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.
The first 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, and we initially 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). Our work unveiled 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). To further study this group of enzymes, we generated crystallographic “snapshots” of the an O2, PLP-dependent hydroxylase published in ACS Chemical Biology in 2018.
A third major effort in our group is focused on N-N bond formation. We asked: how can enzymes form N-N bonds in complex natural products? To pursue this question, we discovered 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). This non-proteinogenic amino acid residue is found in diverse natural products. More recently, we investigated the biosynthetic routes to N-nitroso natural products. N-nitroso molecules are carcinogens thought to be made through non-enzymatic pathways. But we speculated that enzymes might give rise to N-nitroso structures in natural products. We recently published our work on biosynthesis of an N-nitroso natural product in JACS.
Lately, our group is focused on X-RAY CRYSTALLOGRAPHY. 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 (firstname.lastname@example.org) 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).