Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling.
Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling.
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DOI：
10.1007/s11095-014-1564-3
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发表时间：
2015-05
影响因子：
3.7
通讯作者：
Vasiliou, Vasilis
中科院分区：
文献类型：
--
作者：
Jackson, Brian C.;Reigan, Philip;Miller, Bettina;Thompson, David C.;Vasiliou, Vasilis
阐明ALDH 1B 1的其他底物特异性，并确定人ALDH 1B 1多态性对底物特异性的影响。基于计算的分子建模用于预测底物丙醛、4-羟基壬烯醛、硝酸甘油和全反式视黄醇与ALDH 1B 1的结合。基于阳性的计算机模拟结果，探索了纯化的人重组ALDH 1B 1代谢硝酸甘油和全反式视黄醇的能力。此外，重新研究了ALDH 1B 1对4-HNE的代谢。通过查询数据库来寻找ALDH 1B 1的人类多态性，确定了三种主要变体：ALDH 1B 1 *2（A86 V）、ALDH 1B 1 *3（L107 R）和ALDH 1B 1 *5（M253 V）。使用计算建模来预测底物和辅因子（NAD+）与变体的结合。这些人类多态性在细菌系统中产生和表达，并测定比活性。ALDH 1B 1代谢硝酸甘油（并似乎受到抑制），并具有有利的动力学代谢全反式视黄醇。ALDH 1B 1代谢4-HNE的表观亲和力比先前描述的高，但通量低。重组ALDH 1B 1 *2无催化活性，而ALDH 1B 1 *3和ALDH 1B 1 *5都有催化活性。建模表明，ALDH 1B 1 *2活性的缺乏可能是由于NAD+结合不良。建模还表明，ALDH 1B 1 *3可能不太能够代谢全反式视黄醇，ALDH 1B 1 *5可能与NAD+结合较差。ALDH 1B 1代谢硝酸甘油和全反式视黄醇。三种人类多态性之一ALDH 1B 1 *2是催化失活的，可能是由于NAD+结合不良。该变体的表达可能影响干细胞中依赖ALDH 1B 1的代谢功能和乙醇代谢。
To elucidate additional substrate specificities of ALDH1B1 and determine the effect that human ALDH1B1 polymorphisms will have on substrate specificity. Computational-based molecular modeling was used to predict the binding of the substrates propionaldehyde, 4-hydroxynonenal, nitroglycerin, and all-trans retinaldehyde to ALDH1B1. Based on positive in silico results, the capacity of purified human recombinant ALDH1B1 to metabolize nitroglycerin and all-trans retinaldehyde was explored. Additionally, metabolism of 4-HNE by ALDH1B1 was revisited. Databases queried to find human polymorphisms of ALDH1B1 identified three major variants: ALDH1B1*2 (A86V), ALDH1B1*3 (L107R), and ALDH1B1*5 (M253V). Computational modeling was used to predict the binding of substrates and of cofactor (NAD+) to the variants. These human polymorphisms were created and expressed in a bacterial system and specific activity was determined. ALDH1B1 metabolizes (and appears to be inhibited by) nitroglycerin and has favorable kinetics for the metabolism of all-trans retinaldehyde. ALDH1B1 metabolizes 4-HNE with higher apparent affinity than previously described, but with low throughput. Recombinant ALDH1B1*2 is catalytically inactive, whereas both ALDH1B1*3 and ALDH1B1*5 are catalytically active. Modeling indicated that the lack of activity in ALDH1B1*2 is likely due to poor NAD+ binding. Modeling also suggests that ALDH1B1*3 may be less able to metabolize all-trans retinaldehyde and that ALDH1B1*5 may bind NAD+ poorly. ALDH1B1 metabolizes nitroglycerin and all-trans-retinaldehyde. One of the three human polymorphisms, ALDH1B1*2, is catalytically inactive, likely due to poor NAD+ binding. Expression of this variant may affect ALDH1B1-dependent metabolic functions in stem cells and ethanol metabolism.
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DOI：
10.1074/jbc.m109.014548
发表时间：
2010-01-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Beretta M;Gorren AC;Wenzl MV;Weis R;Russwurm M;Koesling D;Schmidt K;Mayer B
通讯作者：
Mayer B
影响因子：
2.7
作者：
Ioannou, Marilia;Serafimidis, Ioannis;Gavalas, Anthony
通讯作者：
Gavalas, Anthony
DOI：
10.1038/nsb0497-317
发表时间：
1997-04-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Liu, ZJ;Sun, YJ;Wang, BC
通讯作者：
Wang, BC
DOI：
10.1111/j.1530-0277.2008.00780.x
发表时间：
2008-11-01
影响因子：
3.2
作者：
Husemoen, Lise Lotte Nystrup;Fenger, Mogens;Linneberg, Allan
通讯作者：
Linneberg, Allan
影响因子：
6.1
作者：
Linneberg, A.;Gonzalez-Quintela, A.;Husemoen, L. L. N.
通讯作者：
Husemoen, L. L. N.