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Journal of Biochemistry Advance Access published online on May 4, 2009
Journal of Biochemistry, doi:10.1093/jb/mvp068
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© The authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Lysophosphatidylmethanol is a pan lysophosphatidic acid receptor agonist and is produced by autotaxin in blood

Tomoko Endo1,2,*, Kuniyuki Kano2,*, Rie Motoki1,*, Kotaro Hama1, Shinichi Okudaira1,2, Mayuko Ishida3, Hideo Ogiso3, Masayuki Tanaka1,2, Norio Matsuki1, Ryo Taguchi3, Motomu Kanai1, Masakatsu Shibasaki1, Hiroyuki Arai1,4 and Junken Aoki2,5

1 Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan., 2 Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, 980-8578, Japan., 3 Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan., 4 CREST and 5 PRESTO, Japan Science and Technology Corporation

Address correspondence to Junken Aoki, Ph.D. at Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, 980-8578, Japan. Tel: 81-3-5841-4723; Fax: 81-3-3818-3173; E-mail: jaoki{at}mail.pharm.tohoku.ac.jp

Received February 23, 2009; Accepted April 16, 2009


  Abstract

Lysophosphatidic acid (LPA) is a simple phospholipid but has numerous biological effects through a series of G protein-coupled receptors specific to LPA. LPA in general is short-lived when applied in vivo, which hinders most pharmacological experiments. In our continuing study to identify stable LPA analogs capable of in vivo applications, we identified here lysophosphatidylmethanol (LPM) as a stable and pan-LPA receptor agonist. A synthetic LPM activated all five LPA receptors (LPA1-5), and stimulates both cell proliferation and LPA receptor-dependent cell motility. In addition, LPM showed a hypertensive effect in rodent when applied in vivo. We found that, when fetal calf serum was incubated in the presence of methanol, formation of LPM occurred rapidly, whereas it was completely blocked by depletion of autotaxin (ATX), a plasma enzyme that converts lysophosphatidylcholine (LPC) to LPA. When recombinant ATX was incubated with LPC in the presence of methanol, both LPM and LPA were produced with a ratio of 1:10, showing that ATX has transphosphatidylation activity in addition to its lysophospholipase D activity. Administration of methanol in mice resulted in the formation of several µM of LPM in plasma, which is much higher than that of LPA. The present study identified LPM as a novel and stable lysophospholipid mediator with LPA-like activities and ATX as a potential synthetic enzyme for LPM.

Key Words: lysophosphatidic acid, lysophosphatidylmethanol, lysophosphatidylcholine, autotaxin, transphosphatidylation

*These three authors equally contributed to this work


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