Family Report for: Thiohydrolase

Under construction: extracted from Xaa-Pro-like_dom. Penicillium sp. Chain-fusing Polyketide Gregatin A GrgF belongs to this family. Thioesterase DcsB: A polyketide cyclase that forms medium-ring Lactones. The nucleophile can be Ser as in beab2-j4wat9 (Beauveria bassiana (White muscardine disease fungus) thioesterase DcsB) or Cys as in pensq-GrgF (Penicillium sp. Chain-fusing Polyketide Gregatin A GrgF). The C115S mutant functions as a thioesterase, while losing the ability to perform chain fusion.

Title: A Polyketide Cyclase That Forms Medium-Ring Lactones
Gao DW, Jamieson CS, Wang G, Yan Y, Zhou J, Houk KN, Tang Y
Ref: Journal of the American Chemical Society, 143:80, 2021 : PubMed
Abstract


ESTHER: Gao_2021_J.Am.Chem.Soc_143_80
PubMedSearch: Gao 2021 J.Am.Chem.Soc 143 80
PubMedID: 33351624
Gene_locus related to this paper: beab2-j4wat9

Abstract

Medium-ring lactones are synthetically challenging due to unfavorable energetics involved in cyclization. We have discovered a thioesterase enzyme DcsB, from the decarestrictine C1 (1) biosynthetic pathway, that efficiently performs medium-ring lactonizations. DcsB shows broad substrate promiscuity toward linear substrates that vary in lengths and substituents, and is a potential biocatalyst for lactonization. X-ray crystal structure and computational analyses provide insights into the molecular basis of catalysis.



        

Title: Molecular Basis for the Biosynthesis of an Unusual Chain-Fused Polyketide Gregatin A
Wang WG, Wang H, Du LQ, Li M, Chen L, Yu J, Cheng GG, Zhan MT, Hu QF and Matsuda Y <2 more author(s)> Wang WG, Wang H, Du LQ, Li M, Chen L, Yu J, Cheng GG, Zhan MT, Hu QF, Zhang L, Yao M, Matsuda Y (- 2)
Ref: Journal of the American Chemical Society, 142:8464, 2020 : PubMed
Abstract


ESTHER: Wang_2020_J.Am.Chem.Soc_142_8464
PubMedSearch: Wang 2020 J.Am.Chem.Soc 142 8464
PubMedID: 32275405
Gene_locus related to this paper: pensq-GrgF

Abstract

Gregatin A (1) is a fungal polyketide featuring an alkylated furanone core, but the biosynthetic mechanism to furnish the intri-guing molecular skeleton has yet to be elucidated. Herein, we have identified the biosynthetic gene cluster of gregatin A (1) in Penicillium sp. sh18, and investigated the mechanism that produces the intriguing structure of 1 by in vivo and in vitro recon-stitution of its biosynthesis. Our study established the biosynthetic route leading to 1, and illuminated that 1 is generated by the fusion of two different polyketide chains, which are, amazingly, synthesized by a single PKS GrgA with the aid of a trans-acting enoylreductase GrgB. Chain fusion, as well as chain hydrolysis, is catalyzed by an alpha/beta hydrolase GrgF, hybridizing the C11 and C4 carbon chains by Claisen condensation. Finally, structural analysis and mutational experiments using GrgF provided insight into how the enzyme facilitates the unusual chain-fusing reaction. In unraveling a new biosynthetic strategy involving a bifunc-tional PKS and a polyketide fusing enzyme, our study expands our knowledge concerning fungal polyketide biosynthesis.