2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition

Abstract Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA is similar to lysophosphatidic acid (LPA) in s...

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Autores principales:	Keiko Fukasawa, Mari Gotoh, Akiharu Uwamizu, Takatsugu Hirokawa, Masaki Ishikawa, Yoshibumi Shimizu, Shinji Yamamoto, Kensuke Iwasa, Keisuke Yoshikawa, Junken Aoki, Kimiko Murakami-Murofushi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e959ecf2a7d64653976c5ac68bc4d772
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spelling	oai:doaj.org-article:e959ecf2a7d64653976c5ac68bc4d7722021-12-02T15:29:02Z2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition10.1038/s41598-021-96931-22045-2322https://doaj.org/article/e959ecf2a7d64653976c5ac68bc4d7722021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96931-2https://doaj.org/toc/2045-2322Abstract Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA is similar to lysophosphatidic acid (LPA) in structure and synthetic pathway, some of cPA biological functions apparently differ from those reported for LPA. We previously investigated the pharmacokinetic profile of 2ccPA, which was found to be rapidly degraded, especially in acidic conditions, yielding an unidentified compound. Thus, not only cPA but also its degradation compound may contribute to the biological activity of cPA, at least for 2ccPA. In this study, we determined the structure and examined the biological activities of 2-carba-lysophosphatidic acid (2carbaLPA) as a 2ccPA degradation compound, which is a type of β-LPA analogue. Similar to LPA and cPA, 2carbaLPA induced the phosphorylation of the extracellular signal-regulated kinase and showed potent agonism for all known LPA receptors (LPA1–6) in the transforming growth factor-α (TGFα) shedding assay, in particular for LPA3 and LPA4. 2carbaLPA inhibited the lysophospholipase D activity of autotaxin (ATX) in vitro similar to other cPA analogues, such as 2ccPA, 3-carba-cPA, and 3-carba-LPA (α-LPA analogue). Our study shows that 2carbaLPA is a novel β-LPA analogue with high potential for the activation of some LPA receptors and ATX inhibition.Keiko FukasawaMari GotohAkiharu UwamizuTakatsugu HirokawaMasaki IshikawaYoshibumi ShimizuShinji YamamotoKensuke IwasaKeisuke YoshikawaJunken AokiKimiko Murakami-MurofushiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Keiko Fukasawa Mari Gotoh Akiharu Uwamizu Takatsugu Hirokawa Masaki Ishikawa Yoshibumi Shimizu Shinji Yamamoto Kensuke Iwasa Keisuke Yoshikawa Junken Aoki Kimiko Murakami-Murofushi 2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition
description	Abstract Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA is similar to lysophosphatidic acid (LPA) in structure and synthetic pathway, some of cPA biological functions apparently differ from those reported for LPA. We previously investigated the pharmacokinetic profile of 2ccPA, which was found to be rapidly degraded, especially in acidic conditions, yielding an unidentified compound. Thus, not only cPA but also its degradation compound may contribute to the biological activity of cPA, at least for 2ccPA. In this study, we determined the structure and examined the biological activities of 2-carba-lysophosphatidic acid (2carbaLPA) as a 2ccPA degradation compound, which is a type of β-LPA analogue. Similar to LPA and cPA, 2carbaLPA induced the phosphorylation of the extracellular signal-regulated kinase and showed potent agonism for all known LPA receptors (LPA1–6) in the transforming growth factor-α (TGFα) shedding assay, in particular for LPA3 and LPA4. 2carbaLPA inhibited the lysophospholipase D activity of autotaxin (ATX) in vitro similar to other cPA analogues, such as 2ccPA, 3-carba-cPA, and 3-carba-LPA (α-LPA analogue). Our study shows that 2carbaLPA is a novel β-LPA analogue with high potential for the activation of some LPA receptors and ATX inhibition.
format	article
author	Keiko Fukasawa Mari Gotoh Akiharu Uwamizu Takatsugu Hirokawa Masaki Ishikawa Yoshibumi Shimizu Shinji Yamamoto Kensuke Iwasa Keisuke Yoshikawa Junken Aoki Kimiko Murakami-Murofushi
author_facet	Keiko Fukasawa Mari Gotoh Akiharu Uwamizu Takatsugu Hirokawa Masaki Ishikawa Yoshibumi Shimizu Shinji Yamamoto Kensuke Iwasa Keisuke Yoshikawa Junken Aoki Kimiko Murakami-Murofushi
author_sort	Keiko Fukasawa
title	2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition
title_short	2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition
title_full	2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition
title_fullStr	2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition
title_full_unstemmed	2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition
title_sort	2-carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e959ecf2a7d64653976c5ac68bc4d772
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2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition

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