Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces

Abstract

The workup isolation scheme, axolotl embryo tail regeneration assay figures treated with compounds 1-9, and full spectroscopic data (NMR and mass) of compounds 1-9 (PDF)The authors declare the following competing financial interest(s): J.S.T. is a co-founder of Centrose (Madison, WI).

Structure and Function of a Dual Reductase–Dehydratase Enzyme System Involved in p-Terphenyl Biosynthesis

“…This central condensation reaction in p -terphenyls is catalyzed by a tridomain nonribosomal peptide synthetase to yield polyporic acid ( 2 , PPA) . PPA is proposed to subsequently undergo reduction and dehydration to give terphenyl triol 3 , but the specific enzyme contributions and/or sequence of events have not been defined. , As part of an effort to explore the microbial diversity and corresponding metabolic potential of actinomycetes associated with thermal vents emanating from underground coal mine fires in Appalachia, ,− we previously reported the discovery of two new p -terphenyl glycosides (terfestatins B and C from Streptomyces RM-5-8), each decorated with the rare unsaturated sugar 4-deoxy-α- l -threo-hex-4-enopyranuronate (Figure , iv). , Herein, we report the elucidation of the putative terfestatin/echoside biosynthetic gene cluster (BGC) from Streptomyces RM-5-8. In addition, we highlight the collaborative role of two enzymes encoded by this gene cluster (TerB and TerC) in the conversion of PPA (Figure , 2 ) to terphenyl triol 3 .…”

Himalaquinones A–G, Angucyclinone-Derived Metabolites Produced by the Himalayan Isolate Streptomyces sp. PU-MM59

“…1,29 Structurally similar cytotoxic natural products were recently determined to function via inhibition of peroxiredoxin 1 (Prx1), leading to an increase of reactive oxygen species (ROS), subsequent inhibition of mTORC1-mediated 4E-BP1 phosphorylation (4E-BP1p), apoptosis induction, and tumor suppression. 34,37,64 Given the positive correlation between inhibition of 4E-BP1 (B) Dose−response of compound 7 against A549 (non-small-cell lung) and PC3 (prostate) human cancer cell lines (72 h). See also Supporting Information, Figure S4 and Table S1.…”

“…While anthraquinones 1 – 6 displayed little to no cancer cell line cytotoxicity at ≤80 μM concentration (Figure ; Supporting Information, Figure S4), angucyclinone 7 displayed potent cytotoxicity against PC3 (prostate cancer cell line, IC 50 = 0.32 μM) and moderate cytotoxicity against A549 (non-small-cell lung cancer cell line, IC 50 = 1.88 μM) (Figure ; Supporting Information, Table S1). In comparison, the structurally related analogues PM070747 and PD 116740 (Supporting Information, Figure S1) were nearly an order of magnitude less cytotoxic against comparable cancer cell lines. , Structurally similar cytotoxic natural products were recently determined to function via inhibition of peroxiredoxin 1 (Prx1), leading to an increase of reactive oxygen species (ROS), subsequent inhibition of mTORC1-mediated 4E-BP1 phosphorylation (4E-BP1p), apoptosis induction, and tumor suppression. ,, Given the positive correlation between inhibition of 4E-BP1 phosphorylation and ROS-mediated cancer cell cytotoxicity in these studies, and the reported ability of angucyclines/angucyclinones to upregulate ROS and modulate mTORC1 function, − 7 and a representative set of related cytotoxic angucycline comparators were evaluated for their ability to inhibit 4E-BP1 phosphorylation. Specifically, this comparator test set included landomycins and saquayamycins that displayed IC 50 s < 500 nM against A549 or PC3 (Figures and ; Supporting Information, Table S1).…”

“… ,− Herein, we describe the fermentation, isolation, and structure elucidation of himalaquinones A–G ( 1 – 7 ) and propose a biosynthetic pathway for these structurally unique metabolites based on well-established precedent. In addition, 1 – 7 , along with a diverse range of representative naturally occurring angucyclin­(on)­es (aquayamycin, rabelomycin, landomycins, saquayamycins, and urdamycin A) were evaluated for cancer cell line cytotoxicity, antimicrobial activity, inhibition of 4E-BP1 phosphorylation, and modulation of axolotl embryo development and tail regeneration. − These studies revealed angucyclinone 7 as an inhibitor of axolotl embryo tail regeneration and cancer cell line growth and suggest the antiproliferative mechanism of 7 may be unique to that of classical angucyclines. As such, this work may prompt further studies to elucidate the potentially unique fundamental mechanism of 5,6-dihydrodiol-bearing angucyclinones.…”

Streptomyces: Still the Biggest Producer of New Natural Secondary Metabolites, a Current Perspective

“…with significant antibacterial activity. Nybomycin D Quinoline G+ Acid mine soil [226] Pentaminomycin C-E Cyclic pentapeptide G+ Fungi [227] Nalidixic acid 1 Quinolone G-Rhizospheric soil [228] Quinomycin I and J Cyclic depsipeptide G+ Mount soil [229] Puromycin B-E Amino-nucleoside G+ Soil [230] Abyssomicin M−X Spirotetronate polyketide G+ Soil [231] Streptoone A Linear polyketide G+ Soil [232] Asenjonamide A-C β-diketone G+ & G-Desert soil [233] Gordonic acid polyketide glycoside G+ Acid mine drainage soil [234] Ulleungmycin A and B Non-ribosmal peptide G+ Volcanic soil [235] Quinomycin A-C Pyranonapthaquinone G+ Mountain Soil [236] Actinomycin Y 6 -Y 9 Bi-cyclic chromopeptide lactone G+ Soil [237] 2-amino-N-( G+-Gram-positive bacteria, G-Gram-negative bacteria, MRSA-Methicillin Resistant Staphylococcus aureus, VRE-Vancomycin Resistant Enterococci.…”