Biochemistry, Chemical Biology, Mass spectrometry; Harvesting genomic information for therapeutics.
Ph.D., , Cornell University
M.S., , Cornell University
B.S., , Northern Arizona University
Awards and Academic Honors
Hearst Foundation Award
Unsolicited ACACC award by Lilly company in Analytical Chemistry
PhRMA Foundation Research Award.
Named to be a V-foundation Scholar
Featured in the journal Scientist as a scientist to watch
Beckman Young Investigator.
American Cancer Society/ Moores Cancer Center research grant
NIH NRSA Kirschstein fellowship
Wentink Award for best thesis in chemical biology
Vincent DuVineaud Award for best poster
McCalister Award for top graduating senior in chemistry
The Dorrestein laboratory began at UCSD Sept. 1, 2006 and is a highly interdisciplinary environment. His lab uses chemical biological, organic chemical, biochemical, genomic, proteomic, bioanalytical, and other modern biomedical approaches to interrogate the classification of therapeutically relevant proteins that are related to the biosynthesis of secondary metabolites or involved in the formation of post-translational modifications. The Dorrestein lab has a FT-ICR mass spectrometer equipped with a nanospray robot to accomplish this research.
Two representative projects that are ongoing in the Dorrestein laboratory are: 1) The characterization of the virulence factor genes from group B streptococci. 2) Orphan polyketide and non-ribosomal peptide synthetase gene clusters.
Most pregnant women in the United States get screened for group B streptococci (GBS) before delivery. The reason for this screen is because GBS can be passed to the fetus during the delivery. Once the newborn is infected by GBS, it can cause invasive infections such as inflammation of the brain, spinal cord, and/or lungs (sepsis, meningnitis, pneumonia etc.) resulting in developmental problems, paralysis or even death. If the mother is treated with antibiotics such ampicillin, 4-24 hours before the delivery, the risks are greatly diminished. We are in the process of functionally characterizing the genes involved in the formation of virulence factors produced by GBS.
Nearly 50% of all our anti-cancer agents and 75% of all anti-microbial agents are natural products or have origins in natural products. Just a few recent examples that have been discovered are: the FDA approved drug, Mylotarg, a DNA cleaving agent called calicheamycin that is linked to an antibody specifically recognizing CD33. CD33 is a protein on the cell surface that is upregulated in 20-25% of leukemias. Epothilone, a natural product from myxobacterium Sorangium cellulosum, that is now in clinical trials to treat breast and lung cancers. Finally, the proteasome inhibitor salinosporamide that has entered first clinical trials to treat myolomas. Each of these therapeutic molecules are produced by microorganisms via the non-ribosomal peptide or the polyketide biosynthetic paradigm. Inspecting the genomes of microorganisms that produce these natural products, one will find that 80-90% of all the genes that encode for polyketide synthase (PKS) or non-ribosomal peptide synthetase (NRPS) genes that are responsible for the generation of bioactive molecules have no known function (orphan genes). In other words, the microorganisms have 8 to 9 times the metabolic potential to produce natural products with therapeutic properties. Currently there is a limited set of tools to harvest this biosynthetic knowledge for the discovery of new therapeutic agents. The Dorrestein laboratory is developing mass spectrometry based tools to harvest this untapped biotherapeutic resource.
Primary Research Area
- Calderone, C. T., Kowtoniuk, W. E., Kelleher, N. L., Walsh, C. T., Dorrestein, P. C. Convergence of isoprene and polyketide biosynthetic machinery: isoprenyl-S-carrier proteins in the pksX pathway of B. subtilis. Proceedings of the National Academy of Sciences of the United States of America . (2006), 103, 8977-8982.
- Dorrestein, P.C., Kelleher, N.L., Dissecting Non-ribosomal and Polyketide Biosynthetic Machineries Using Electrospray Ionization Fourier-Transform Mass Spectrometry. Natural Products Reports, (2006) 23 893-918.
- Dorrestein, P. C., Van Lanen, S.G., Wenli, L., Chunhua Zhao, Zixin Deng, Ben Shen, Neil L. Kelleher. The Bifunctional Phosphatase/ Glyceryl Transferase Belonging to the HAD Superfamily Diverts the Primary Metabolite 1,3-Bisphosphoglycerate into Polyketide Derived Secondary Metabolites. (2006) Journal of the American Chemical Society.128 (32); 10386-10387.
- Dorrestein, P.C. , Blackhall, J., Straight, P.D., Fischbach, M.A., Garneau-Tsodikova, S., Edwards, D.J., McLaughlin, S., Lin, M., Gerwick, W.H., Kolter, R., Walsh, C.T., Kelleher, N.L. Activity Screening of Carrier Domains within Nonribosomal Peptide Synthetases Using Complex Substrate Mixtures and Large Molecule Mass Spectrometry. Biochemistry (2006) 45(6), 1537-1546.
- Dorrestein, P.C., Stefanie B. Bumpus, Christopher T. Calderone, Sylvie Garneau-Tsodikova, Zachary Aron, Paul Straight, Roberto Kolter, Christopher T. Walsh and Neil L. Kelleher, Facile Detection of Acyl- and Peptidyl- intermediates on Thiotemplate Carrier Domains via Phosphopantetheinyl Elimination Reactions During Tandem Mass Spectrometry. Biochemistry (2006) 45 (6), 1537 1546.