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海洋天然产物奥多酰胺的靶点鉴定：奥多酰胺通过靶向ATP酶钠/钾转运亚基α1（ATP1A1）诱导细胞凋亡性死亡。

Target Identification of Marine Natural Product Odoamide:Odoamide Induces Apoptotic Cell Death by Targeting ATPase Na/K Transporting Subunit Alpha 1 (ATP1A1).

作者信息

Katsumata Ryosuke, Kamiyama Hiroshi, Sagane Koji, Yamamoto Yuji, Azuma Hiroshi, Nishibata Kyoko, Kotake Yoshihiko, Nakano Shizuka, Okubo Shinya, Teruya Toshiaki, Okuda Akifumi, Takase Yasutaka

机构信息

Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan.

Faculty of Education, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa, 903-0213, Japan.

出版信息

Chembiochem. 2025 Mar 15;26(6):e202400762. doi: 10.1002/cbic.202400762. Epub 2025 Jan 24.

DOI:10.1002/cbic.202400762
PMID:39754293
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11907391/
Abstract

Marine natural products show a large variety of unique chemical structures and potent biological activities. Elucidating the target molecule and the mechanism of action is an essential and challenging step in drug development starting with a natural product. Odoamide, a member of aurilide-family isolated from Okinawan marine cyanobacterium, has been known to exhibit highly potent cytotoxicity against various cancer cell lines. In this study, we investigated the target protein and the cytotoxic mechanism of odoamide. Compared to existing anticancer agents, odoamide showed a unique fingerprint in the JFCR39 cancer cell panel and a characteristic pattern in gene expression profiling. Affinity chromatography utilizing a biologically active odoamide probe identified ATPase Na/K transporting subunit alpha 1 (ATP1A1) as a specific binding protein. Additionally, cells resistant to odoamide were found to have mutations at Gly98 and Gly99 of the ATP1A1 protein. The apparently attenuated cytotoxic and apoptotic activities of odoamide in odoamide-resistant cells suggests that the induction of these activities by odoamide is critically dependent on its interaction with ATP1A1. We conclude that odoamide induces apoptotic cell death by targeting ATP1A1, and we discuss the impact of affinity-based target identification for natural products and the potential of ATP1A1 inhibitors for drug discovery.

摘要

海洋天然产物呈现出多种多样独特的化学结构和强大的生物活性。从天然产物出发进行药物开发时，阐明目标分子和作用机制是至关重要且具有挑战性的一步。奥多酰胺是从冲绳海洋蓝藻中分离出的奥里利德家族的一员，已知其对多种癌细胞系具有高效的细胞毒性。在本研究中，我们研究了奥多酰胺的靶蛋白和细胞毒性机制。与现有的抗癌药物相比，奥多酰胺在JFCR39癌细胞系中显示出独特的指纹图谱，在基因表达谱中呈现出特征性模式。利用具有生物活性的奥多酰胺探针进行亲和层析，确定ATP酶钠/钾转运亚基α1（ATP1A1）为特异性结合蛋白。此外，发现对奥多酰胺耐药的细胞在ATP1A1蛋白的第98位和第99位甘氨酸处发生了突变。奥多酰胺在耐药细胞中明显减弱的细胞毒性和凋亡活性表明，奥多酰胺诱导这些活性关键取决于其与ATP1A1的相互作用。我们得出结论，奥多酰胺通过靶向ATP1A1诱导凋亡性细胞死亡，并且我们讨论了基于亲和性的天然产物靶点鉴定的影响以及ATP1A1抑制剂在药物发现中的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/a2f03ac0d2f5/CBIC-26-e202400762-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/2bd07fafebe9/CBIC-26-e202400762-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/2e56195b5b63/CBIC-26-e202400762-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/5a3bf9143e54/CBIC-26-e202400762-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/a2f03ac0d2f5/CBIC-26-e202400762-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/2bd07fafebe9/CBIC-26-e202400762-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/2e56195b5b63/CBIC-26-e202400762-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/5a3bf9143e54/CBIC-26-e202400762-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff0f/11907391/a2f03ac0d2f5/CBIC-26-e202400762-g001.jpg

相似文献

1
Target Identification of Marine Natural Product Odoamide:Odoamide Induces Apoptotic Cell Death by Targeting ATPase Na/K Transporting Subunit Alpha 1 (ATP1A1).海洋天然产物奥多酰胺的靶点鉴定：奥多酰胺通过靶向ATP酶钠/钾转运亚基α1（ATP1A1）诱导细胞凋亡性死亡。
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本文引用的文献

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Research progress on morphology and mechanism of programmed cell death.程序性细胞死亡的形态学和机制研究进展。
Cell Death Dis. 2024 May 10;15(5):327. doi: 10.1038/s41419-024-06712-8.
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Cell death.细胞死亡。
Cell. 2024 Jan 18;187(2):235-256. doi: 10.1016/j.cell.2023.11.044.
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The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death.细胞凋亡、坏死性凋亡、细胞焦亡和铁死亡的生化途径。
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ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy.ATP1A1是黑色素瘤治疗中一个有前景的新靶点，并且可以被其生理配体蟾毒灵抑制，以恢复靶向治疗的疗效。
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Functional Analysis and Clinical Importance of ATP1A1 in Colon Cancer.ATP1A1 在结肠癌中的功能分析及临床意义。
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Ouabain at nanomolar concentrations is cytotoxic for biliary tract cancer cells.哇巴因在纳摩尔浓度下对胆道癌细胞具有细胞毒性。
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Targeted and functional genomics approaches to the mechanism of action of lagunamide D, a mitochondrial cytotoxin from marine cyanobacteria.靶向和功能基因组学方法研究 lagunamide D 的作用机制，lagunamide D 是一种来自海洋蓝藻的线粒体细胞毒素。
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Multivalent mannose-conjugated siRNA causes robust gene silencing in pancreatic macrophages in vivo.多价甘露糖缀合的小干扰RNA（siRNA）在体内可使胰腺巨噬细胞发生强效基因沉默。
Eur J Pharm Biopharm. 2023 Feb;183:61-73. doi: 10.1016/j.ejpb.2022.12.017. Epub 2023 Jan 2.
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