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

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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.

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Abbreviations

1,2 DNG:

1,2 dinitroglycerin

1,3 DNG:

1,3 dinitroglycerin

4-HNE:

4-hydroxynonenal

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors wish to thank the Computational Chemistry and Biology Core Facility at the University of Colorado Anschutz Medical Campus for their contributions to these studies. The authors wish to thank the laboratory of Dr. Tom Hurley (Indiana University, Indianapolis, IN) for providing the modified ALDH1B1 plasmid and for a critical reading of the manuscript. The Protein Production / Tissue Culture / MoAB Shared Resource at the University of Colorado Cancer Center provided expression of ALDH1B1 in eukaryotic cells, and is supported by the Cancer Center Support Grant (P30CA046934). This work was supported, in part, by the following NIH Grants—EY11490, AA021724, and AA022057. Fellowship support to B.C.J. (F31 AA020728) is also acknowledged.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, 12850 E. Montview Blvd., Aurora, Colorado, 80045, USA

    Brian C. Jackson, Philip Reigan & Bettina Miller

  2. Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, 80045, USA

    David C. Thompson

  3. Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06520-8034, USA

    Vasilis Vasiliou

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  1. Brian C. Jackson
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Correspondence to Vasilis Vasiliou.

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Figure S1

Amino acid alignment of ALDH1B1 and ALDH2. An alignment was generated by T-COFFEE (23). Amino acids are classified as identical (*), highly similar (:), somewhat similar (.), or dissimilar ( ). Secondary structures are labeled by homology with ALDH2 with beta pleated sheets tinted blue and alpha helices tinted green. ALDH1B1 polymorphic variants are indicated by arrows and labeled as *2, *3, and *5. (PDF 54 kb)

Figure S2

Representative three dimensional docking poses for substrates of ALDH1B1. Amino acids of ALDH1B1 that make hydrogen bonds to the substrate are displayed as ball-and-stick figures and are labeled. Substrates are shown as stick figures (non-polar hydrogen atoms and bond order are not shown). Hydrogen bonds are shown as dashed green lines. (PDF 374 kb)

Figure S3

Scoring functions for ALDH1B1 wild type and variant homology models. Initial models were ranked by DOPE score, an unnormalized score with an arbitrary scale designed for choosing the most native-like model from multiple homology models (37). Also shown is the Z-score, a normalized DOPE score in which scores >0 indicate relatively poor models, and scores < −1 are considered more ‘native-like’. The minimization energy of the final minimized homology model is also shown. Positive numbers or large differences in this score between models might indicate some major defect in protein structure. (PDF 20 kb)

Figure S4

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Jackson, B.C., Reigan, P., Miller, B. et al. Human ALDH1B1 Polymorphisms may Affect the Metabolism of Acetaldehyde and All-trans retinaldehyde—In Vitro Studies and Computational Modeling. Pharm Res 32, 1648–1662 (2015). https://doi.org/10.1007/s11095-014-1564-3

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