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.
Haoran and Lydia uncovered mechanism of controlled radical initiation in radical SAM enzyme!
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!
Rotation student Brycen Aldrich received a poster award at the Biochemistry retreat!
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!
Yanan’s work on enzymes involved in azetidine amino acid biosynthesis is out in Nature Chemistry!
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.
Yanan’s work on oxidative C-C bond cleavage in antifungal nucleoside biosynthesis is now online!
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’s study on the mechanism of radical SAM enzyme DynA is published in JACS!
In this work, Bach uncovered a novel mechanism used by radical SAM enzyme DynA to catalyze the cross-linking in dynobactin biosynthesis. Specifically, DynA utlizes a radical-mediated nucleophilic mechanism for the unprecedented C-N cross-link through a p-quinone methide intermediate. This quinone methide-dependent mechanism of RiPPs cross-linking is distinct from the previously reported RiPPs cross-linking mechanisms and represents a novel mechanism in RiPPs biosynthesis. Congrats, Bach!
Bach received a poster award in Biochemistry retreat!
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!
Yokoyama lab moved to a new space
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!
Bach receives an AHA fellowship!
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!
Our new concept paper on nucleoside natural product biosynthesis and genome mining is published.
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.
