Radical Enzymology

 Ribonucleotide Reductase: AN Exemplar of PCET in Biology

PCET is a ubiquitous mechanism in biology, serving as the basis for mediating steps involving biosynthesis of metabolites, radical generation and transport, and the activation of substrates at cofactors. The control of highly reactive radical intermediates is achieved via the coupling of proton and electron transfer processes. Management of radicals in biology by PCET is of particular relevance to human health, as radical-based enzymes are therapeutic targets for wide-ranging applications including chemotherapy, anti-retroviral and anti-bacterial drugs, and anti-inflammatory agents.  Of the radical-based enzymes that operate by PCET, ribonucleotide reductase (RNR) is exceptional in its biological function. RNR is paramount to human health owing to the enzyme’s function in nucleic acid metabolism and consequently its central role in cancer. An interdisciplinary approach integrates a suite of experimental methods encompassing biochemistry, steady-state and transient biophysical spectroscopies, synthesis, and electrochemistry to elucidate the radical transport pathways of RNR. We have found that small changes in proton distances induced by conformational changes significantly impact PCET kinetics and consequently overall RNR function in regulating healthy cellular homeostasis. With this understanding of PCET in RNR, the radical pathway can be targeted and interrupted, thus providing the opportunity for the design of new drugs for the treatment of cancer.