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.

Enzymatic mechanism of the tumoricidal action of 4-iodo-3-nitrobenzamide.

Activation of the prodrug 4-iodo-3-nitrobenzamide critically depends on the cellular reducing system specific to cancer cells. In non-malignant cells, reduction of this prodrug to the non-toxic amine occurs by the flavoprotein of complex?I of mitochondria receiving Mg2+-ATP-dependent reducing equivalents from NADH to NADPH via pyridine nucleotide transhydrogenation. This hydride transfer is deficient in malignant cells; therefore, the lethal synthesis of 4-iodo-3-nitrosobenzamide takes place selectively.

Persistent radicals of trivalent tin and lead.

In this report we present synthetic, crystallographic, and new electron paramagnetic resonance (EPR) spectroscopic work that shows that the synthetic route leading to the recently reported, first persistent plumbyl radical *PbEbt3 (Ebt = ethylbis(trimethylsilyl)silyl), that is, the oxidation of the related PbEbt3-anion, was easily extended to the synthesis of other persistent molecular mononuclear radicals of lead and tin. At first, various novel solvates of homoleptic potassium metallates KSnHyp3 (4a), KPbHyp3 (3a), KSnEbt3 (4b), KPbIbt3 (3c), and KSnIbt3 (4c) (Hyp = tris(trimethylsilyl)silyl, Ibt = isopropylbis(trimethylsilyl)silyl), as well as some heteroleptic metallates, such as [Li(OEt2)2][Sn(n)BuHyp2] (3d), [Li(OEt2)2][Pb(n)BuHyp2] (4d), [Li(thf)4][PbPhHyp2] (3e), and [K(thf)7][PbHyp2{N(SiMe3)2}] (3f), were synthesized and crystallographically characterized. Through oxidation by tin(II) and lead(II) bis(trimethylsilyl)amides or the related 2,6-di-tert-butylphenoxides, they had been oxidized to yield in most cases the corresponding radicals.

Dependence of trans-ADP-ribosylation and nuclear glycolysis on the Arg 34-ATP complex of Zn2+ finger I of poly-ADP-ribose polymerase-1.

The H-bonded complex of ATP with Arg 34 of Zn2+ finger I of poly-ADP-ribose polymerase-1 (PARP-1) determines trans-oligo-ADP-ribosylation from NAD+ to proteins other than PARP-1. This mechanism was tested in lysolecithin fractions of non-malignant and cancer cells separately and after their recombination. Cellular PARP-1 activity was recovered when the centrifugal sediment was recombined with the supernatant fraction containing cellular ADP-ribose oligomer acceptor proteins.

Identification of poly(ADP-ribose) polymerase-1 as the OXPHOS-generated ATP sensor of nuclei of animal cells.

Our results show that in the intact normal animal cell mitochondrial ATP is directly connected to nuclear PARP-1 by way of a specific adenylate kinase enzymatic path. This mechanism is demonstrated in two models: (a) by its inhibition with a specific inhibitor of adenylate kinase, and (b) by disruption of ATP synthesis through uncoupling of OXPHOS. In each instance the de-inhibited PARP-1 is quantitatively determined by enzyme kinetics.