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Prenylated indole-terpenoids with antidiabetic activities from Penicillium sp. HFF16 from the rhizosphere soil of Cynanchum bungei Decne.

ABSTRACT: Finding novel and effective suppression of hepatic glucagon response antidiabetic compounds is urgently required for the development of new drugs against diabetes. Fungi are well known for their ability to produce new bioactive secondary metabolites. In this study, four new prenylated indole-terpenoids (1-4), named encindolenes I-L, as well as a known analogue (5), were isolated from the fungus Penicillium sp. HFF16from the rhizosphere soil of Cynanchum bungei Decne. The structures of the compounds were elucidated by spectroscopic data and ECD analysis. In the antidiabetic activity assay, compounds 1-5 could inhibit glucagon-induced hepatic glucose output with EC₅₀ values of 67.23, 102.1, 49.46, 25.20, and 35.96 μM, respectively, and decrease the intracellular cAMP contents in primary hepatocytes.

SUBMITTER: Liu X

PROVIDER: S-EPMC10018213 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Prenylated indole-terpenoids with antidiabetic activities from Penicillium sp. HFF16 from the rhizosphere soil of Cynanchum bungei Decne.

Liu Xijin X Kong Fandong F Xiao Na N Li Xiaoyu X Zhang Mingyu M Lv Fujin F Liu Xiaolin X Kong Xiangchuan X Bi Jing J Lu Xinyi X Kong Daqing D Hao Gangping G Zhou Liman L Pan Guojun G

Frontiers in microbiology 20230302

Finding novel and effective suppression of hepatic glucagon response antidiabetic compounds is urgently required for the development of new drugs against diabetes. Fungi are well known for their ability to produce new bioactive secondary metabolites. In this study, four new prenylated indole-terpenoids (1-4), named encindolenes I-L, as well as a known analogue (5), were isolated from the fungus Penicillium sp. HFF16from the rhizosphere soil of Cynanchum bungei Decne. ...[more]

PMID: 36937284

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Project description:Cyclodipeptide synthases (CDPSs) catalyze the formation of cyclodipeptides using aminoacylated tRNAs as the substrates and have great potential in the production of diverse 2,5-diketopiperazines (2,5-DKPs). Genome mining of Streptomyces leeuwenhoekii NRRL B-24963 revealed a two-gene locus, saz, encoding CDPS SazA and a unique fused enzyme (SazB) harboring two domains: phytoene synthase-like prenyltransferase (PT) and methyltransferase (MT). Heterologous expression of the saz gene(s) in Streptomyces albus J1074 led to the production of four prenylated indole alkaloids, among which streptoazines A to C (compounds 3 to 5) are new compounds. Expression of different gene combinations showed that the SazA catalyzes the formation of cyclo(l-Trp-l-Trp) (cWW; compound 1), followed by consecutive prenylation and methylation by SazB. Biochemical assays demonstrated that SazB is a bifunctional enzyme, catalyzing sequential C-3/C-3' prenylation(s) by SazB-PT and N-1/N-1' methylation(s) by SazB-MT. Of note, the substrate selectivity of SazB-PT and SazB-MT was probed, revealing the stringent specificity of SazB-PT but relative flexibility of SazB-MT.IMPORTANCE Natural products with a 2,5-diketopiperazine (2,5-DKP) skeleton have long sparked interest in drug discovery and development. Recent advances in microbial genome sequencing have revealed that the potential of cyclodipeptide synthase (CDPS)-dependent pathways encoding new 2,5-DKPs are underexplored. In this study, we report the genome mining of a new CDPS-encoding two-gene operon and activation of this cryptic gene cluster through heterologous expression, leading to the discovery of four indole 2,5-DKP alkaloids. The cyclo(l-Trp-l-Trp) (cWW)-synthesizing CDPS SazA and the unusual prenyltransferase (PT)-methyltransferase (MT) fused enzyme SazB were characterized. Our results expand the repertoire of CDPSs and associated tailoring enzymes, setting the stage for accessing diverse prenylated alkaloids using synthetic biology strategies.

Dataset Information

Prenylated indole-terpenoids with antidiabetic activities from Penicillium sp. HFF16 from the rhizosphere soil of Cynanchum bungei Decne.

Publications

Prenylated indole-terpenoids with antidiabetic activities from <i>Penicillium</i> sp. HFF16 from the rhizosphere soil of <i>Cynanchum bungei</i> Decne.

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