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Updated: Apr 16, 2026

Biosynthesis of a Flavonol from a Flavanone by Establishing a One-pot Bienzymatic Cascade
Published on: August 14, 2019
Enzymatic basis of "hybridity" in thiomarinol biosynthesis
Zachary D Dunn1, Walter J Wever, Nicoleta J Economou
1Department of Chemistry, University of North Carolina at Chapel Hill, Carolina Center for Genome Sciences, Chapel Hill, NC, 27599 (USA).
Abstract:
Thiomarinol is a naturally occurring double-headed antibiotic that is highly potent against methicillin-resistant Staphylococcus aureus. Its structure comprises two antimicrobial subcomponents, pseudomonic acid analogue and holothin, linked by an amide bond. TmlU was thought to be the sole enzyme responsible for this amide-bond formation. In contrast to this idea, we show that TmlU acts as a CoA ligase that activates pseudomonic acid as a thioester that is processed by the acetyltransferase HolE to catalyze the amidation. TmlU prefers complex acyl acids as substrates, whereas HolE is relatively promiscuous, accepting a range of acyl-CoA and amine substrates. Our results provide detailed biochemical information on thiomarinol biosynthesis, and evolutionary insight regarding how the pseudomonic acid and holothin pathways converge to generate this potent hybrid antibiotic. This work also demonstrates the potential of TmlU/HolE enzymes as engineering tools to generate new "hybrid" molecules.
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