Structure-function investigation of 3-methylaspartate ammonia lyase reveals substrate molecular determinants for the deamination reaction.

Tytuł:: Structure-function investigation of 3-methylaspartate ammonia lyase reveals substrate molecular determinants for the deamination reaction.
Autorzy:: Saez-Jimenez V; Division of Industrial Biotechnology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
Maršić ŽS; Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark.
Lambrughi M; Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark.
Shin JH; Division of Industrial Biotechnology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
van Havere R; Division of Industrial Biotechnology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
Papaleo E; Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark.
Olsson L; Division of Industrial Biotechnology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
Mapelli V; Division of Industrial Biotechnology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
Źródło:: PloS one [PLoS One] 2020 May 21; Vol. 15 (5), pp. e0233467. Date of Electronic Publication: 2020 May 21 (Print Publication: 2020).
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: San Francisco, CA : Public Library of Science
MeSH Terms:: Models, Molecular*
Ammonia-Lyases/*metabolism
Binding Sites ; Deamination ; Molecular Docking Simulation ; Protein Conformation ; Structure-Activity Relationship
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Substance Nomenclature:: EC 4.3.1.- (Ammonia-Lyases)
EC 4.3.1.2 (methylaspartate ammonia-lyase)
Entry Date(s):: Date Created: 20200522 Date Completed: 20200812 Latest Revision: 20240328
Update Code:: 20240329
PubMed Central ID:: PMC7241714
DOI:: 10.1371/journal.pone.0233467
PMID:: 32437404
: Czasopismo naukowe

Pełny tekst

The enzymatic reactions leading to the deamination of β-lysine, lysine, or 2-aminoadipic acid are of great interest for the metabolic conversion of lysine to adipic acid. Enzymes able to carry out these reactions are not known, however ammonia lyases (EC 4.3.1.-) perform deamination on a wide range of substrates. We have studied 3-methylaspartate ammonia lyase (MAL, EC 4.3.1.2) as a potential candidate for protein engineering to enable deamination towards β-lysine, that we have shown to be a competitive inhibitor of MAL. We have characterized MAL activity, binding and inhibition properties on six different compounds that would allow to define the molecular determinants necessary for MAL to deaminate our substrate of interest. Docking calculations showed that β-lysine as well as the other compounds investigated could fit spatially into MAL catalytic pocket, although they probably are weak or very transient binders and we identified molecular determinants involved in the binding of the substrate. The hydrophobic interactions formed by the methyl group of 3-methylaspartic acid, together with the presence of the amino group on carbon 2, play an essential role in the appropriate binding of the substrate. The results showed that β-lysine is able to fit and bind in MAL catalytic pocket and can be potentially converted from inhibitor to substrate of MAL upon enzyme engineering. The characterization of the binding and inhibition properties of the substrates tested here provide the foundation for future and more extensive studies on engineering MAL that could lead to a MAL variant able to catalyse this challenging deamination reaction.
Competing Interests: The authors have declared that no competing interests exist.

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