Ribonucleotide Reductases (RNRs): Structure and Function

Ribonucleotide reductases (RNRs) catalyze the conversion of nucleotides to deoxynucleotides in all organisms and play an essential role in DNA replication and DNA repair. They are able to harness the amazing reactivity of free radicals to effect chemically difficult reactions with exquisite specificity. They utilize diverse metallo-cofactors to generate an essential protein-based thiyl radical that initiates substrate reduction. In class I RNRs, a diferric-tyrosyl radical cofactor is proposed to generate the thiyl radical by means of a 35 Å proton-coupled electron transfer pathway, which is unprecedented in biology. Because of their central role, they are also successful targets of several drugs used clinically in the treatment of a number of malignancies.

Current projects in the group include:

(*) Investigating the radical propagation pathway utilized by Class I RNRs through the use of unnatural amino acids using methodology developed by the Schultz lab (Scripps). (In collaboration with the Nocera lab.)
(*) Studying biosynthesis, activation, and regulation of Class I RNRs in E. coli and S. cerevisiae.
(*) Elucidating interactions between protein subunits of Class I RNR using photo-crosslinking.
(*) Examining regulation of RNRs: allosteric effetcs on subunit interactions, subunit localization, and tyrosyl radical concentration.
(*) Revealing mechanisms of clinically useful drugs: gemcitibine, hydroxyurea.

PUBLIC HEALTH RELEVANCE: Ribonucleotide reductases (RNRs) are enzymes responsible for the conversion of nucleotides to deoxynucleotides, the monomeric building blocks of DNA. Thus, they play a key role in regulating DNA replication and repair, and are a successful clinical target for several types of cancer. The aim of this proposal is to study RNR's unique mechanism, the understanding of which will aid in developing novel RNR inhibitors.