Pieter Dorrestein went to Northern Arizona University primarily for the rocks. The rocky landscape made it the obvious choice for an aspiring geologist, and the rock climbing was just as appealing. In 1997, as a sophomore, Dorrestein heard that chemist John MacDonald was looking for a climbing partner. Once they'd paired up, the two hit it off and Dorrestein became fascinated with MacDonald's work in molecular crystal structure. He joined MacDonald's lab that same year.
I got so fascinated by these large molecular structures — not just small molecule crystallography, but large molecule crystallography," Dorrestein says. "So I started reading papers on crystal structure."
In 1998, Dorrestein began graduate work at Cornell University, with the intention of building small molecules that interact with proteins. However, he soon switched into Tadhg Begley's lab, which was concentrating on vitamin biosynthesis â?? a process that also involves small molecular interactions, but with a real health application, Dorrestein says. He quickly lost focus on crystallization, and set to work uncovering the enzymatic process of vitamin B1 (thiamin) synthesis. By expressing the gene products necessary to the vitamin's biosynthesis in Escherichia coli, Dorrestein successfully isolated the enzymatic steps to B1's formation.
After finishing his PhD, Dorrestein wanted to further investigate interactions between small molecules and proteins by using high-resolution mass spectrometry tools. So in 2004, he began a postdoc in Neil Kelleher's lab at the University of Illinois, Urbana-Champagne. In the two years of his postdoc, Dorrestein developed two novel assays to determine the molecules that are attached to particular proteins and how they interact. He published more than 15 papers, including one in 2005 in which he demonstrated that the natural antifungal, pyoluteorin, uses the enzyme halogenase in a novel way to generate its potency.
One of the assays that Dorrestein designed can detect bioactive natural compounds (i.e., secondary metabolites) such as toxins, odors, and pheromones. This tool may be useful for screening for new therapeutic drug targets.
In 2006, Dorrestein accepted an assistant professorship at the University of California, San Diego, Skaggs School of Pharmacology and Pharmaceutical Sciences. Building on the assays he designed, Dorrestein is pushing into new frontiers for using mass spectrometry to find potential therapeutic agents. In collaboration with William Gerwick at Scripps Research Institute, Dorrestein is examining marine sponges that house large colonies of cyanobacteria in symbiotic relationships.
Using high-resolution imaging and genomics, Dorrestein has already begun to isolate the exact organisms that are producing bioactive compounds in these heterogeneous samples. Going further, his team is close to identifying the gene clusters in certain organisms that are producing secondary metabolites, which may have therapeutic potential.
This newest project is a long way from crystallography, and another case of getting swept up in exciting science, says Dorrestein. "If you had asked me six to eight months ago if I would have gone this direction, I would have laughed at you."
Title: Assistant Professor, UCSD Skaggs School of Pharmacy
1. J.H. Park et al., "Biosynthesis of the thiazole moiety of thiamin pyrophosphate (Vitamin B1)," Biochemistry, 42:12430-8, 2003. (Cited in 46 papers) 2. P.C. Dorrestein et al., "Dichlorination of a pyrrolyl-S-carrier protein by FADH(2)-dependent halogenase PltA during pyoluteorin biosynthesis," PNAS, 102:13843-8, 2005. (Cited in 32 papers) 3. P.C. Dorrestein et al., "Facile detection of acyl and peptidyl intermediates on thiotemplate carrier domains via phosphopantetheinyl elimination reactions during tandem mass spectrometry," Biochemistry, 45:12756-66, 2006. (Cited in 7 papers)