title: Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Jackson
authors.forename: Philip
authors.initials: P
authors.lastname: Reigan
authors.forename: Bettina
authors.initials: B
authors.lastname: Miller
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.forename: Vasilis
authors.initials: V
authors.lastname: Vasiliou
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D000595:Amino Acid Sequence; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005996:Nitroglycerin / Q000378:metabolism; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D012172:Retinaldehyde / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D000447:Aldehydes; D000080924:Aldehyde Dehydrogenase 1 Family; C524846:ALDH1B1 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin; D000079:Acetaldehyde; C027576:4-hydroxy-2-nonenal; D012172:Retinaldehyde