Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets

Brandon L. Greene, Gyunghoon Kang, Chang Cui, Marina Bennati, Daniel G. Nocera, Catherine L. Drennan, Jo Anne Stubbe

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)45-75
Number of pages31
JournalAnnual review of biochemistry
Volume89
DOIs
StatePublished - Jun 20 2020
Externally publishedYes

Keywords

  • mechanisms
  • Ribonucleotide reductases
  • structures
  • therapeutics

ASJC Scopus subject areas

  • Biochemistry

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