Dataset Information

Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling.

ABSTRACT: 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.

SUBMITTER: Jackson BC

PROVIDER: S-EPMC4382438 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling.

Jackson Brian C BC Reigan Philip P Miller Bettina B Thompson David C DC Vasiliou Vasilis V

Pharmaceutical research 20141121 5

<h4>Purpose</h4>To elucidate additional substrate specificities of ALDH1B1 and determine the effect that human ALDH1B1 polymorphisms will have on substrate specificity.<h4>Methods</h4>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 retinal ...[more]

PMID: 25413692

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Dataset Information

Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling.

Publications

Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling.

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