Lysophosphatidylmethanol is a pan lysophosphatidic acid receptor agonist and is produced by autotaxin in blood.
Lysophosphatidic acid (LPA) is a simple phospholipid but has numerous biological effects through a series of G-protein-coupled receptors specific to LPA. In general, LPA is short-lived when applied in vivo, which hinders most pharmacological experiments. In our continuing study to identify stable LPA analogues 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 (LPA(1-5)), 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 micromoles 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.
Endo
Tomoko
T
The University of Tokyo, Hongo, Bunkyo-ku, Japan.
Kano
Kuniyuki
K
Motoki
Rie
R
Hama
Kotaro
K
Okudaira
Shinichi
S
Ishida
Mayuko
M
Ogiso
Hideo
H
Tanaka
Masayuki
M
Matsuki
Norio
N
Taguchi
Ryo
R
Kanai
Motomu
M
Shibasaki
Masakatsu
M
Arai
Hiroyuki
H
Aoki
Junken
J
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020404:Glycerophospholipids / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000097:blood / Q000378:metabolism*; D043264:Phosphodiesterase I / Q000097:blood / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000097:blood / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists*; D000099189:Lysophospholipase D
D020404:Glycerophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D