Young-Soo Hong

Dokdothiocin, a ribosomally synthesized and post-translationally modified peptide (RiPP) belonging to the thiopeptide family, was isolated from Streptomyces sp. 20A130. Its structure was elucidated by extensive NMR analyses, high-resolution mass spectrometry, and chemical derivatization, revealing a 29-membered macrocyclic scaffold bearing oxazole, thiazole, and a central pyridine ring. Dokdothiocin differs from previously reported thiopeptides in macrocycle size, heterocycle arrangement, and residue-specific modifications, including the incorporation of a 3-hydroxyproline residue within the macrocyclic framework. Bioinformatic analysis of the corresponding biosynthetic gene cluster is consistent with a maturation pathway involving heterocycle formation and pyridine aromatization. Functionally, dokdothiocin attenuated lipopolysaccharide-induced activation of BV2 microglial cells by reducing nitric oxide production and suppressing NF-κB signaling, highlighting it as a structurally distinctive thiopeptide scaffold with antineuroinflammatory potential.

A screen of ~ 4000 actinomycetes strains identified Streptomyces sp. W3009 as a producer of the antituberculosis agent pyridomycin. Using a mass spectrometry-based metabolomics approach coupled with molecular networking, we identified seven pyridomycin derivatives, six of which were novel. Three of these novel compounds were linear, featuring a unique 3-hydroxypicolinic acid– l -threonine–3-(3-pyridyl)- l -alanine (3HP–T–3PA) scaffold. Their structures were elucidated via detailed NMR studies. While two cyclic derivatives ( 4 and 5 ) showed modest antitubercular activity, the three linear derivatives, despite possessing the key 3HP–T–3PA moiety, exhibited no inhibitory activity. This intensive MS-based approach demonstrates the important role of such techniques in the discovery of novel biologically active core structures and their natural derivatives. Graphical Abstract

Two new lipopeptides jejupeptins A (1) and B (2), together with a known compound eurystatin B (3), were isolated from a culture of Streptomyces sp. KCB15JA151. The chemical structures of the compounds were elucidated by using a combination of 1D and 2D NMR spectroscopy analyses. Comprehensive spectroscopic analysis revealed that compounds 1 and 2 possess a 1-aminoethyl-2-hydroxy-4-oxopentanoic acid moiety. A plausible biosynthetic pathway for these compounds was proposed. Biological evaluation demonstrated that compounds 1 and 2 exhibit protective effects against corticosterone-induced apoptosis and cellular oxidative stress without any associated cytotoxicity.

Two new lipopeptides, ulleungpeptins A and B (1 and 2), were isolated from cultures of Streptomyces sp. 13F051. Spectroscopic analyses revealed that both compounds consist of a 2,4-decadienoic acid moiety conjugated to a hexapeptide incorporating the non-proteinogenic amino acid 3,5-dihydroxyphenylglycines (Dpgs). Detailed NMR studies established that the two compounds differ in the configuration of the double bonds within the 2,4-decadienoic acid moiety. The absolute configurations of the amino acid residues were determined by advanced Marfey's analysis, supported by bioinformatic predictions. Bioactivity evaluation demonstrated that compounds 1 and 2 inhibit angiogenesis in HUVEC cells without exhibiting cytotoxicity.

3-Hydroxyphloretin (3-OH phloretin), a dihydrochalcone compound containing a catechol moiety, is naturally present in apples and exhibits potent anti-adipogenic, anti-obesity, and anticancer activities. In this study, we developed a modular co-culture platform enabling the de novo biosynthesis of 3-OH phloretin from glucose in Escherichia coli. We demonstrated that 4-coumarate 3-hydroxylase (Sam5), derived from Saccharothrix espanaensis, efficiently catalyzes the hydroxylation of phloretin to 3-OH phloretin. The engineered co-culture system comprised two functional modules: an upstream module that converts l-tyrosine to phloretic acid through the expression of tyrosine ammonia-lyase and enoate reductase genes, and a downstream module that converts phloretic acid to 3-OH phloretin via the sequential action of 4-coumarate-CoA ligase, a mutated chalcone synthase, and Sam5. Using this system, we successfully achieved the de novo production of 3-OH phloretin at a titer of 4.69 mg/L from glucose. In parallel, the artificial biosynthetic pathway also yielded phloretic acid and 3-hydroxyphloretic acid (3-OH phloretic acid) at titers of 161.7 and 176.2 mg/L, respectively, in an engineered l-tyrosine-overproducing E. coli strain. To the best of our knowledge, this study represents the first successful establishment of an artificial biosynthetic route for the production of both 3-OH phloretic acid and 3-OH phloretin directly from glucose in E. coli. This platform lays the groundwork for the microbial production of valuable dihydrochalcone compounds and holds promise for further optimization toward industrial-scale applications.

Two new polyketide-cyclic peptide hybrids jejupeptins A (1) and B (2), together with a known compound eurystatin B (3), were isolated from a culture of Streptomyces sp. KCB15JA151. The chemical structures of the compounds were elucidated using a combination of 1D and 2D NMR spectroscopy and DP4+ probability analyses. Comprehensive spectroscopic analysis revealed that 1 and 2 are the first examples of hybrid peptide-polyketides possessing an unprecedented 4-amino-3-hydroxymethyl-3-methyl-2-oxopentanoic acid moiety. A plausible biosynthetic pathway for these compounds was proposed. Biological evaluation demonstrated that compounds 1 and 2 exhibit protective effects against corticosterone-induced apoptosis and cellular oxidative stress without any associated cytotoxicity.

The pluramycin family of natural products has diverse substituents at the C2 position, which are closely related to their biological activity. Therefore, it is important to understand the biosynthesis of C2 substituents. In this study, we describe the biosynthesis of C2 moieties in Streptomyces sp. W2061, which produces kidamycin and rubiflavinone C-1, containing anthrapyran aglycones. Sequence analysis of the loading module (Kid13) of the PKS responsible for the synthesis of these anthrapyran aglycones is useful for confirming the incorporation of atypical primer units into the corresponding products. Kid13 is a ketosynthase-like decarboxylase (KSQ)-type loading module with unusual dual acyltransferase (AT) domains (AT_1-1 and AT_1-2). The AT_1-2 domain primarily loads ethylmalonyl-CoA and malonyl-CoA for rubiflavinone and kidamycinone and rubiflavinone, respectively; however, the AT_1-1 domain contributed to the functioning of the AT_1-2 domain to efficiently load ethylmalonyl-CoA for rubiflavinone. We found that the dual AT system was involved in the production of kidamycinone, an aglycone of kidamycin, and rubiflavinone C-1 by other shared biosynthetic genes in Streptomyces sp. W2061. This study broadens our understanding of the incorporation of atypical primer units into polyketide products.