The influence of ATP on poly(ADP-ribose) metabolism.
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.
Bauer
Pal I
PI
Department of Anatomy, The University of California School of Medicine, San Francisco, CA 94143, USA.
Kenesi
Erzsebet
E
Mendeleyev
Jerome
J
Kun
Ernest
E
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002330:Carmustine / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006026:Glycoside Hydrolases / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020125:Mutation, Missense; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D018411:Spodoptera; D013379:Substrate Specificity; D016335:Zinc Fingers / Q000235:genetics
D011064:Poly Adenosine Diphosphate Ribose; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase; D002330:Carmustine