Dopamine-Derived Guanidine Alkaloids from a Didemnidae Tunicate: Isolation, Synthesis, and Biological Activities.
Ryuichi Sakai, Ken Matsumura, Hajime Uchimasu, Kei Miyako, Tohru Taniguchi, V Raghavendra Rao Kovvuri, Anjana Delpe Acharige, Kenneth G Hull, Daniel Romo, Lakkana Thaveepornkul, Sarin Chimnaronk, Hiroko Miyamoto, Ayato Takada, Hiromi Watari, Masaki J Fujita, Jiro Sakaue
The Journal of organic chemistry, 2024年04月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Mellpaladines A-C (1-3) and dopargimine (4) are dopamine-derived guanidine alkaloids isolated from a specimen of Palauan Didemnidae tunicate as possible modulators of neuronal receptors. In this study, we isolated the dopargimine derivative 1-carboxydopargimine (5), three additional mellpaladines D-F (6-8), and serotodopalgimine (9), along with a dimer of serotonin, 5,5'-dihydroxy-4,4'-bistryptamine (10). The structures of these compounds were determined based on spectrometric and spectroscopic analyses. Compound 4 and its congeners dopargine (11), nordopargimine (15), and 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)ethan-1-amine (16) were synthetically prepared for biological evaluations. The biological activities of all isolated compounds were evaluated in comparison with those of 1-4 using a mouse behavioral assay upon intracerebroventricular injection, revealing key functional groups in the dopargimines and mellpaladines for in vivo behavioral toxicity. Interestingly, these alkaloids also emerged during a screen of our marine natural product library aimed at identifying antiviral activities against dengue virus, SARS-CoV-2, and vesicular stomatitis Indiana virus (VSV) pseudotyped with Ebola virus glycoprotein (VSV-ZGP).

Total synthesis of lycoperdic acid and stereoisomers (part 2): Completion of the synthesis and biological evaluation
Kenji Morokuma, Hiromi Watari, Maika Mori, Ryuichi Sakai, Raku Irie, Masato Oikawa
Tetrahedron, 133623, 133623, Elsevier BV, 2023年08月
研究論文（学術雑誌）

Interaction of Polyamine-modified Marine Peptide Aculeine A with Cell Membranes: Disruption or Entry
Hiromi Watari, Reimi Kishi, Satoko Matsunaga, Takayuki Nishikawa, Yuji Sawada, Akito Honda, Masaki J Fujita, Ryuichi Sakai
Chemistry Letters, 52, 3, 185, 189, The Chemical Society of Japan, 2023年03月05日, ［査読有り］, ［筆頭著者］
研究論文（学術雑誌）

A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation
Hiromi Watari, Hiromu Kageyama, Nami Masubuchi, Hiroya Nakajima, Kako Onodera, Pamela J. Focia, Takumi Oshiro, Takashi Matsui, Yoshio Kodera, Tomohisa Ogawa, Takeshi Yokoyama, Makoto Hirayama, Kanji Hori, Douglas M. Freymann, Misa Imai, Norio Komatsu, Marito Araki, Yoshikazu Tanaka, Ryuichi Sakai
Nature Communications, 13, 1, 7262, 7262, Springer Science and Business Media LLC, 2022年11月25日, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that traffics to the cell surface and constitutively activates the receptor. However, the molecular basis for this mechanism is elusive because oncogenic activation occurs only in the cell-intrinsic complex and is thus cannot be replicated with external agonists. Here, we describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. In-depth characterization of lectin-induced activation showed that, similar to oncogenic activation, sugar chain-mediated activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. Overall, the existence of sugar-mediated MPL activation, in which the mode of activation is different from the original ligand, suggests that receptor activation is unpredictably diverse in living organisms.

Hidden pathway for cytokine receptor activation: a marine sponge-derived lectin reveals sugar-mediated thrombopoietin receptor activation
Hiromi Watari, Hiromu Kageyama, Nami Masubuchi, Hiroya Nakajima, Kako Onodera, Pamela Focia, Takumi Oshiro, Takashi Matsui, Yoshio Kodera, Tomohisa Ogawa, Takeshi Yokoyama, Makoto Hirayama, Kanji Hori, Douglas Freymann, Norio Komatsu, Marito Araki, Yoshikazu Tanaka, Ryuichi Sakai
2022年04月01日

Hidden pathway for cytokine receptor activation: Structural insights into a marine sponge-derived lectin that activates the thrombopoietin receptor via recognition of the fucose moiety
Hiromi Watari, Hiromu Kageyama, Nami Masubuchi, Hiroya Nakajima, Kako Onodera, Pamela J. Focia, Takumi Oshiro, Takashi Matsui, Yoshio Kodera, Tomohisa Ogawa, Takeshi Yokoyama, Makoto Hirayama, Kanji Hori, Douglas M. Freymann, Norio Komatsu, Marito Araki, Yoshikazu Tanaka, Ryuichi Sakai
Cold Spring Harbor Laboratory, 2021年10月29日
ABSTRACT

N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that constitutively activates the receptor. However, the molecular basis for this mechanism has not been studied because no external agonists existed. We describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. ThC-induced activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. MPL is subject to sugar-mediated activation, where the kinetics differ from those of cytokines. This result suggests the presence of diverse receptor activation pathways in human thrombopoiesis.

One-sentence summary

A marine sponge lectin catalyzes thrombopoietin receptor dimerization and activation, exhibiting strong synergy with thrombopoietin, and modulates internalization of the receptor.

A novel sponge-derived protein thrombocorticin is a new agonist for thrombopoietin receptor
Hiromi Watari, Hiroya Nakajima, Wataru Atsuumi, Takanori Nakamura, Takeshi Nanya, Yuji Ise, Ryuichi Sakai
Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 221, 82, 88, Elsevier BV, 2019年07月, ［査読有り］, ［筆頭著者］
研究論文（学術雑誌）

Cytological effects of a novel sponge derived protein toxin, soritesidine　　　　　　　　　　　　　　　
Hiromi Watari, Masaya Kitano, Yuri Ishibashi, Ryuichi Sakai, The 38th Symposium on Natural Products, 2023年10月

MECHANISM OF CYTOKINE RECEPTOR ACTIVATION BY MARINE SPONGE LECTIN　　　　　　　　　　　　　　　
Hiromi Watari, Hiroki Kageyama, Nami Masubuchi, Marito Araki, Yoshikazu Tanaka, Ryuichi Sakai, ECMNP-MaNaPro 2023, 2023年09月, ［筆頭著者］

受容体の新規活性化機構を掘り起こす海洋天然物　　　　　　　　　　　　　　　
辺浩美, 第１５回化学生態学研究会, 2023年06月, ［招待有り］

海綿由来レクチン ThC によるサイトカイン受容体 新規活性化機構の解明　　　　　　　　　　　　　　　
令和4年度 日本農芸化学会 北海道・東北支部 合同支部会, 2022年09月

海綿由来レクチンをプローブとしたサイトカイン受容体 新規活性化機構の解明　　　　　　　　　　　　　　　
第64回天然有機化合物討論会, 2022年09月

高濃度PEG含有蛋白質結晶からのLC-MSによるアミノ酸解析
大城拓未, 影山大夢, 小野寺かこ, 辺浩美, 中島寛也, 小川智久, 小川智久, 横山武司, 田中良和, 酒井隆一, 松井崇, 松井崇, 小寺義男, 小寺義男, 日本プロテオーム学会大会プログラム・抄録集, 2022 (Web), 2022年

Activation of thrombopoietin receptor by sponge derived protein: A Novel mechanism of activation of c-Mpl　　　　　　　　　　　　　　　
Pacifichem 2021, 2021年12月

Marine sponge lectin reveals the mechanism of sugar-chain mediated activation of MPL
辺浩美, 影山大夢, 中島寛弥, 小野寺かこ, 増渕菜弥, 大城拓未, 松井崇, 小寺義男, 小川智久, 平山真, 堀貫治, 横山武司, 小松則夫, 小松則夫, 荒木真理人, 荒木真理人, 田中良和, 酒井隆一, 日本血液学会学術集会抄録(Web), 83rd, 2021年