TY - JOUR
T1 - Ribonucleotide Reductases
T2 - Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets
AU - Greene, Brandon L.
AU - Kang, Gyunghoon
AU - Cui, Chang
AU - Bennati, Marina
AU - Nocera, Daniel G.
AU - Drennan, Catherine L.
AU - Stubbe, Jo Anne
N1 - Publisher Copyright:
© 2020 Annual Reviews Inc.. All rights reserved.
PY - 2020/6/20
Y1 - 2020/6/20
N2 - 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.
AB - 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.
KW - mechanisms
KW - Ribonucleotide reductases
KW - structures
KW - therapeutics
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U2 - 10.1146/annurev-biochem-013118-111843
DO - 10.1146/annurev-biochem-013118-111843
M3 - Review article
C2 - 32569524
AN - SCOPUS:85083822147
SN - 0066-4154
VL - 89
SP - 45
EP - 75
JO - Annual review of biochemistry
JF - Annual review of biochemistry
ER -