Biosynthesis of trans-AT PKS-Derived Shuangdaolides Featuring a trans-acting Enzyme for Online Epoxidation

Modifications of Protein‐Bound Substrates by Trans‐Acting Enzymes in Natural Products Biosynthesis

“…B59. [12] Similar compounds were also found in other strains of Streptomyces, e. g., dumulmycin from Streptomyces sp. DM28.…”

“…The formation of 2hydroxycyclopentenone has been proposed to be mediated by the opening of 16,17-epoxide on the polyketide skeleton. [12] In contrast to the online epoxidation in spliceostatin biosynthesis, which is catalyzed by a FMO domain found within the PKS, [21] the epoxide moiety in the shuangdaolide pathway is installed during the polyketide chain elongation by SdlR, a multi-domain protein that is comprised of a ketoreductase (KR), an ACP, an FMO, and an FSH1 domain. [12] However, only the FMO domain, which contains a NAD(P)-binding motif that belongs to the group B subfamily of flavin proteins, appears to be responsible for the epoxidation reaction.…”

“…[12] In contrast to the online epoxidation in spliceostatin biosynthesis, which is catalyzed by a FMO domain found within the PKS, [21] the epoxide moiety in the shuangdaolide pathway is installed during the polyketide chain elongation by SdlR, a multi-domain protein that is comprised of a ketoreductase (KR), an ACP, an FMO, and an FSH1 domain. [12] However, only the FMO domain, which contains a NAD(P)-binding motif that belongs to the group B subfamily of flavin proteins, appears to be responsible for the epoxidation reaction. In addition, the epoxidation catalyzed by SdlR occurs at a position seven carbon atoms away from the thioester, which is distinct from other on-line modifications by an integrated domain within the PKS, which usually modify the chain at the α, β, or γ-carbon positions (Figure 6).…”

“…Other ACP-bound compound modifications involving trans-acting enzymes include the on-line methyl esterification catalyzed by a discrete SAM-dependent methyltransferase during aurantinin polyketide biosynthesis, [11] and the on-line epoxidation of a polyketide chain catalyzed by a discrete cytochrome P450 enzyme during shuangdaolide biosynthesis. [12] The previously reported variant of acyl-CoA dehydrogenase, TcsD, from the FK506 pathway catalyzes the dehydrogenation of ACP-bound short fatty acids, leading to the formation of the extender unit allylmalonyl-CoA, was re-examined. [13] This led to a revised pathway to allylmalonyl-CoA and provided a better understanding of TcsD and other bacterial acyl-CoA dehydrogenase-like enzymes.…”

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“…Systematic gene inactivation of the sdl biosynthetic gene cluster that generates macrocyclic polyketides, which possess rare internal 2-hydroxycyclopentenone moieties such as shaungdaolide D 26 has allowed the characterisation of several key enzymes and a proposed biosynthetic pathway. 26 The studies revealed the role of the multidomain protein, SdlR that catalyses 16,17-epoxidation during chain elongation and the tailoring of oxidation enzymes, SdlB and SdlQ. Heterologous expression in the fungal host Aspergillus oryzae has been used to probe the biosynthesis of fungal tetraketide pyrones including multiforisin I, 27 .…”