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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.
- 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.)
- Subjects :
- Biocatalysis
Crystallography, X-Ray
Density Functional Theory
Methyltransferases chemistry
Methyltransferases genetics
Models, Molecular
Molecular Structure
Polyisoprenyl Phosphates chemistry
Sesquiterpenes chemistry
Streptomyces enzymology
Substrate Specificity
Methyltransferases metabolism
Polyisoprenyl Phosphates metabolism
Sesquiterpenes metabolism
Subjects
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