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

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. Shaaban

doi:10.1021/acs.jnatprod.9b01015

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

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. Shaaban

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

We 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.

Original language	English
Pages (from-to)	3469-3476
Number of pages	8
Journal	Journal of Natural Products
Volume	82
Issue number	12
DOIs	https://doi.org/10.1021/acs.jnatprod.9b01015
State	Published - Dec 27 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society and American Society of Pharmacognosy.

Funding

This work was supported by National Institutes of Health Grant Nos. R24 OD21479 (S.R.V., J.S.T.), R01 CA203257 (Q.B.S., J.S.T.), R01 CA175105 (Q.B.S.), and R01 GM115261 (J.S.T.), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, and the National Center for Advancing Translational Sciences (UL1TR000117 and UL1TR001998). We thank the College of Pharmacy NMR Center (University of Kentucky) for NMR support.

Funders	Funder number
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R01CA203257
National Childhood Cancer Registry – National Cancer Institute

ASJC Scopus subject areas

Analytical Chemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Complementary and alternative medicine
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Wang, X., Elshahawi, S. I., Ponomareva, L. V., Ye, Q., Liu, Y., Copley, G. C., Hower, J. C., Hatcher, B. E., Kharel, M. K., Van Lanen, S. G., She, Q. B., Voss, S. R., Thorson, J. S., & Shaaban, K. A. (2019). Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces. Journal of Natural Products, 82(12), 3469-3476. https://doi.org/10.1021/acs.jnatprod.9b01015

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

abstract = "We 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.",

author = "Xiachang Wang and Elshahawi, {Sherif I.} and Ponomareva, {Larissa V.} and Qing Ye and Yang Liu and Copley, {Gregory C.} and Hower, {James C.} and Hatcher, {Bruce E.} and Kharel, {Madan K.} and {Van Lanen}, {Steven G.} and She, {Qing Bai} and Voss, {S. Randal} and Thorson, {Jon S.} and Shaaban, {Khaled A.}",

note = "Publisher Copyright: {\textcopyright} 2019 American Chemical Society and American Society of Pharmacognosy.",

year = "2019",

month = dec,

day = "27",

doi = "10.1021/acs.jnatprod.9b01015",

language = "English",

volume = "82",

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Wang, X, Elshahawi, SI, Ponomareva, LV, Ye, Q, Liu, Y, Copley, GC, Hower, JC, Hatcher, BE, Kharel, MK, Van Lanen, SG , She, QB , Voss, SR , Thorson, JS & Shaaban, KA 2019, 'Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces', Journal of Natural Products, vol. 82, no. 12, pp. 3469-3476. https://doi.org/10.1021/acs.jnatprod.9b01015

Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces. / Wang, Xiachang; Elshahawi, Sherif I.; Ponomareva, Larissa V. et al.
In: Journal of Natural Products, Vol. 82, No. 12, 27.12.2019, p. 3469-3476.

Research output: Contribution to journal › Article › peer-review

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T1 - Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces

AU - Wang, Xiachang

AU - Elshahawi, Sherif I.

AU - Ponomareva, Larissa V.

AU - Ye, Qing

AU - Liu, Yang

AU - Copley, Gregory C.

AU - Hower, James C.

AU - Hatcher, Bruce E.

AU - Kharel, Madan K.

AU - Van Lanen, Steven G.

AU - She, Qing Bai

AU - Voss, S. Randal

AU - Thorson, Jon S.

AU - Shaaban, Khaled A.

PY - 2019/12/27

Y1 - 2019/12/27

N2 - We 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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