News

Our new paper, published in PNAS, resolves a decades-long question about how MoaC constructs the core of molybdenum cofactor (Moco), a small molecule required for essential metabolic enzymes. By combining biochemical experiments, mass spectrometry, and X-ray crystallography, we captured short-lived reaction intermediates and discovered that MoaC temporarily forms a covalent bond with its substrate. This bond acts as a molecular tether, carrying and positioning a carbon atom during a complex molecular rearrangement. We term this previously unrecognized strategy “guiding covalent catalysis.” The findings reveal a new way enzymes can control complex chemistry and suggest that related mechanisms may operate in the biosynthesis of other essential cofactors.

Ken gave a beautiful seminar at Duke Biochemistry, drawing attendees from across campus. He highlighted the outstanding science produced by many current and former lab members over the past ~15 years, with work published in leading journals.

Our work on fungal β-1,3-glucan synthase, in close collaboration with Seok-Yong Lee’s lab, has been published in Nature. Using cryo-EM, we reveal how the clinically important antifungal caspofungin inhibits β-1,3-glucan synthase, how resistance mutations arise, and how enzyme activity is regulated. Unexpectedly, caspofungin binds the enzyme through the nascent polysaccharide product, overturning the prevailing model of direct enzyme binding. Together, these results provide a structural framework for future antifungal drug design.

Bach has been awarded the competitive Katherine Goodman Stern Fellowship from Duke Graduate School. Supported by a generous endowment established by Katherine Stern, the fellowship provides an annual stipend as well as coverage of tuition and mandatory fees to advanced PhD students who are in the write-up stage of their dissertations. This award recognizes Bach’s outstanding academic and research accomplishments. Congrats, Bach!

Bach’s new paper on the mechanism of the radical SAM oxygenase DarE, in collaboration with the Dave Britt lab (UC Davis) and the Alex Smirnov lab (NC State University), is now published in JACS. DarE catalyzes ether cross-link formation between two tryptophan residues during darobactin antibiotic RiPP biosynthesis. In this study, we trapped and characterized a key tryptophan Cβ-centered radical, illuminating a mechanism for enzyme-catalyzed de novo ether formation via a radical-mediated O₂ addition reaction. Congratulations, Bach!!

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 new study published in PNAS, Haoran and Lydia, together with collaborators in the Weitao Yang and Pei Zhou labs at Duke and the Alexey Silakov lab at Penn State, uncovered a substrate-triggered radical initiation. Using radical SAM enzyme MoA as a model, they discovered that MoaA uses its conformationally flexible C-terminal tail with two conserved Gly residues (GG motif) at the C-terminus as a sensor to detect substrate guanosine 5′-triphosphate (GTP) binding and trigger reductive SAM cleavage. Importantly, they also found that mutations disrupting this regulatory mechanism lead to Moco deficiency disease in humans. Congratulations to Haoran and Lydia!

Brycen received a poster award at the Biochemistry Department’s annual retreat for his presentation on Yanan’s work and his rotation research into the functional characterization of novel HDO enzymes. Congratulations, Brycen!

In this study, we demonstrate that PolF, a member of the haem-oxygenase-like dimetal oxidase/oxygenase (HDO) superfamily, catalyzes the conversion of L-isoleucine (L-Ile) and L-valine into their azetidine derivatives via a 3,4-desaturated intermediate. Mechanistic analyses reveal that a μ-peroxo-Fe(III)₂ ​ intermediate mediates the cleavage of unactivated C–H bonds, while subsequent reactions—including C–N bond formation—likely proceed through radical pathways. Additionally, we identify PolE, a DUF6421 family enzyme, as an Fe- and pterin-dependent oxidase that promotes L-Ile desaturation, thereby enhancing substrate flux for PolF. Collectively, these findings shed light on azetidine biosynthesis and expand our understanding of HDO enzyme catalysis. The significance of our work was also highlighted in the news section of the School of Medicine.