Faculty

Jarrod FrenchJarrod B. French, Assistant Professor

B.Sc. Brock University, St. Catharines, ON, Canada, 2004
Ph.D. Cornell University, Ithaca, NY, 2010
CIHR Postdoctoral Fellow, The Pennsylvania State University, 2011 – 2013

 

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Structural Biology, Chemical Biology and Enzymology of Metabolic Pathways and Protein Complexes

We take a highly interdisciplinary approach to study the structure, function and control of enzymes and enzyme complexes involved in cellular metabolism. We are particularly interested in understanding how multi-protein macromolecular machines provide spatial and temporal control over metabolic pathways in cells. Our long term goal is to characterize the structure, functions and control mechanisms of these protein assemblies and to exploit this information to develop novel treatments for cancer and inflammatory diseases such as rheumatoid arthritis. To this end, we employ a variety of techniques including X-ray crystallography, mechanistic enzymology, microscopy and chemical biology.

Characterization of multifunctional proteins involved in purine and pyrimidine biosynthesis in eukaryotes

image 1Structure of L. donovani OMPDC-OPRT, a bifuntional enzyme that catalyzes the final two steps of pyrmidine biosynthesis

Many enzymes in humans and other eukaryotes catalyze multiple steps in metabolic pathways. These multi-domain enzymes are usually very difficult to characterize due to their inherent flexibility and large size. Often these proteins undergo significant conformational changes in response to ligand binding, post-translational modification or when interacting with other proteins. Understanding the structure of such multi-domain enzymes provides a significant opportunity for drug development. Enzymes involved in purine and pyrimidine biosynthesis are of particular interest as this metabolic pathway has been validated as an anti-cancer target (greater than 20% of all clinically approved cancer treatments are purine or pyrimidine anti-metabolites).

Structure and control of the purinosome

Recently, a multi-enzyme metabolic machine involved in purine biosynthesis was discovered. This dynamic and reversible protein complex, called the purinosome, forms when cells are depleted of purines and has been demonstrated to be a potential target for anti-cancer chemotherapeutics. We are investigating the structure and assembly process of this protein agglomerate and hope to use this information to understand how such phenomena may help control metabolism in cells. We are also interested in how such complexes may influence metabolic reprogramming in cancer cells.

image 2HeLa cells grown in normal growth media exhibit a diffuse distribution of biosynthetic enzymes (left), but when purines are depleted from the media, the enzymes cluster into purinosomes.

 

image 3

Drug discovery

One of the long term goals of our research is to use our knowledge of the structure and function of enzymes and protein complexes to develop drugs to treat human disease. Using novel assays, we employ both conventional high-throughput methodologies as well as structure-guided approaches to identify, characterize and optimize lead compounds.

Publications

Guo, F., French, J.B., Li, P., Zhao, H., Chan, K.Y., Fick, J.R.,  Benkovic, S.J., and Huang, T.J. (2013) Probing cell-cell communication with microfluidic devices. Lab on a Chip. 13(16): 3152-62.

Liu, C.T., Hanoian, P., French, J.B., Pringle, T.H., Hammes-Schiffer, S., and Benkovic, S.J. (2013) Functional Significance of Evolving Protein Sequence in Dihydrofolate Reductase from Bacteria to Humans. Proc. Natl. Acad. Sci. U.S.A. 110(25): 10159-64.     

Zhao, Y., Chen, D., Yue, H, French, J.B., Benkovic, S.J. and Huang, T.J. (2013) Single Molecule Studies on Chip. Lab on a Chip. 13(12): 2183-98.

Zhao, H., French. J.B., Fang, Y. and Benkovic, S.J. (2013) The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humans. Chem. Comm. 49(40): 4444-4452.

French, J.B., Zhao, H., Niessen,S., An, S., Cravatt, B.F., and Benkovic, S.J. (2013) The Hsp90/Hsp70 Chaperone Machinery is Involved in the Assembly of the Purinosome. Proc. Natl. Acad. Sci. U.S.A. 110(7): 2528-33.

Fang, Y., French, J.B., Zhao, H., and Benkovic, S.J. (2013) G protein-coupled receptor regulation of de novo purine biosynthesis: a novel druggable mechanism. Biotechnol. Genet. Eng. 29(1): 31-48.     

Deng, Y., Gam, J., French, J.B., Zhao, H. and Benkovic, S.J. (2012) Mapping Protein-Protein Interactions in the Purinosome.  J. Biol. Chem. 287(43): 36201-7.

French, J.B.,  Yates, P.A., Soysa, D.R., Boitz, J.M., Carter, N.S., Chang, B., Ullman, B., Ealick, S.E. (2011) The Leishmania donovani UMP Synthase is Essential for Promastigote Viability and has an Unusual Tetrameric Structure that Exhibits Substrate-Controlled Oligomerization.  J. Biol. Chem. 286(23): 20930-41.

French, J.B., Begley, T.P., Ealick, S.E. (2011) Structure of Trifunctional THI20 from Yeast.  Acta Cryst D. 67, 784-791.

French, J.B., Ealick, S.E. (2011) Structure of 5-Hydroxy Isourate Hydrolase from Klebsiella pneumoniae and Mechanistic Implications. Acta Cryst D.  67(Pt 8): 671-7.

French, J.B., Neau, D., Ealick, S.E. (2010) Characterization of the Structure and Function of Klebsiella pneumoniae Allantoin Racemase. J. Mol. Biol.  410(3): 447-460.

French, J.B., Cen, Y., Vrablik, T.L., Xu, P., Allen, E., Hanna-Rose, W., Sauve, A.A. (2010) Chacterization of Nicotinamidases: Steady-State Kinetic Parameters, Class-Wide Inhibition by Nicotinaldehydes and Catalytic Mechanism. Biochemistry. 49(49): 10421-39.

French, J.B., Ealick, S.E. (2010) Structural and Mechanistic Studies on Klebsiella pneumoniae 2-Oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline Decarboxylase. J. Biol. Chem. 285(46): 35446-54.

French, J.B.,  Cen, Y., Sauve, A.A., Ealick, S.E. (2010) High Resolution Crystal Structures of Streptococcus pneumoniae Nicotinamidase with Trapped Intermediates Provide Insights into Catalytic Mechanism and Inhibition by Aldehydes. Biochemistry 49(40): 8803-8812.

French, J.B., Ealick, S.E. (2010) Biochemical and Structural Characterization of a Ureidoglycine Aminotransferase in the Klebsiella pneumoniae Uric Acid Catabolic Pathway. Biochemistry (Rapid Report). 49: 5975-7.

French, J.B., Cen, Y., Sauve, A.A. (2008) Plasmodium falciparum Sir2 is an NAD+-dependent deacetylase and an acetyllysine-dependent and acetyllysine-independent NAD+ glycohydrolase. Biochemistry 47: 10227-39.

French, J.B., Holland, G., Holland, H.L., Gordon, H.L. (2004) A Comparative Molecular Field Analysis of the Biotransformation of Sulfides by Rhodococcus erythropolis. J. Molec. Cat. B: Enzym. 31: 87-96.

Holland, H.L., Brown, F.M., Barrett, F., French, J., Johnson, D. (2003) Biotransformations of β-ketosulfides to produce chiral β-hydroxysulfoxides. J. Ind. Microbiol. Biotech. 30: 292-296.

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