Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways

Sorbicillinoids are a class of fungal polyketides with diverse structures and distinguished bioactivities. Although remarkable progress has been achieved in their chemistry and biosynthesis, the efflux of sorbicillinoids is poorly understood. Here, we found MFS transporter AcsorT was responsible for the biosynthesis of sorbicillinoids in Acremonium chrysogenum. Combinatorial knockout and subcellular location demonstrated that the plasma membrane-associated AcsorT was responsible for the transportation of sorbicillinol and subsequent formation of oxosorbicillinol and acresorbicillinol C via the berberine bridge enzyme-like oxidase AcsorD in the periplasm. Homology modeling and site-directed mutation revealed that Tyr 303 and Arg 436 were the key residues of AcsorT, which was further explained by molecular dynamics simulation. Based on our study, it was suggested that AcsorT modulates sorbicillinoid production by coordinating its biosynthesis and export, and a transport model of sorbicillinoids was proposed in A. chrysogenum.

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Enzymatic Ring Contraction for the Biosynthesis of Sulfur-Containing Cyclopentachromone

Nie,

Sun,

Liu

et al. 2024

J. Am. Chem. Soc.

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Cyclopentachromone, distinguished by its 6/6/5 heterotricyclic ring structure, is a key building block in many bioactive natural products, yet its enzymatic origin remains unclear. We identified a new class of cyclopentachromone-containing compounds, termed isochromosulfines, characterized by unique C−S bonds. A distinct FADdependent monooxygenase, IscL, was identified to catalyze the formation of the 6/6/5 cyclopentadiene intermediate, 2S-remisporine A, from a 6/6/6 xanthone precursor via benzene ring contraction. The high reactivity of 2S-remisporine A further promotes a spontaneous thiol-Michael addition reaction with thiol-containing compounds, forming the C−S bond in isochromosulfines. Additionally, we demonstrate that IscL homologues mediate a bifurcated pathway of benzene ring modification in the xanthone intermediate, leading to either ring contraction or cleavage, which is determined by a critical residue at position 230 to be phenylalanine or tyrosine. Our findings highlight the pivotal role of IscL in forming the 6/6/5 cyclopentachromone scaffold and offer deep insights into its catalytic mechanism. Our work lays the foundation for genome mining of cyclopentachromone-containing compounds and shows the potential application of IscL in biocatalysis.

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Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways

Cited by 6 publications

References 67 publications

Design, synthesis and biological evaluation of novel diphenylamine analogues as NLRP3 inflammasome inhibitors

Design, synthesis and biological evaluation of novel diphenylamine analogues as NLRP3 inflammasome inhibitors

MFS Transporter as the Molecular Switch Unlocking the Production of Cage-Like Acresorbicillinol C

Enzymatic Ring Contraction for the Biosynthesis of Sulfur-Containing Cyclopentachromone

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