Murakami-Murofushi K, Kobayashi S, Onimura K, Matsumoto M, Shioda M, Yoshida S, Shoji M, Murofushi H
Department of Biology, Faculty of Science, Ochanomizu University, Tokyo, Japan.
Biochim Biophys Acta. 1995 Aug 24;1258(1):57-60. doi: 10.1016/0005-2760(95)00097-v.
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.
PHYLPA是一种独特的溶血性磷脂酸（LPA），它对包括DNA聚合酶α、δ和ε在内的DNA聚合酶α家族具有选择性抑制作用；但未观察到对DNA聚合酶β或γ的抑制作用。为了揭示PHYLPA对DNA聚合酶的抑制分子机制，合成了四种立体异构体和一些其他衍生物，并研究了它们对DNA聚合酶的影响。在合成的八种衍生物中，PHYLPA - 1（天然PHYLPA；1 - O - [(9'S,10'R)-9',10'-亚甲基十六烷酰基]-sn -甘油2,3 -环磷酸钠）和PHYLPA - 2（3 - O - [(9'S,10'R)-9',10'-亚甲基十六烷酰基]-sn -甘油1,2 -环磷酸钠）是DNA聚合酶α家族的强效特异性抑制剂。但其立体异构体PHYLPA - 3（1 - O - [(9'R,10'S)-9',10'-亚甲基十六烷酰基]-sn -甘油2,3 -环磷酸钠）和PHYLPA - 4（3 - O - [(9'R,10'S)-9',10'-亚甲基十六烷酰基]-sn -甘油1,2 -环磷酸钠）是弱抑制剂，这表明含环丙烷脂肪酸的立体化学对抑制活性至关重要。一些不含环丙烷脂肪酸的衍生物——棕榈酰基 -、油酰基 - 和棕榈油酰基 - PHYLPA——在一定程度上表现出抑制作用；但不含环磷酸的1 - 棕榈酰基和1 - 油酰基溶血磷脂酸对DNA聚合酶没有明显的抑制活性。因此，抑制程度显然取决于脂肪酸部分和环磷酸的立体化学。
