from genes to molecules

We are a chemical biology group that focuses on the study of natural products. Natural products are highly evolved and functionally privileged compounds that often display complex chemical structures. These molecules have inspired generations of synthetic organic chemists, unveiled numerous fundamental biological processes as chemical probes, and served as the most significant source of chemical matter for drug discovery.

As the field of genomics has expanded, it has revealed a vast untapped wealth of natural products encoded in the DNA of sequenced organisms, particularly bacteria. Our lab has developed new tools to expedite the discovery of natural products from genomic information, including molecules from bacteria that cannot be cultivated in a lab. In particular, our lab focuses on Ribosomally synthesized and Post-translationally modified Peptides (RiPPs) which have genetically encoded substrates and an incredible diversity of post-translational modifications. Using a genes-to-molecule approach, we have uncovered numerous structurally unique RiPP molecules and revealed the unprecedented mechanistic enzymology through which they form. We can then leverage this knowledge to produce new-to-nature compounds with improved properties or novel activity with the long-term goal of unleashing the full synthetic potential of Nature to reshape the diagnosis and treatment of human disease.

outsmarting bacteria since 2009»

Plantazolicin, a genetically-encoded molecule

recent news

Kyle has published a chapter in Methods in Enzymology describing bioinformatic and experimental protocols for RiPP recognition elements, peptide-binding domains that are prevalent in RiPP biosynthetic pathways.

Congratulations to Mayuresh for passing his preliminary exam!

Welcome to the newest members of the lab, Xiaopeng Liu and Dominic Luciano from chemical biology!

Congratulations to Austin for passing his preliminary exam!

Miriam Bregman from analytical chemistry has joined the lab, welcome Miriam!

Ashley presented at the Biochemistry's Postdoc Rising Stars Symposium at the University of Utah. Her talk was titled "Harnessing big data and cell-free protein synthesis to study lasso peptide biosynthesis."

Former member Adam DiCaprio, along with collaborators in the Nair and van der Donk labs, published a paper in Chem. Rev. reviewing the modes of action of bacterial RiPP natural products.

Congrats to Lonnie for successfully defending his PhD! He is the 15th student from the DAM lab to obtain a PhD.

highlights

Andrew and collaborators in the Nair, Bowers, and Pogorelov labs published a paper in J. Am. Chem. Soc. investigating the thus far elusive mechanism by which pyridine synthases such as TbtD catalyze macrocycle formation in thiopeptide biosynthesis. Through a combination of targeted mutagenesis, kinetic assays, substrate analogs, enzyme–substrate cross-linking, and chemical rescue experiments, we delineate the role of a conserved tyrosine in heterocycle aromatization. We anticipate this information to be of use in future engineering efforts with these enzymes.

A collaboration between our lab, the Zhao lab, and the van der Donk lab developed a robotic system for RiPP biosynthetic gene cluster refactoring, which was used along with RODEO and heterologous expression in E. coli to isolate 30 novel modified peptides. These peptides represent six different classes of RiPPs, and three of them exhibited antibacterial activity against members of the ESKAPE pathogens.

A collaboration between our lab and the van der Donk lab, facilitated by our joint student Dinh Nguyen, describes an enzymatic pathway capable of synthesizing pyridine-based cyclic peptides from 14- to 68-membered rings with diverse sequences. This pathway can be utilized with other post-translational modification enzymes (e.g., azole-forming enzymes) to form macrocyclic rings with backbone structures beyond amide moieties. Last but not least, we report the substrate recognition mechanism of the enzymatic pathway: the variable region on the substrate peptide is in between two distinct recognition handles, with each contributing to site-selective substrate modification.

Tim and collaborators in the Gerlt lab published a paper in ACS Bio Med Chem Au which describes a new web-based resource: RadicalSAM.org. The genomic enzymology portal compiles and classifies all salient information on the sequence-function space of radical SAM enzymes, one of the largest and most diverse enzyme superfamilies known. We anticipate this tool will aid in the discovery of new enzyme chemistry.


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