How does nature construct complex molecules? What pathways and enzymes convert common precursors into bioactive drugs? The goal of my lab is to investigate the biosynthetic pathways in soil-dwelling bacteria that produce some of our most powerful antibiotics.
Many projects in our lab begin with the amino acid TRYPTOPHAN. This indole-containing molecule can be routed down a variety of pathways to generate chemical diversity. The first studies in my group focused on bisindoles called “cladoniamides.” We asked: how can this unusual scaffold be generated? It turns out that nature employs a widely used pathway to molecules called “indolocarbazoles” and adds in flavin-dependent monooxygenases, methyltransferases, and non-enzymatic chemistry to facilitate the astonishing rearrangement that gives the cladoniamide structure (see figure at right, or read our review on this area).
The second major project in my lab focused on the antibiotic INDOLMYCIN, an “old” antibiotic whose biogenetic origins were largely obscure. We attacked this problem with genome sequencing, deletion mutagenesis, and in vitro reconstitution to ultimately reveal that tryptophan- and arginine-derived precursors come together to give the unique oxazolinone scaffold of indolmycin (published in PNAS, 2015).
While studying the biogenesis of indolmycin, we happened upon enzymes Ind4 and Ind5, which turned out to be, respectively, a PLP-dependent oxidase and a stereospecific imine reductase (check out our paper in Nature Chemical Biology, published in 2016).
We also investigated how L-piperazic acid, a non-proteinogenic amino acid is constructed. We identified KtzT as the key, heme-dependent enzyme that catalyzes N-N bond formation of N-OH-L-ornithine to give L-piperazic acid. (check out our paper in Nature Chemical Biology, published in 2017).
Lately, our group has begun to focus on X-RAY CRYSTALLOGRAPHY. You can see our recent study on an O2, PLP-dependent hydroxylase published in ACS Chemical Biology in 2018. At the same time, we continue to pursue our work on elucidation of pathways to interesting natural products. Furthermore, our group is starting to expand into bacteria and pathways that play a key role in human biology.
We are currently seeking outstanding postdoctoral fellows to join our group. Please email me (email@example.com) with your CV and statement of interest. Postdoctoral fellows with experience in bacterial genetics, chemistry, and X-ray crystallography are especially welcomed to apply.
Graduate student inquiries are welcome. A prerequisite to admission into my group is admission into Chemistry – please see the Chemistry homepage for more information (https://www.chem.ubc.ca/graduate-admissions).