Computational analysis of human medium-chain dehydrogenases/reductases revealing substrate- and coenzyme-binding characteristics.

Autor: Östberg LJ; Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: linus.ostberg@conoa.se., Höög JO; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: jan-olov.hoog@ki.se., Persson B; Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, SE-751 05 Uppsala, Sweden. Electronic address: bpn@icm.uu.se.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 Feb 25; Vol. 390, pp. 110876. Date of Electronic Publication: 2024 Jan 22.
DOI: 10.1016/j.cbi.2024.110876
Abstrakt: The medium-chain dehydrogenase/reductase (MDR) superfamily has more than 600,000 members in UniProt as of March 2023. As the family has been growing, the proportion of functionally characterized proteins has been falling behind. The aim of this project was to investigate the binding pockets of nine different MDR protein families based on sequence conservation patterns and three-dimensional structures of members within the respective families. A search and analysis methodology was developed. Using this, a total of 2000 eukaryotic MDR sequences belonging to nine different families were identified. The pairwise sequence identities within each of the families were 80-90 % for the mammalian sequences, like the levels observed for alcohol dehydrogenase, another MDR family. Twenty conserved residues were identified in the coenzyme part of the binding site by matching structural and conservation data of all nine protein families. The conserved residues in the substrate part of the binding pocket varied between the nine MDR families, implying divergent functions for the different families. Studying each family separately made it possible to identify multiple conserved residues that are expected to be important for substrate binding or catalysis of the enzymatic reaction. By combining structural data with the conservation of the amino acid residues in each protein, important residues in the binding pocket were identified for each of the nine MDRs. The obtained results add new positions of interest for the binding and activity of the enzyme family as well as fit well to earlier published data. Three distinct types of binding pockets were identified, containing no, one, or two tyrosine residues.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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