Nyuzenamide C, an Antiangiogenic Epoxy Cinnamic Acid-Containing Bicyclic Peptide from a Riverine <i>Streptomyces</i> sp.

An, Joon Soo; Kim, Myoun‐Su; Han, Jae‐Ho; Jang, Sung Chul; Im, Ji Hyeon; Cui, Jinsheng; Lee, Yeonjin; Nam, Sang‐Jip; Shin, Jongheon; Lee, Sang Kook; Yoon, Yeo Joon; Oh, Dong‐Chan

doi:10.1021/acs.jnatprod.1c00837

Cited by 16 publications

(34 citation statements)

References 68 publications

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“…Epoxinnamide ( 1 ) is structurally related to nyuzenamides A-C ( Figures S2 and S7 ), as they also have a bicyclic deca-depsipeptide backbone tethered with an alkenyl cinnamic acid-derived acyl chain [ 16 , 21 ]. However, they have two different amino acids in their deca-peptide cycles: 1 possesses β -hydroxyleucine and threonine instead of β -hydroxyphenylalanine and valine incorporated in the nyuzenamides.…”

Section: Resultsmentioning

confidence: 99%

“…N11-34 and DM14) revealed that these strains are phylogenetically distinct consistently with the structural difference of epoxinnamide and the nyuzenamides ( Figure S12 ). The epoxy cinnamic acid moiety is very unique and has been extremely rarely reported in nature, with only nyuzenamide C and NC-1 as examples [ 12 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…The relative configurations of the α - and β -positions in the Dht and Hle units were determined through analysis of vicinal proton–proton coupling constants ( 3 J HH ) and key ROESY correlations ( Figure 3 ). Analogously to nyuzenamide C, vicinal protons H-6 and H-7 showed a large coupling constant ( 3 J H6H7 = 10.5 Hz) [ 21 ]. ROESY correlations in Dht unit revealed that 1 has the identical relative configuration of Dht with nyuzenamide C, 6 R * and 7 S * ( Figure 3 a).…”

Section: Resultsmentioning

confidence: 99%

“…Based on the analysis of the whole-genome sequence by utilizing antiSMASH 6.0 [ 38 ] ( Table S4 ), a putative biosynthetic gene cluster (BGC) of epoxinnamide ( 1 ) was identified. The BGC of 1 showed a 57% similarity with BGC of atratumycin [ 13 ] and exhibited high homology (74%) to the BGC of nyuzenamide C [ 21 ], which is structurally most similar to epoxinnamide ( Figure S7 ). The BGC of epoxinnamide ( 1 ) consists of four modular, non-ribosomal peptide synthetase (NRPS)-encoding genes, and biosynthetic genes of unusual amino acids units and epoxypropyl cinnamic acid ( Figure 4 a and Table S5 ).…”

Section: Resultsmentioning

confidence: 99%

“…UTJ3 [ 19 , 20 ], and nyuzenamide C (an antiangiogenesis agent and quinone reductase inducer) from Streptomyces sp. DM14 [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Epoxinnamide: An Epoxy Cinnamoyl-Containing Nonribosomal Peptide from an Intertidal Mudflat-Derived Streptomyces sp.

et al. 2022

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Cinnamoyl-containing nonribosomal peptides (CCNPs) form a unique family of actinobacterial secondary metabolites and display various biological activities. A new CCNP named epoxinnamide (1) was discovered from intertidal mudflat-derived Streptomyces sp. OID44. The structure of 1 was determined by the analysis of one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) data along with a mass spectrum. The absolute configuration of 1 was assigned by the combination of advanced Marfey’s method, 3JHH and rotating-frame overhauser effect spectroscopy (ROESY) analysis, DP4 calculation, and genomic analysis. The putative biosynthetic pathway of epoxinnamide (1) was identified through the whole-genome sequencing of Streptomyces sp. OID44. In particular, the thioesterase domain in the nonribosomal peptide synthetase (NRPS) biosynthetic gene cluster was proposed as a bifunctional enzyme, which catalyzes both epimerization and macrocyclization. Epoxinnamide (1) induced quinone reductase (QR) activity in murine Hepa-1c1c7 cells by 1.6-fold at 5 μM. It also exhibited effective antiangiogenesis activity in human umbilical vein endothelial cells (IC50 = 13.4 μM).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…UTJ3 [ 19 , 20 ], and nyuzenamide C (an antiangiogenesis agent and quinone reductase inducer) from Streptomyces sp. DM14 [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Epoxinnamide: An Epoxy Cinnamoyl-Containing Nonribosomal Peptide from an Intertidal Mudflat-Derived Streptomyces sp.

et al. 2022

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Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus

Lee

Han

et al. 2022

Angewandte Chemie

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Natural products provide an important source of pharmaceuticals and chemical tools. Traditionally, assessment of unexplored microbial phyla has led to new natural products. However, with every new microbe, the number of orphan biosynthetic gene clusters (BGC) grows. As such, the more difficult proposition is finding new molecules from well-studied strains. Herein, we targeted Streptomyces rimosus, the widely-used oxytetracycline producer, for the discovery of new natural products. Using MALDI-MS-guided high-throughput elicitor screening (HiTES), we mapped the global secondary metabolome of S. rimosus and structurally characterized products of three cryptic BGCs, including momomycin, an unusual cyclic peptide natural product with backbone modifications and several non-canonical amino acids. We elucidated important aspects of its biosynthesis and evaluated its bioactivity. Our studies showcase HiTES as an effective approach for unearthing new chemical matter from "drained" strains.

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A Versatile Thioesterase Involved in Dimerization during Cinnamoyl Lipid Biosynthesis

Deng,

Liu,

Wang

et al. 2024

Angewandte Chemie

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The cinnamoyl lipid compound youssoufene A1 (1), featuring a unique dearomatic carbon‐bridged dimeric skeleton, exhibits increased inhibition against multidrug resistant Enterococcus faecalis compared to monomeric youssoufenes. However, the formation process of this intriguing dearomatic dimerization remains unknown. In this work, an unusual“gene‐within‐gene”thioesterase (TE) gene ysfF was functionally characterized. The gene was found to naturally encodes two proteins, an entire YsfF with α/β‐hydrolase and 4‐hydroxybenzoyl‐CoA thioesterase (4‐HBT)‐like enzyme domains, and a nested YsfFHBT (4‐HBT‐like enzyme). Using intracellular tagged carrier‐protein tracking (ITCT) strategy, in vitro reconstitution and in vivo experiments, we found that: i) both domains of YsfF displayed thioesterase activities; ii) YsfF/YsfFHBT could accomplish the 6π‐electrocyclic ring closure for benzene ring formation; and iii) YsfF and cyclase YsfX together were responsible for the ACP‐tethered dearomatic dimerization process, possibly via an unprecedent Michael‐type addition reaction. Moreover, site‐directed mutagenesis experiments demonstrated that N301, E483 and H566 of YsfF are critical residues for both the 6π‐electrocyclization and dimerization processes. This study enhances our understanding of the multifunctionality of the TE protein family.

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Nyuzenamide C, an Antiangiogenic Epoxy Cinnamic Acid-Containing Bicyclic Peptide from a Riverine Streptomyces sp.

Cited by 16 publications

References 68 publications

Epoxinnamide: An Epoxy Cinnamoyl-Containing Nonribosomal Peptide from an Intertidal Mudflat-Derived Streptomyces sp.

Epoxinnamide: An Epoxy Cinnamoyl-Containing Nonribosomal Peptide from an Intertidal Mudflat-Derived Streptomyces sp.

Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus

A Versatile Thioesterase Involved in Dimerization during Cinnamoyl Lipid Biosynthesis

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