Poly-ADP-ribose polymerases PARPs

Ataxia telangiectasia mutated (ATM), poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, DNA replication factor C, DNA topoisomerase I, DNA fragmentation factor (DFF)45, inhibitor of caspase-activated DNAse (ICAD), lamins A, Bl, and C TRAF-1, Rafl, Ras, GAP, GDP dissociation inhibitor of Rho family GTPases, phospholipase A2, Statl... 

Kun E, Kirsten E, Ordahl CP (2002) Coenzymatic activity of randomly broken or intact double-stranded DNAs in auto and histone HI trans-poly(ADP-ribosylation), catalyzed by poly(ADP-ribose) polymerase (PARP I). J Biol Chem 277 39066-39069 Kun E, Kirsten E, Mendeleyev J, Ordahl CP (2004) Regulation of the enzymatic catalysis of poly(ADP-ribose) polymerase by dsDNA, polyamines, Mg2-F, Ca2-F, histones HI and H3, and ATP. Biochemistry 43 210-216... 

TuUn A, Spradling A (2003) Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science 299 560—562... 

TuUn A, Stewart D, Spradling A (2002) The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev 16 2108-2119... 

PARP binds to DNA surrounding single- or double-strand breaks and attaches polymers of ADP-ribose to itself and other proteins. This increases the negative charge in this area, thus facilitating DNA repair. Payne et al. reported increased poly(ADP-ribose) polymerase (PARP) activity in Jurkat cells treated with sodium deoxycholate. Activation of PARP in colonic cells was similarly reported by Glinghammer et al " following treatment with this bile acid. 

Schelman WR, Sandhu SK, Moreno GV et al (2011) First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc). J Clin Oncol 29 abstr 3102... 

The amide ring-closure method has also been used in a solid-phase combinatorial synthesis of inhibitors of poly(ADP-ribose)polymerase (PARP-1). The penultimate intermediates 770 were cleaved from the resin with trifluoroacetic acid, and this was followed by ring closure with sodium hydroxide, at room temperature, to give the quinazolinone products 771 <2004JME4151>. 

Since isoquinolinones are known to be very potent inhibitors of poly(ADP-ribose)polymerase (PARP), thieno[3,4-( ]pyridin-4-ones have been studied for their potential as PARP inhibitors <1999BMC297>. Early studies indicate that the sulfur analogues also act as potent PARP inhibitors. Thienopyridine diazonium salts can be converted into heterocyclic dyes that are useful as disperse dyes for polyester fabrics <2005DP(64)223, 2006DP(70)60>. 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

Kummar, S., Kinder, R., Gutierrez, M., Rubinstein, L., Parchment, R., Phillips, L., Low, J., Murgo, A., Tomaszewski, J., and Doroshow, J. (2007). Inhibition of poly (ADP-ribose) polymerase (PARP) by ABT-888 in patients with advanced malignancies Results of a phase 0 trial. In American Society of Clinical Oncology Meeting. Chicago, IL. 

Costantino, G., Macchiarulo, A., Camaio-ni, E., Pellicciari, R. Modeling of Poly(-ADP-ribose)polymerase (PARP) Inhibitors. Docking of Ligands and Quantitative Structure-Activity Relationship Analysis. J. Med. Chem. 2001, 44, 3786-3794. 

Griffin RJ, et al. Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA 156. repair enzyme poly(ADP-ribose) polymerase (PARP). J. Med. 

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