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

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.

One pathway, two cyclic pentapeptides: heterologous expression of BE-18257 A-C and pentaminomycins A-E fromStreptomyces cacaoiCA-170360

“…This strain has also been recently described as the producer of cacaoidin, the founding member of class V lanthipeptides (lanthidins) (Ortiz-López et al, 2020;Román-Hurtado et al, 2020). In this work, we demonstrate that pentaminomycins A-E and BE-18257 A-C are synthesized in this strain by a pathway highly similar to that described recently in other S. cacaoi strains (Kaweewan et al, 2020;Hwang et al, 2020). To that end, we have cloned and heterologously expressed both the complete BGC and a partial pathway that lacks the NRPS encoding pentaminomycins.…”

“…The proposed cluster harbors regulatory, transport-related and biosynthetic genes, including cytochromes P450 and two NRPS, each of them predicted to synthesize one type of pentapeptide. The cluster lacks any gene harboring a thioesterase (TE) domain but contains a stand-alone enzyme belonging to the Penicillin Binding Protein (PBP) family, that, likewise to what has been demonstrated for SurE in the biosynthesis of surugamide (Matsuda et al, 2019a;2019b;Zhou et al, 2019), is proposed to act as a trans-acting TE cyclizing both BE-18257 A-B and pentaminomycins C-E (Kaweewan et al, 2020;Hwang et al, 2020).…”

“…cyclopeptides have been reported, such as pargamicins A-D (Igarashi et al, 2008;Hashizume et al, 2017), cyclotetrapeptides cyclo-(Leu-Pro-Ile-Pro) and cyclo(Tyr-Pro-Phe-Gly) (Abdalla, 2016), the cyclic pentapeptides BE-18257BE-18257 A-D (Miyata et al, 1992a;1992b) and the pentaminomycins A-E (Jang et al, 2018;Kaweewan et al, 2020;Hwang et al, 2020). Cyclic pentapeptides BE-18257 A-D, were first isolated from Streptomyces sp.…”

“…Pentaminomycin A has antimelanogenic activity against alphamelanocyte stimulating hormone (α-MSH)-stimulated B16F10 melanoma cells (Jang et al, 2018) and pentaminomycin C is active against Gram positive bacteria but no against Gram negative bacteria (Kaweewan et al, 2020). Both pentaminomycins C and D act as autophagy inducers on HEK293 cells (Hwang et al, 2020).…”

“…Recently, Kaweewan et al (2020) and Hwang et al (2020) proposed a biosynthetic gene cluster (BGC) for the production of pentaminomycins C-E and the cyclic pentapeptides BE-18257 A-B. The proposed cluster harbors regulatory, transport-related and biosynthetic genes, including cytochromes P450 and two NRPS, each of them predicted to synthesize one type of pentapeptide.…”