Study Explains How One Enzyme Can Synthesize All Four DNA Bases
A single enzyme, ribonucleotide reductase (RNR), is responsible for making all four deoxyribonucleotides (dNTPs) and ensuring that they are present at the ratios required to synthesize new DNA. This is possible because RNRs change their substrate specificity in response to dNTP abundance. For example, when dGTP is abundant it binds RNR, increase its affinity for ADP, and thus shifts synthesis to dATP. Scientists in the Drennan lab at the Massachusetts Institute of Technology have long been fascinated by this unusual enzyme and now describe the allosteric changes that underlie RNR’s ability to shift specificity and maintain the proper dNTP pool in our cells.
Unlike other effectors, that “merely” up- or downregulate an enzyme’s activity, when dNTPs bind RNR they can change the enzyme’s specificity. Using X-ray crystallography Zimanyi et al solved the structure of the E. coli class la RNR bound to all four substrate/specificity effector pairs (CDP/dATP, UDP/dATP, ADP/dGTP, and GDP/TTP). These structures show that when a substrate/effector pair is bound, RNR’s active site clamps down and loop 2 of the protein adopts effector-specific conformations. When a matching substrate/effector pair is bound these structural rearrangement allow an arginine residue to reach over the active site, latching it shut and creating an environment that facilitates the radical-based chemistry required for deoxyribonicleotide synthesis. When a mismatched substrate/effector pair is bound the active site remains “unlatched,” presumably allowing the mis-matched substrate to diffuse out of the active site.
RNR is already a target for cancer treatment since cancer cells require large pools of deoxyribonucleotides. The wealth of structural information provided by Zimanyi et al may now allow more rational drug design and thus more effective cancer treatments. The Drennan lab is also interested in expanding their studies to human RNRs since understanding the differences between human and bacterial RNRs could potentially allow RNR inhibitors to be used to treat bacterial and viral infections.
Source: Massachusetts Institute of Technology