title: Selective inhibition of DNA polymerase-alpha family with chemically synthesized derivatives of PHYLPA, a unique Physarum lysophosphatidic acid.
abstract: PHYLPA, a unique Physarum lysophosphatidic acid (LPA), showed selective inhibition of a family of DNA polymerase alpha, including DNA polymerases alpha, delta and epsilon; but no inhibition of DNA polymerase beta or gamma was observed. To reveal the molecular mechanism of inhibition of DNA polymerases by PHYLPA, four stereoisomers and some other derivatives were synthesized and their effects on DNA polymerases were studied. Among eight derivatives synthesized, PHYLPA-1 (the natural PHYLPA; sodium 1-O-[(9'S,10'R)-9',10'-methanohexadecanoyl]-sn-glycerol 2,3-cyclic phosphate) and PHYLPA-2 (sodium 3-O-[9'S,10'R)-9',10'-methanohexadecanoyl]-sn-glycerol 1,2-cyclic phosphate) were strong and specific inhibitors of a family of DNA polymerase alpha. But their stereoisomers PHYLPA-3 (sodium 1-O-[9'R,10'S)-9',10'-methanohexadecanoyl]-sn-glycerol 2,3-cyclic phosphate) and PHYLPA-4 (sodium 3-O-[9'R,10'S)-9',10'-methanohexadecanoyl-sn-glycerol 1,2 cyclic phosphate) were weak inhibitors, showing the critical importance of stereochemistry of a cyclopropane-containing fatty acid for the inhibitory activity. Some derivatives having no cyclopropane-containing fatty acids--palmitoyl-, oleoyl-, and palmitoleoyl-PHYLPA--showed inhibition to some extent; but 1-palmytoyl and 1-oleoyl lysophosphatidic acid, which has no cyclic phosphate, did not show an apparent inhibitor activity on DNA polymerases. Hence, the extent of the inhibition apparently depends on the stereochemistry of both the fatty acid moiety and the cyclic phosphate.
authors.affiliation: Department of Biology, Faculty of Science, Ochanomizu University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Murakami-Murofushi
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Onimura
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: M
authors.initials: M
authors.lastname: Shioda
authors.forename: S
authors.initials: S
authors.lastname: Yoshida
authors.forename: M
authors.initials: M
authors.lastname: Shoji
authors.forename: H
authors.initials: H
authors.lastname: Murofushi
mesh_terms: D000818:Animals; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D019301:Oleic Acid; D009829:Oleic Acids; D019308:Palmitic Acid; D010169:Palmitic Acids; D010743:Phospholipids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010804:Physarum; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D009829:Oleic Acids; D010169:Palmitic Acids; D010743:Phospholipids; D019301:Oleic Acid; D019308:Palmitic Acid; D004257:DNA Polymerase II