Yokoyama Lab

Bach received a fellowship from the Triangle Center of Evolutional Medicine to study the natural evolution of naturally-occurring peptide antibiotics.  While >60% of FDA-approved antibiotics originate from Nature, how these antibiotics evolved is largely unexplored.  In this project, Bach will study the evolutional course of antibiotics using the recently discovered ribosomally synthesized and posttranslationally modified peptides (RiPPs) antibiotics.  The results will provide novel insights into the natural evolution of antibiotics and may reveal an evolution-based approach to discovering novel antibiotics.  Congratulations, Bach!

In this work, Hai found that DarE radical SAM enzyme uses O2 to form the ether crosslink in the darobactin A biosynthesis. This is the first radical SAM enzyme that uses O2 as a co-substrate. In general, radical SAM enzymes are known to be inactivated by O2. Thus, this finding significantly extends the scope of radical SAM catalysis.

As a conclusion of the summer undergraduate research fellowship in Chemistry (SURF), Elisha and Rachel presented their work in the SURF conference.  They were both very busy explaining their achievements to the audience.  Very well done!  Also kudos to their mentors, Abhi and Hai.  We all feel very proud of both of you for your development over the summer and the past year.  Hope to see your study flourish even more in the Fall and beyond.  

Our paper on the chitin synthase (CHS) structure in collaboration with the Lee lab at Duke was published online on Nature Structural & Molecular Biology.  This paper reports the first 3D structure of CHS2 from Candida albicans in complex with substrate or inhibitors including nikkomycin Z.  CHS is a proven target of antifungals that are currently used for agricultural purposes or under clinical investigation. This work is an important step toward our atomic resolution understanding of catalysis, inhibition, and regulation of CHS and is critical for the future structure-guided development of CHS-targeting antifungals.

Haoran successfully defended his Ph.D. dissertation on April 1.  He received many compliments for his achievements represented by a comment by Prof. Oas saying that among the theses he had seen, Haoran’s thesis had the most diverse biophysical methods applied to solve the important biochemical question.  Haoran will move on to a postdoc position in Wenjun Zhang’s lab at UC Berkeley.  Congratulations, Haoran, and wish you continue your strong career!

This manuscript highlights the achievements of Matthew with significant help by Jib and Yanan and describes our successful characterization of the biosynthesis of malayamycin A, a unique C6-sugar nucleoside antifungal.  The study revealed that the biosynthesis proceeds through cryptic phosphorylation analogous to that in nikkomycin and polyoxin.  The study also revealed a divergent biosynthesis of high-carbon sugar nucleoside natural products, their evolutional relationships, and the potential for future genome mining discovery. 

Haoran was selected as a recipient of 2021-2022 Chancellor’s Award for Research Excellence (CARE). His research project focuses on the mechanism of MoaA radical SAM enzyme in the molybdenum cofactor (Moco) biosynthesis and  Moco deficiency disease (MoCD) in humans. Parts of his achievements have already been published in JACS (in 2020 and 2021). Haoran’s achievements have broad scientific and translational impacts as they provided unprecedented insights into the mechanism of enzyme-catalyzed radical reactions and significant implications in the future development of MoCD therapeutics. Congratulations, Haoran!!

In this perspective, we summarized the role of Moco in humans and pathogenic bacteria and the recent progress on the functional and mechanistic characterization of MoaA and MoaC.  We also highlighted key unsolved questions in the field, especially in the context of human disease.  We hope this perspective will foster the progress of the field.

Haoran’s paper about the redox function of the auxiliary cluster in MoaA was highlighted in the JACS spotlight.  See the earlier post for the details of the work.

Haoran’s paper about the catalytic function of the auxiliary cluster of MoaA is now published online on JACS.  In this work we determined the reduction potentials of the two 4Fe-4S clusters in MoaA and compared them with theoretical reduction potentials of the putative aminyl radical intermediate. The results suggested PCET mechanism for the aminyl radical reduction. Furthermore, the EPR characterization of the C4′ radical revealed an electronic coupling between GTP and the auxiliary cluster, suggesting a potentially missing mechanism of catalysis.