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. 2020 Sep 10;8(9):1390.
doi: 10.3390/microorganisms8091390.

Pentaminomycins C-E: Cyclic Pentapeptides as Autophagy Inducers from a Mealworm Beetle Gut Bacterium

Sunghoon Hwang  1 , Ly Thi Huong Luu Le  2 , Shin-Il Jo  3 , Jongheon Shin  1 , Min Jae Lee  2 , Dong-Chan Oh  1
Affiliations

Pentaminomycins C-E: Cyclic Pentapeptides as Autophagy Inducers from a Mealworm Beetle Gut Bacterium

Sunghoon Hwang et al. Microorganisms. .

Abstract

Pentaminomycins C-E (1-3) were isolated from the culture of the Streptomyces sp. GG23 strain from the guts of the mealworm beetle, Tenebrio molitor. The structures of the pentaminomycins were determined to be cyclic pentapeptides containing a modified amino acid, N5-hydroxyarginine, based on 1D and 2D NMR and mass spectroscopic analyses. The absolute configurations of the amino acid residues were assigned using Marfey's method and bioinformatics analysis of their nonribosomal peptide biosynthetic gene cluster (BGC). Detailed analysis of the BGC enabled us to propose that the structural variations in 1-3 originate from the low specificity of the adenylation domain in the nonribosomal peptide synthetase (NRPS) module 1, and indicate that macrocyclization can be catalyzed noncanonically by penicillin binding protein (PBP)-type TE. Furthermore, pentaminomycins C and D (1 and 2) showed significant autophagy-inducing activities and were cytoprotective against oxidative stress in vitro.

Keywords: OSMAC; autophagy inducer; biosynthetic pathway; cyclic peptides; gut bacteria; insect; mealworm.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of pentaminomycins C–E (1–3).
Figure 2
Figure 2
Key COSY and HMBC correlations of pentaminomycin D (2).
Figure 3
Figure 3
Proposed biosynthesis pathway for the BE-18257s and the pentaminomycins. (A) Genetic organization of putative biosynthetic gene cluster of the pentaminomycins. (B) Putative biosynthetic pathway for the pentaminomycins and the BE-18257s with the nonribosomal peptide synthetase (NRPS) modular organization. C, condensation domain; A, adenylation domain; PCP, peptidyl carrier protein; E, epimerase domain.
Figure 4
Figure 4
Effects of pentaminomycins C–E (1–3) on cellular autophagy in mammalian cells. HEK293T cells were treated with various concentrations of pentaminomycins for 8 h. (A) Whole cell lysates were harvested and subjected to SDS-PAGE followed by immunoblotting against the indicated antibodies. (B) Quantification of LC3-II and GABARAPL1-II in the presence of pentaminomycins (12.5 µM) using the multiple immunoblot images. Data were normalized to those of non-lipidated proteins. Data represent mean ± SD from three independent experiments. **, p < 0.01 and ***, p < 0.001 (one-way analysis of variance (ANOVA) with Bonferroni’s multiple comparison test). (C) Pentaminomycins C and D, but not E, induce global cellular autophagy. HEK293T cells were cotreated with pentaminomycins C–E (20 μM) and a downstream autophagy inhibitor bafilomycin A1 (BafA1; 100 nM) for 12 h. (D) Quantification of GABARAPL1-II normalized to GABARAPL1-I in the presence or absence of pentaminomycins and BafA1. *, p < 0.05 (one-way ANOVA with Bonferroni’s multiple comparison test).
Figure 5
Figure 5
Alleviation of menadione-mediated cytotoxicity by (A) pentaminomycin C and (B) pentaminomycin D. Oxidative stress was induced by menadione (25 μM) for the indicated time periods in HEK93 cells, which were cotreated with either pentaminomycin C or D. The relative cell viability was assessed using the CellTiter-Glo assay and the values are represented as mean ± SD (n = 3).
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