 Stewart Shuman

Stewart Shuman is a biochemist who investigates how enzymes modify and repair nucleic acids. His laboratory combines biochemistry, structural biology and genetics to connect a particular chemical reaction with the protein machinery that performs it.^[ref]

With Anupam K. Chakravarty, Shuman tested competing reaction mechanisms for the RNA ligase RtcB. The question concerned the chemistry of the broken RNA ends: did a cyclic phosphate join directly to an opposing hydroxyl end, or did opening and activation precede sealing? Their 2012 experiments supported a GTP-dependent pathway involving hydrolysis, activated reaction intermediates and formation of a new phosphodiester bond.^[ref]

The logical force of such an experiment can be seen without assuming that a successful final reaction reveals every step. Suppose mechanisms A and B both predict a joined RNA molecule, but A requires GTP even when the starting end already contains a cyclic phosphate, whereas B predicts that this substrate bypasses the GTP requirement. Comparing otherwise equivalent reactions with and without GTP distinguishes those predictions. Detecting an intermediate also requires attention to chemical kinetics: a species appearing only after product accumulation cannot explain an earlier obligatory step. These are general reasons to combine selective changes in starting chemistry with time-resolved measurements, rather than identifying a reaction mechanism solely from the final product.