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Structural and Molecular Basis of the Catalytic Mechanism of Geranyl Pyrophosphate C6-Methyltransferase: Creation of an Unprecedented Farnesyl Pyrophosphate C6-Methyltransferase.

Authors :
Tsutsumi H
Moriwaki Y
Terada T
Shimizu K
Shin-Ya K
Katsuyama Y
Ohnishi Y
Source :
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2022 Jan 03; Vol. 61 (1), pp. e202111217. Date of Electronic Publication: 2021 Nov 23.
Publication Year :
2022

Abstract

Prenyl pyrophosphate methyltransferases enhance the structural diversity of terpenoids. However, the molecular basis of their catalytic mechanisms is poorly understood. In this study, using multiple strategies, we characterized a geranyl pyrophosphate (GPP) C6-methyltransferase, BezA. Biochemical analysis revealed that BezA requires Mg <superscript>2+</superscript> and solely methylates GPP. The crystal structures of BezA and its complex with S-adenosyl homocysteine were solved at 2.10 and 2.56 Å, respectively. Further analyses using site-directed mutagenesis, molecular docking, molecular dynamics simulations, and quantum mechanics/molecular mechanics calculations revealed the molecular basis of the methylation reaction. Importantly, the function of E170 as a catalytic base to complete the methylation reaction was established. We also succeeded in switching the substrate specificity by introducing a W210A substitution, resulting in an unprecedented farnesyl pyrophosphate C6-methyltransferase.<br /> (© 2021 Wiley-VCH GmbH.)

Details

Language :
English
ISSN :
1521-3773
Volume :
61
Issue :
1
Database :
MEDLINE
Journal :
Angewandte Chemie (International ed. in English)
Publication Type :
Academic Journal
Accession number :
34626048
Full Text :
https://doi.org/10.1002/anie.202111217