GarethJennings 185x245Post-doctoral Fellow, UCSD

Skaggs School of Pharmacy and Pharmaceutical Sciences

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My research efforts center on the inner workings of cytochromes P450. My interest in these enzymes arose out of my Ph.D. work, in which I was investigating the catalytic intermediates involved in Mycobacterium tuberculosis CYP51A1 demethylation of the substrate, lanosterol. CYP51A1, or lanosterol 14alpha-demethylase, is an enzyme that is critical for sterol biosynthetic pathways in all biological kingdoms. CYP51A1 is an important topic of research not only because it has an intriguing catalytic cycle that facilitates the cleavage of an unactivated carbon-carbon bond but because of its clinical relevance as a drug target. Azole antifungals have been successful in clearing fungal infections in plants and animals, by their inhibition of sterol biosynthesis by CYP51A1 in fungi. These fungicidal drugs have been a critical tool for the understanding of protein-inhibitor interactions and development of new inhibitors of CYP51A1 in other infectious organisms.

My current work in Dr Podust’s laboratory is focused on structure/function studies of cytochromes P450 of infectious organisms, making use of X-ray crystallography and spectroscopy. These studies will serve as the platform for the validation of these enzymes as drug targets, as well as the structure activity relationships of current and new therapeutics in the treatment of parasitic diseases.

PUBLICATIONS

Rapid Chagas Disease Drug Target Discovery Using Directed Evolution in Drug-Sensitive Yeast. ACS Chem Biol. 2017 Feb 17;12(2):422-434. doi: 10.1021/acschembio.6b01037. Ottilie S, Goldgof GM, Calvet CM, Jennings GK, LaMonte G, Schenken J, Vigil E, Kumar P, McCall LI, Lopes ES, Gunawan F, Yang J, Suzuki Y, Siqueira-Neto JL, McKerrow JH, Amaro RE, Podust LM, Durrant JD, Winzeler EA.

N-Heterocyclic Carbene Capture by Cytochrome P450 3A4. Mol Pharmacol. 2016 Jul;90(1):42-51. doi: 10.1124/mol.116.103721. Epub 2016 Apr 28. Jennings GK, Ritchie CM, Shock LS, Lyons CE, Hackett JC.

Evidence for an elevated aspartate pK(a) in the active site of human aromatase. J Biol Chem. 2015 Jan 9;290(2):1186-96. doi: 10.1074/jbc.M114.595108. Epub 2014 Nov 25. Di Nardo G, Breitner M, Bandino A, Ghosh D, Jennings GK, Hackett JC, Gilardi G.

Spin equilibrium and O₂-binding kinetics of Mycobacterium tuberculosis CYP51 with mutations in the histidine-threonine dyad. J Inorg Biochem. 2014 Jul;136:81-91. doi: 10.1016/j.jinorgbio.2014.03.017. Epub 2014 Apr 12. Jennings GK, Modi A, Elenewski JE, Ritchie CM, Nguyen T, Ellis KC, Hackett JC.