致癌物反式二氢二醇多环芳烃的氧化;而钾门控离子通道（AKR 6家族）的β-亚基控制Kv通道开放。AKR通常为37 kDa单体，具有（α/β）8桶基序，在桶的后部显示控制底物特异性的大环，并具有保守的辅因子结合结构域。AKR催化有序的双双动力学机制，其中NAD（P）H辅因子首先结合并且最后离开。在有利于NADPH的酶中，NADP+的释放速率由缓慢的异构化步骤控制，该步骤对kcat设置了上限。AKR保留由Tyr 55、Asp 50、Lys 84和His 117（AKR 1C 9编号）组成的保守催化四联体。短链淀粉酶/还原酶（SDR）的催化机制是保守的，即使它们显示出不同的蛋白质折叠。这些AKR 1B 1、AKR 1C 1 - 1C 3、AKR 1D 1和AKR 1B 10中有15种人AKR分别与糖尿病并发症、类固醇激素依赖性恶性肿瘤、胆汁酸缺乏和视黄酸信号传导缺陷有关。抑制剂计划在世界范围内存在，以靶向这些酶中的每一种来治疗上述疾病。AKR 1C和AKR 1D 1酶的遗传突变分别与男性生殖器发育缺陷和胆汁酸缺乏有关，并且发生在进化保守的氨基酸中。人类AKR具有大量的nsSNP和剪接变体，但在许多情况下缺乏功能基因组学。AKR及其变体现在准备使用现代基因组学和信息学方法进行研究，以确定它们与人类健康和疾病的关系。
The aldo-keto reductase (AKR) protein superfamily contains > 190 members that fall into 16 families and are found in all phyla. These enzymes reduce carbonyl substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation byproducts. Exceptions include the reduction of steroid double bonds catalyzed by AKR1D enzymes (5β-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the (β-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening. AKRs are usually 37 kDa monomers, have an (α/β)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. AKRs catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last. In enzymes that favor NADPH, the rate of release of NADP+ is governed by a slow isomerization step which places an upper limit on kcat. AKRs retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117 (AKR1C9 numbering). There is conservation of the catalytic mechanism with short-chain dehydrogenases/reductases (SDRs) even though they show different protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1-1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively. Inhibitor programs exist worldwide to target each of these enzymes to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1 enzymes are implicated in defects in the development of male genitalia and bile acid deficiency, respectively, and occur in evolutionary conserved amino acids. The human AKRs have a large number of nsSNPs and splice variants, but in many instances functional genomics is lacking. AKRs and their variants are now poised to be interrogated using modern genomic and informatics approaches to determine their association with human health and disease.
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影响因子：
4.1
作者：
Di Costanzo L;Drury JE;Christianson DW;Penning TM
通讯作者：
Penning TM
影响因子：
--
作者：
Bauman, DR;Steckelbroeck, S;Penning, TM
通讯作者：
Penning, TM
DOI：
10.1038/nsb0895-687
发表时间：
1995-08-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
ELKABBANI, O;JUDGE, K;FLYNN, TG
通讯作者：
FLYNN, TG
影响因子：
11.5
作者：
Fukumoto, S;Yamauchi, N;Aburatani, H
通讯作者：
Aburatani, H
影响因子：
4.8
作者：
Drury, Jason E.;Mindnich, Rebekka;Penning, Trevor M.
通讯作者：
Penning, Trevor M.