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  Ribonucleotide reductases: Structure, chemistry, and metabolism suggest new therapeutic targets

Greene, B. L., Kang, G., Cui, C., Bennati, M., Nocera, D. G., Drennan, C. L., et al. (2020). Ribonucleotide reductases: Structure, chemistry, and metabolism suggest new therapeutic targets. Annual Review of Biochemistry, 89, 45-75. doi:10.1146/annurev-biochem-013118-111843.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-A0FC-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-A1B7-5
Genre: Journal Article

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3240493.pdf (Publisher version), 4MB
 
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 Creators:
Greene, B. L., Author
Kang, G., Author
Cui, C., Author
Bennati, M.1, Author              
Nocera, D. G., Author
Drennan, C. L., Author
Stubbe, J., Author
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1Research Group of Electron Paramagnetic Resonance, MPI for Biophysical Chemistry, Max Planck Society, ou_578606              

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Free keywords: ribonucleotide reductases, structures, mechanisms, therapeutics
 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. RNRs’ central 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.

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Language(s): eng - English
 Dates: 2020-062020-06
 Publication Status: Published in print
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 Rev. Method: Peer
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Title: Annual Review of Biochemistry
Source Genre: Journal
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Pages: - Volume / Issue: 89 Sequence Number: - Start / End Page: 45 - 75 Identifier: -