Bauer Pal I, Kenesi Erzsebet, Mendeleyev Jerome, Kun Ernest
Department of Anatomy, The University of California School of Medicine, San Francisco, CA 94143, USA.
Int J Mol Med. 2005 Aug;16(2):321-4.
ATP affects poly(ADP-ribose) metabolism at two distinct sites: it inhibits poly(ADP-ribose) polymerase-1 and activates the glycohydrolase directly. The inhibitory site of ATP on poly(ADP-ribose) polymerase-1 was identified by amino acid exchange mutation to be at the arginine 34 residue in the first Zn2+ finger. Mutation of 138 arginine residue of Zn2+ finger 2 had negligible influence on the inhibitory action of ATP, pinpointing arginine 34 of the first Zn2+ finger as the specific ATP site. The glycohydrolase protein was activated by ATP when the substrate was a long-chain ADP-ribose polymer, but not with a short-chain substrate. Isolated cell nuclei also responded to both inhibition of poly(ADP-ribose) polymerase by ATP and to poly(ADP-ribose) glycohydrolase activation by ATP, demonstrating that enzymological results can be extrapolated to cellular systems. The activation of poly(ADP-ribose) polymerase in nuclei by an alkylating drug was completely suppressed by ATP, demonstrating that the bioenergetic competence of cells can regulate the cytocidal action of DNA alkylating drugs. The potential significance of bioenergetic regulation of poly(ADP-ribose) metabolism is proposed.
ATP在两个不同位点影响聚（ADP - 核糖）代谢：它抑制聚（ADP - 核糖）聚合酶 -1并直接激活糖苷水解酶。通过氨基酸交换突变确定ATP对聚（ADP - 核糖）聚合酶 -1的抑制位点在第一个Zn2 +指中的精氨酸34残基处。Zn2 +指2的138位精氨酸残基突变对ATP的抑制作用影响可忽略不计，从而确定第一个Zn2 +指中的精氨酸34为特定的ATP作用位点。当底物为长链ADP - 核糖聚合物时，糖苷水解酶蛋白被ATP激活，但短链底物则不然。分离的细胞核也对ATP抑制聚（ADP - 核糖）聚合酶以及ATP激活聚（ADP - 核糖）糖苷水解酶有反应，这表明酶学结果可以外推到细胞系统。ATP完全抑制了烷基化药物对细胞核中聚（ADP - 核糖）聚合酶的激活，表明细胞的生物能量状态可以调节DNA烷基化药物的细胞杀伤作用。本文提出了聚（ADP - 核糖）代谢生物能量调节的潜在意义。
