np9b01015_si_001.pdf (2.69 MB)
Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces
journal contribution
posted on 2019-12-13, 13:35 authored by Xiachang Wang, Sherif I. Elshahawi, Larissa V. Ponomareva, Qing Ye, Yang Liu, Gregory C. Copley, James C. Hower, Bruce E. Hatcher, Madan K. Kharel, Steven G. Van Lanen, Qing-Bai She, S. Randal Voss, Jon S. Thorson, Khaled A. ShaabanWe report the isolation and characterization of three
new nybomycins
(nybomycins B–D, 1–3) and
six known compounds (nybomycin, 4; deoxynyboquinone, 5; α-rubromycin, 6; β-rubromycin, 7; γ-rubromycin, 8; and [2α(1E,3E),4β]-2-(1,3-pentadienyl)-4-piperidinol, 9) from the Rock Creek (McCreary County, KY) underground coal
mine acid reclamation site isolate Streptomyces sp. AD-3-6. Nybomycin D (3) and deoxynyboquinone (5) displayed moderate (3) to potent (5) cancer cell line cytotoxicity and displayed weak to moderate anti-Gram-(+)
bacterial activity, whereas rubromycins 6–8 displayed little to no cancer cell line cytotoxicity but
moderate to potent anti-Gram-(+) bacterial and antifungal activity.
Assessment of the impact of 3 or 5 cancer
cell line treatment on 4E-BP1 phosphorylation, a predictive marker
of ROS-mediated control of cap-dependent translation, also revealed
deoxynyboquinone (5)-mediated downstream inhibition of
4E-BP1p. Evaluation of 1–9 in a recently
established axolotl embryo tail regeneration assay also highlighted
the prototypical telomerase inhibitor γ-rubromycin (8) as a new inhibitor of tail regeneration. Cumulatively, this work
highlights an alternative nybomycin production strain, a small set
of new nybomycin metabolites, and previously unknown functions of
rubromycins (antifungal activity and inhibition of tail regeneration)
and also provides a basis for revision of the previously proposed
nybomycin biosynthetic pathway.
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coal mine acid reclamation sitedeoxynyboquinoneAD -3-6. Nybomycin DMining Reclamation Site-Associated Streptomycescancer cell line cytotoxicity4 E-BP 1 phosphorylationtelomerase inhibitor γ- rubromycin5 cancer cell line treatmenttail regenerationantifungal activitynybomycin biosynthetic pathwayaxolotl embryo tail regeneration assayKYalternative nybomycin production strain4 E-BP 1p Evaluation
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