Cobalamin-Dependent Radical S -Adenosylmethionine Enzymes: Capitalizing on Old Motifs for New Functions
Name
acsbiomedchemau.1c00051.pdf
Description
Published version
Size
13.58 MB
Format
Adobe PDF
Checksum (MD5)
cdb68be539c3f942c410cc95a9c0f56b
Author(s)
Bridwell-Rabb, Jennifer
Li, Bin
Drennan, Catherine L
Date Issued
2022
Journal
ACS Bio & Med Chem Au
Publisher
American Chemical Society (ACS)
Citation
Bridwell-Rabb, Jennifer, Li, Bin and Drennan, Catherine L. 2022. "Cobalamin-Dependent Radical S -Adenosylmethionine Enzymes: Capitalizing on Old Motifs for New Functions." ACS Bio & Med Chem Au, 2 (3).
Version
Final published version
Abstract
The members of the radical S-adenosylmethionine (SAM) enzyme superfamily are responsible for catalyzing a diverse set of reactions in a multitude of biosynthetic pathways. Many members of this superfamily accomplish their transformations using the catalytic power of a 5'-deoxyadenosyl radical (5'-dAdo•), but there are also enzymes within this superfamily that bind auxiliary cofactors and extend the catalytic repertoire of SAM. In particular, the cobalamin (Cbl)-dependent class synergistically uses Cbl to facilitate challenging methylation and radical rearrangement reactions. Despite identification of this class by Sofia et al. 20 years ago, the low sequence identity between members has led to difficulty in predicting function of uncharacterized members, pinpointing catalytic residues, and elucidating reaction mechanisms. Here, we capitalize on the three recent structures of Cbl-dependent radical SAM enzymes that use common cofactors to facilitate ring contraction as well as radical-based and non-radical-based methylation reactions. With these three structures as a framework, we describe how the Cbl-dependent radical SAM enzymes repurpose the traditional SAM- and Cbl-binding motifs to form an active site where both Cbl and SAM can participate in catalysis. In addition, we describe how, in some cases, the classic SAM- and Cbl-binding motifs support the diverse functionality of this enzyme class, and finally, we define new motifs that are characteristic of Cbl-dependent radical SAM enzymes.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1021/ACSBIOMEDCHEMAU.1C00051
