Author: Dr Ken Yokoyama, Ph.D.

We are excited to share that Yanan’s recent Nature Chemistry paper on azetidine amino acid biosynthesis by two non-heme iron enzymes has been highlighted in Nature Chemical Biology: link. In this work, we uncovered how these enzymes construct a highly strained azetidine ring — a key building block in many bioactive small molecules — through an unprecedented radical mechanism. Our findings expand understanding of enzymatic chemistry and open new avenues for bioengineering novel molecules. Congratulations to the entire team for this achievement!

The study reveals how the radical SAM enzyme MoaA controls essential yet potentially dangerous radical chemistry by using its flexible C-terminal tail to sense the correct substrate and safely trigger radical formation. Disruption of this mechanism in humans leads to a fatal disease. This discovery also provides a testable model for radical initiation across the radical SAM enzyme superfamily. Read “How an Enzyme Controls Essential Radical Chemistry — and Its Links to Human Disease” on the PNAS Showcase.

In this study, we characterized the mechanism of oxidative C-C bond cleavage reaction catalyzed by Fe and 2-oxoglutarate-dependent oxidase, PolD. This enzyme diverges the biosynthetic pathways between C6 and C7-sugar nucleoside antifungals, and therefore, its mechanistic and structural understanding is important for the future genome-mining discovery of novel antifungals. The results suggested that the reaction is initiated by an unexpected O-H bond homolysis. Aliphatic O-H bonds have very high bond dissociation energy (~105 kcal/mol), and this report represents, to our knowledge, the very first example of radical initiation by O-H activation in Fe and 2-OG enzymes.

Bach received a poster award during the Biochemistry Department’s annual retreat. He presented his discovery of a novel mechanism of the radical SAM enzyme DynA in catalyzing post-translational crosslinking in dynobactin biosynthesis. Congratulations, Bach!

We moved to a new space within the Nanaline Duke building.  More unified and less compartmentalized space.  It was quite a bit of effort but well worth it. Well done, everyone!

A graduate student, Bach Nguyen, is awarded the prestigious predoctoral fellowship from the American Heart Association (AHA). His proposed project aims to study the functions and mechanisms of enzymes responsible for the biosynthesis of peptide antibiotics that selectively kill Gram-negative pathogens, whose infections could lead to severe complications and devastating consequences on the cardiovascular system. Congratulations, Bach!

Many nucleoside antibiotics and antifungals are biosynthesized through divergent mechanisms. This concept paper reviews the recent developments in our understanding of their biosynthesis and discusses the potential for genome-mining discovery of novel nucleoside antibiotics and antifungals based on a thorough analysis of the genome sequence information.  This paper is a part of the Next Generation of Chemical Biology issue.

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.