Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets
Name
nihms-1063546.pdf
Description
Accepted version
Size
3.14 MB
Format
Unknown
Checksum (MD5)
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Author(s)
Greene, Brandon L.
Kang, Gyunghoon
Cui, Chang
Bennati, Marina
Norcera, Daniel G.
Drennan, Catherine L
Stubbe, JoAnne
Date Issued
2020
Journal
Annual Review of Biochemistry
Publisher
Annual Reviews
Version
Author's final manuscript
Abstract
© 2020 Annual Reviews Inc.. All rights reserved. Ribonucleotide reductases (RNRs) catalyze the de novo conversion of nucleotides to deoxynucleotides in all organisms, controlling their relative ratios and abundance. In doing so, they play an important role in fidelity of DNA replication and repair. RNRscentral role in nucleic acid metabolism has resulted in five therapeutics that inhibit human RNRs. In this review, we discuss the structural, dynamic, and mechanistic aspects of RNR activity and regulation, primarily for the human and Escherichia coli class Ia enzymes. The unusual radical-based organic chemistry of nucleotide reduction, the inorganic chemistry of the essential metallo-cofactor biosynthesis/maintenance, the transport of a radical over a long distance, and the dynamics of subunit interactions all present distinct entry points toward RNR inhibition that are relevant for drug discovery. We describe the current mechanistic understanding of small molecules that target different elements of RNR function, including downstream pathways that lead to cell cytotoxicity. We conclude by summarizing novel and emergent RNR targeting motifs for cancer and antibiotic therapeutics.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1146/ANNUREV-BIOCHEM-013118-111843
