Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a devastating digestive system carcinoma with high incidence and death rates. PDAC cells are dependent on the Gln metabolism, which can preferentially utilize glutamic oxaloacetate transaminase 1 (GOT1) to maintain the redox homeostasis of cancer cells. The...

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Autores principales:	Shan Yan, Changxing Qi, Wei Song, Qianqian Xu, Lianghu Gu, Weiguang Sun, Yonghui Zhang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	natural products GOT1 enzyme X-ray crystallography pancreatic ductal adenocarcinoma cells glutamine metabolism Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b78d13f81a4248dc980c30bf5d299d20
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spelling	oai:doaj.org-article:b78d13f81a4248dc980c30bf5d299d202021-11-25T18:12:37ZDiscovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma10.3390/md191105881660-3397https://doaj.org/article/b78d13f81a4248dc980c30bf5d299d202021-10-01T00:00:00Zhttps://www.mdpi.com/1660-3397/19/11/588https://doaj.org/toc/1660-3397Pancreatic ductal adenocarcinoma (PDAC) is a devastating digestive system carcinoma with high incidence and death rates. PDAC cells are dependent on the Gln metabolism, which can preferentially utilize glutamic oxaloacetate transaminase 1 (GOT1) to maintain the redox homeostasis of cancer cells. Therefore, small molecule inhibitors targeting GOT1 can be used as a new strategy for developing cancer therapies. In this study, 18 butyrolactone derivatives (<b>1</b>–<b>18</b>) were isolated from a marine-derived <i>Aspergillus terreus</i>, and asperteretone B (<b>5</b>), aspulvinone H (AH, <b>6</b>), and (+)-3′,3′-di-(dimethylallyl)-butyrolactone II (<b>12</b>) were discovered to possess significant GOT1-inhibitory activities in vitro, with IC<sub>50</sub> values of (19.16 ± 0.15), (5.91 ± 0.04), and (26.38 ± 0.1) µM, respectively. Significantly, the molecular mechanism of the crystal structure of GOT1–AH was elucidated, wherein AH and the cofactor pyrido-aldehyde 5-phosphate competitively bound to the active sites of GOT1. More importantly, although the crystal structure of GOT1 has been discovered, the complex structure of GOT1 and its inhibitors has never been obtained, and the crystal structure of GOT1–AH is the first reported complex structure of GOT1/inhibitor. Further in vitro biological study indicated that AH could suppress glutamine metabolism, making PDAC cells sensitive to oxidative stress and inhibiting cell proliferation. More significantly, AH exhibited potent in vivo antitumor activity in an SW1990-cell-induced xenograft model. These findings suggest that AH could be considered as a promising lead molecule for the development of anti-PDAC agents.Shan YanChangxing QiWei SongQianqian XuLianghu GuWeiguang SunYonghui ZhangMDPI AGarticlenatural productsGOT1 enzymeX-ray crystallographypancreatic ductal adenocarcinoma cellsglutamine metabolismBiology (General)QH301-705.5ENMarine Drugs, Vol 19, Iss 588, p 588 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	natural products GOT1 enzyme X-ray crystallography pancreatic ductal adenocarcinoma cells glutamine metabolism Biology (General) QH301-705.5
spellingShingle	natural products GOT1 enzyme X-ray crystallography pancreatic ductal adenocarcinoma cells glutamine metabolism Biology (General) QH301-705.5 Shan Yan Changxing Qi Wei Song Qianqian Xu Lianghu Gu Weiguang Sun Yonghui Zhang Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma
description	Pancreatic ductal adenocarcinoma (PDAC) is a devastating digestive system carcinoma with high incidence and death rates. PDAC cells are dependent on the Gln metabolism, which can preferentially utilize glutamic oxaloacetate transaminase 1 (GOT1) to maintain the redox homeostasis of cancer cells. Therefore, small molecule inhibitors targeting GOT1 can be used as a new strategy for developing cancer therapies. In this study, 18 butyrolactone derivatives (<b>1</b>–<b>18</b>) were isolated from a marine-derived <i>Aspergillus terreus</i>, and asperteretone B (<b>5</b>), aspulvinone H (AH, <b>6</b>), and (+)-3′,3′-di-(dimethylallyl)-butyrolactone II (<b>12</b>) were discovered to possess significant GOT1-inhibitory activities in vitro, with IC<sub>50</sub> values of (19.16 ± 0.15), (5.91 ± 0.04), and (26.38 ± 0.1) µM, respectively. Significantly, the molecular mechanism of the crystal structure of GOT1–AH was elucidated, wherein AH and the cofactor pyrido-aldehyde 5-phosphate competitively bound to the active sites of GOT1. More importantly, although the crystal structure of GOT1 has been discovered, the complex structure of GOT1 and its inhibitors has never been obtained, and the crystal structure of GOT1–AH is the first reported complex structure of GOT1/inhibitor. Further in vitro biological study indicated that AH could suppress glutamine metabolism, making PDAC cells sensitive to oxidative stress and inhibiting cell proliferation. More significantly, AH exhibited potent in vivo antitumor activity in an SW1990-cell-induced xenograft model. These findings suggest that AH could be considered as a promising lead molecule for the development of anti-PDAC agents.
format	article
author	Shan Yan Changxing Qi Wei Song Qianqian Xu Lianghu Gu Weiguang Sun Yonghui Zhang
author_facet	Shan Yan Changxing Qi Wei Song Qianqian Xu Lianghu Gu Weiguang Sun Yonghui Zhang
author_sort	Shan Yan
title	Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma
title_short	Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma
title_full	Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma
title_fullStr	Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma
title_full_unstemmed	Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma
title_sort	discovery of got1 inhibitors from a marine-derived <i>aspergillus terreus</i> that act against pancreatic ductal adenocarcinoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b78d13f81a4248dc980c30bf5d299d20
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Discovery of GOT1 Inhibitors from a Marine-Derived <i>Aspergillus terreus</i> That Act against Pancreatic Ductal Adenocarcinoma

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