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Computational studies of human class V alcohol dehydrogenase - the odd sibling
Karolinska Inst, Sci Life Lab, Dept Med Biochem & Biophys, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Sci Life Lab, Dept Med Biochem & Biophys, Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
2016 (English)In: BMC Biochemistry, ISSN 1471-2091, E-ISSN 1471-2091, Vol. 17, 16Article in journal (Refereed) Published
Abstract [en]

Background: All known attempts to isolate and characterize mammalian class V alcohol dehydrogenase (class V ADH), a member of the large ADH protein family, at the protein level have failed. This indicates that the class V ADH protein is not stable in a non-cellular environment, which is in contrast to all other human ADH enzymes. In this report we present evidence, supported with results from computational analyses performed in combination with earlier in vitro studies, why this ADH behaves in an atypical way. Results: Using a combination of structural calculations and sequence analyses, we were able to identify local structural differences between human class V ADH and other human ADHs, including an elongated beta-strands and a labile a-helix at the subunit interface region of each chain that probably disturb it. Several amino acid residues are strictly conserved in class I-IV, but altered in class V ADH. This includes a for class V ADH unique and conserved Lys51, a position directly involved in the catalytic mechanism in other ADHs, and nine other class V ADH-specific residues. Conclusions: In this study we show that there are pronounced structural changes in class V ADH as compared to other ADH enzymes. Furthermore, there is an evolutionary pressure among the mammalian class V ADHs, which for most proteins indicate that they fulfill a physiological function. We assume that class V ADH is expressed, but unable to form active dimers in a non-cellular environment, and is an atypical mammalian ADH. This is compatible with previous experimental characterization and present structural modelling. It can be considered the odd sibling of the ADH protein family and so far seems to be a pseudoenzyme with another hitherto unknown physiological function.

Place, publisher, year, edition, pages
2016. Vol. 17, 16
Keyword [en]
Alcohol dehydrogenase, Mutational pressure, Pseudoenzyme, Sequence analysis, Structural calculations
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-304447DOI: 10.1186/s12858-016-0072-yISI: 000381571300001PubMedID: 27455956OAI: oai:DiVA.org:uu-304447DiVA: diva2:1033016
Funder
eSSENCE - An eScience Collaboration
Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2017-11-30Bibliographically approved

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