Human ALDH1B1 Polymorphisms may Affect the Metabolism of Acetaldehyde and All-trans retinaldehyde—In Vitro Studies and Computational Modeling

Abstract

Purpose To elucidate additional substrate specificities of ALDH1B1 and determine the effect that human ALDH1B1 polymorphisms will have on substrate specificity. Methods 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. Results 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. Conclusions 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.

NOR1 Suppresses Cancer Stem‐Like Cells Properties of Tumor Cells via the Inhibition of the AKT‐GSK‐3β‐Wnt/β‐catenin‐ALDH1A1 Signal Circuit

“…ALDH1B1 can regulate the expression of PI3K and AKT via the FABP5/PPARD signaling pathway, and can regulate the expression of β‐catenin, thus promoting the occurrence of colorectal cancer (Singh et al, ). The ALDH1A1 and ALDH1B1 protein sequences are 62% similar, and as both are known to catalyze the formation of RA (Jackson et al, ; Singh et al, ), it is possible that ALDH1A1 also plays a role in the regulation of the FABP5/PPARD‐PI3K/AKT‐Wnt/β‐catenin signaling pathway.…”

ALDH1B1 links alcohol consumption and diabetes

“…This result corroborates our previous in vitro study showing that ALDH1B1 is second only to ALDH2 in oxidizing acetaldehyde, and indicates that ALDH1B1 plays a functionally significant role in acetaldehyde clearance in vivo . This finding may have clinical implications given that several functional polymorphisms of ALDH1B1 gene have been identified in the human population [8]. Alcohol hypersensitivity has been observed in carriers of the ALDH1B1*2 variant [5], which metabolizes acetaldehyde at a slower rate than wild-type ALDH1B1 [8].…”

“…In line with this notion, human studies have identified ALDH1B1 polymorphisms to be associated with symptoms of acetaldehyde toxicity including ethanol hypersensitivity, hypertension and ethanol aversion in Caucasian populations [5, 6], where the well-studied ALDH2*2 variant is nearly absent [7]. In addition to its acetaldehyde metabolic effects, ALDH1B1 has the catalytic capacity for oxidation of retinaldehyde [8], which is supportive of ALDH1B1 playing a role in the differentiation and development of normal and cancer stem cells [9]. In this context, we have observed that ALDH1B1 is expressed specifically in the stem cell compartment in the normal colon and is drastically induced in human colon cancerous tissues [10].…”

Aldehyde dehydrogenase 1B1: a novel immunohistological marker for colorectal cancer

“…Based on its possible ability to enzymatically convert retinal to retinoic acid, ALDH1B1 is presumed to promote differentiation of stem cells ( Chute et al , 2006 ; Jackson et al , 2015 ). Indeed, a previous study reported that ALDH1B1 protein expression in human CRC was increased in line with the extent of differentiation ( Langan et al , 2012 ).…”