Regulation of malignant phenotype and bioenergetics by a π-electron donor-inducible mitochondrial MgATPase.
The recognition of poly ADP-ribose transferase-1 (PARP-1) as an ATP sensor receiving this energy source by way of a specific adenylate kinase ATP wire (AK) from mitochondrial ATP synthase (F0F1), and directly regulating cellular mRNA and DNA synthesis, was the first step towards the identification of an effect by PARP-1 that is of fundamental significance. The molecular target of AK-ATP is Arg 34 of the Zn finger I of PARP-1, which is also a site for cation-π interactions as a target of π-electron donors. We now identify this π-electron receptor site as the second active center of PARP-1 which by interaction with a π-electron donor-inducible MgATPase reversibly controls a malignant vs. non-malignant phenotype through energizing the NADH➝NADP+ transhydrogenase, a reaction which is the metabolic connection of PARP-1 to cell function. The specific enzyme-inducing action of the π-electrons is executed by the PARP-1 -topoisomerase I - DNA complex of the nuclei regulating both the nature and the quantity of cellular enzymes that constitute cell-specific physiology.
Department of Anatomy, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, School of Medicine, San Francisco, CA 94143, USA. ernestkun@comcast.net
Ernest
E
Kun
Jerome
J
Mendeleyev
Eva
E
Kirsten
Alaeddin
A
Hakam
Albert M
AM
Kun
Anna
A
Fekete
Pal I
PI
Bauer
Zsuzsanna
Z
Dunai
Rudolf
R
Mihalik
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D009250:NADP Transhydrogenases / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D000970:Antineoplastic Agents; D007211:Indoles; D009243:NAD; D000255:Adenosine Triphosphate; D009250:NADP Transhydrogenases; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017301:Ca(2+) Mg(2+)-ATPase