Terpestacin, a new syncytium formation inhibitor from Arthrinium sp.

Oka, Masahisa; Iimura, Seiji; Tenmyo, Osamu; Sawada, Yosuke; Sugawara, Masaru; Ohkusa, Noriyuki; Yamamoto, Haruaki; Kawano, Kimio; Hu, Shiu‐Lok; Fukagawa, Yasuo; Oki, Taikan

doi:10.7164/antibiotics.46.367

Cited by 75 publications

(49 citation statements)

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“…Terpestacin strongly inhibits the functional response to hypoxia of human umbilical vein endothelial cells in vitro and angiogenesis within the embryonic chick chorioallantoic membrane in vivo. In addition to this anti-angiogenic activity, terpestacin has previously been reported to inhibit syncytium formation during human immunodeficiency virus infection and has been chemically synthesized (11)(12)(13). However, neither the molecular target of this compound nor the cellular mechanism of its anti-angiogenic activity has been identified.…”

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confidence: 93%

Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing

Jung

Shim

Lee

et al. 2010

Journal of Biological Chemistry

110

102

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Cellular oxygen sensing is required for hypoxia-inducible factor-1␣ stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Here we find that terpestacin, a small molecule previously identified in a screen of microbial extracts, binds to the 13.4-kDa subunit (UQCRB) of mitochondrial Complex III, resulting in inhibition of hypoxia-induced reactive oxygen species generation. Consequently, such inhibition blocks hypoxia-inducible factor activation and tumor angiogenesis in vivo, without inhibiting mitochondrial respiration. Overexpression of UQCRB or its suppression using RNA interference demonstrates that it plays a crucial role in the oxygen sensing mechanism that regulates responses to hypoxia. These findings provide a novel molecular basis of terpestacin targeting UQCRB of Complex III in selective suppression of tumor progression.Progression of many solid tumors requires angiogenesis (1). Mitochondrial function has been linked to angiogenesis, because mitochondria are the primary sites of oxygen consumption, and angiogenesis is an oxygen concentration-sensitive process (2). Reports suggest that reactive oxygen species (ROS) 3 generation at mitochondrial Complex III is necessary and sufficient to trigger HIF-1␣ stabilization during hypoxia, and cells lacking mitochondrial DNA and electron transport activity ( cells) fail to exhibit increased ROS or up-regulation of HIF-1␣ target genes during hypoxia (3-5). Inhibitors of Complex III such as myxothiazol and stigmatellin also block mitochondrial ROS generation and inhibit the stabilization and transcriptional activity of HIF-1␣ during hypoxia. These findings suggest that the generation of ROS from mitochondrial Complex III is a critical event in the signaling of cellular hypoxia (6, 7). However, details regarding which of the components of Complex III contribute to this signaling remain to be described.Biological screening tools are useful for identifying naturally occurring small molecules capable of inducing a specific phenotype change (8, 9). We performed a large scale screen of microbial extracts in an attempt to identify small molecules that could inhibit the angiogenic response to pro-angiogenic stimuli, such as hypoxia, in endothelial cells. We identified terpestacin as a small molecule with unique bicyclo sesterterpene structure capable of inhibiting the angiogenic response at concentrations below the toxic threshold (10). Terpestacin strongly inhibits the functional response to hypoxia of human umbilical vein endothelial cells in vitro and angiogenesis within the embryonic chick chorioallantoic membrane in vivo. In addition to this anti-angiogenic activity, terpestacin has previously been reported to inhibit syncytium formation during human immunodeficiency virus infection and has been chemically synthesized (11-13). However, neither the molecular target of this compound nor the cellular mechanism of its anti-angiogenic activity has been identified.In the present study we identified the binding protein of terpestacin and...

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confidence: 93%

Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing

Jung

Shim

Lee

et al. 2010

Journal of Biological Chemistry

110

102

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“…This inhibitory potency is not signiˆcantly diŠerent from that of terpestacin (2), which has also been isolated as a phytotoxic compound from Bipolaris cynodontis. 14) This shows that the absolute conˆguration at C-11 has no eŠect on the phytotoxic activity.…”

Section: H-nmr Data Of (R)-(")-and (S )-(+)-Mtpa Esters Ofmentioning

confidence: 76%

“…1) A spectroscopic analysis determined the planar structure of siccanol to be identical with that of terpestacin (2) from Arthrinium sp., which had been isolated as an inhibitor of syncytium formation caused by the human immunodeˆciency virus (HIV). 2,3) However, the stereochemistry of these compounds was thought to be diŠerent, because their optical rotation values diŠered: [a]D for siccanol was "239 , while it has been reported to be +269for terpestacin. The absolute structure of terpestacin has been established on the basis of spectroscopic analyses and a total synthesis.…”

mentioning

confidence: 99%

Phytotoxic Sesterterpene, 11-Epiterpestacin, fromBipolaris sorokinianaNSDR-011

Nihashi¹,

Lim²,

Tanaka³

et al. 2002

Bioscience, Biotechnology, and Biochemistry

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The structure of siccanol, a phytotoxic sesterterpene of fungal origin, was analyzed after chemical conversion by NMR spectroscopy. Siccanol was found to be an epimer of terpestacin that has been isolated from Arthrinium sp., and was thus renamed 11-epiterpestacin. Its stereochemistry was also identical with that of fusaproliferin, a structurally related mycotoxin from Fusarium proliferatum. Therefore, this sesterterpene may also be referred to as 24-deacetyl fusaproliferin. The phytotoxicity of 11-epiterpestacin was almost equal to that of terpestacin, but signiˆcantly higher than that of fusaproliferin.

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“…Previous chemical investigations of fungal strains of the genus, Arthrinium, a dematiaceous anamorph of the teleomorph genus Apiospora, revealed a plethora of structurally interesting secondary metabolites such as arthrinone, 29 arthrichitin, 30 terpestacin, 31 CAF-603, 32 norlichexanthone, 33 apiosporamide, 34 the cyclopeptides TMC-95A-D, 35 and the pimarane-type diterpene myrocin A. 36 We now report the isolation and structural elucidation of five new diterpenoids (1)(2)(3)(4)(5) as well as five known natural products (6)(7)(8)(9)(10), and on their antiproliferative activities against a panel of human and murine cell lines (Chart 1).…”

Section: Introductionmentioning

confidence: 99%

Arthrinins A–D: Novel diterpenoids and further constituents from the sponge derived fungus Arthrinium sp.

Ebada

Schulz

Wray³

et al. 2011

Bioorganic & Medicinal Chemistry

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Terpestacin, a new syncytium formation inhibitor from Arthrinium sp.

Abstract: Terpestacin, a new antibiotic which inhibits syncytium formation, was isolated from Arthrinium sp. FA1744(ATCC74132). The structure of terpestacin was elucidated as a bicyclic sesterterpene on the basis of spectroscopic data and chemical derivatization.

Cited by 75 publications

References 5 publications

Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing

Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing

Phytotoxic Sesterterpene, 11-Epiterpestacin, fromBipolaris sorokinianaNSDR-011

Arthrinins A–D: Novel diterpenoids and further constituents from the sponge derived fungus Arthrinium sp.

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