Chris Reinhardt graduated with a B.Sc. in Chemistry and Biology from the State University of New York, University at Buffalo in 2015. While there, Chris worked under the direction of Prof. John Richard where he employed triosephosphate isomerase (a diffusion-controlled enzyme) as a model to study the use of flexible loops, hydrophobic caging and dianion binding energy as general mechanisms for rate acceleration in biological catalysis. In 2016 Chris joined Prof. Jefferson Chan’s laboratory at the University of Illinois at Urbana-Champaign where he is currently developing new methods for measuring enzyme-catalyzed kinetic isotope effects to aid in the development of highly specific chemical biology probes. Following graduation, Chris hopes to continue on to a postdoctoral position and ultimately a career in academia.
The overuse of antibiotics has generated an unprecedented number of multiple drug resistant and extensively drug resistant bacteria, which have rendered our current antibiotic arsenal ineffective. For example, tuberculosis (TB), a once curable bacterial infection, is now exhibiting significant drug resistance where these strains have notably lowered survival rates. Since approximately one third of the world’s population is estimated to be infected with TB, this presents a clear and imminent threat. As such, it is critical to develop new chemical biology tools to study the pathogenic mechanisms of these microbes. With a more complete understanding it will be possible to develop new therapeutics.
A promising method for developing potent and specific small molecule probes is by designing transition state analogs (TSAs). By mimicking the transition state with a stable counterpart, it is possible to specifically target and thermodynamically trap proteins in an unproductive state. Current methods for developing TSAs using kinetic isotope effect measurements are limited by the need for radioactive nuclei or difficult to access contiguous isotopic labels. To combat this problem, we developed a novel continuous carbon NMR based approach to measure competitive enzymatic kinetic isotope effects. Herein we report the biosynthesis of natural substrate analogs and precursors for the chemoenzymatic synthesis of isotopically labeled nicotinamide adenine dinucleotide.