Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo

Rankin, Patrick W.; Jacobson, Elaine L.; Benjamin, Robert C.; Moss, Joel; Jacobson, Myron K.

doi:10.1016/s0021-9258(18)83741-3

Cited by 236 publications

(29 citation statements)

References 28 publications

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“…The regulation of the metabolic enzymic activity of ADPRT, which is the process of poly(ADP-ribose) formation from NAD+, has been predominantly related to the formation and accessibility of DNA strand breaks. In fact, only trace polymerase activity can be detected in intact cells by adenine labelling, as reported by Aboul-Ela et al (1988), and extensive DNA damage by N-methyl-N'-nitro-N-nitrosoguanidine had to be applied to obtain significant enzymic rates (Aboul-Ela et al, 1988;Rankin et al, 1989). However, the enzyme content of a large variety of eukaryotic cells is surprisingly high (Yamanaka et al, 1988;Ludwig et al, 1988), and it has been calculated that under physiological conditions only I % of the enzyme protein accounts for poly(ADP-ribosyl)ation.…”

Section: Discussionmentioning

confidence: 99%

Macromolecular association of ADP-ribosyltransferase and its correlation with enzymic activity

Bauer

Büki

Hakam

et al. 1990

Biochemical Journal

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The macromolecular self-association of ADP-ribosyltransferase protein in solution was studied by several experimental techniques: quantitative gel filtration, electrophoretic analyses in non-denaturing gels, and cross-linking the enzyme protein with glutaraldehyde, dimethyl pimelimidate, dimethyl suberimidate, dimethyl 3,3'-dithiobisproprionimidate and tetranitromethane. The self-association of the polypeptide components obtained by plasmin digestion was also determined by using the above cross-linking agents. Monomers and cross-linked dimers of the enzyme protein, possessing enzymic activity, were separated in non-denaturing gels by electrophoresis. The basic polypeptide fragments, exhibiting molecular masses of 29 kDa and 36 kDa, self-associated, whereas the polypeptides with molecular masses of 56 kDa and 42 kDa associated only to a negligible extent, indicating that the peptide regions that also bind DNA and histones are probable sites of self-association in the intact enzyme molecule. Macromolecular association of the enzyme was indicated by a protein-concentration-dependent red-shift in protein fluorescence. The specific enzymic activity of the isolated ADP-ribosyltransferase depended on the concentration of the enzyme protein, and at 2.00 microM concentration the enzyme was self-inhibitory. Dilution of the enzyme protein to 30-40 nM resulted in a large increase in its specific activity. Further dilution to 1-3 nM coincided with a marked decrease of specific activity. Direct enzymic assays of electrophoretically separated monomers and cross-linked dimers demonstrated that the dimer appears to be the active molecular species that catalyses poly(ADP-ribose) synthesis. The NAD+ glycohydrolase activity of the enzyme was also dependent on protein concentration and was highest at 1-3 nM enzyme concentration, when polymerase activity was minimal, indicating that the monomeric enzyme behaved as a glycohydrolase, whereas poly(ADP-ribosyl)ation of enzyme molecules was maximal when the enzyme tends to be self-associated to the dimeric form.

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Section: Discussionmentioning

confidence: 99%

Macromolecular association of ADP-ribosyltransferase and its correlation with enzymic activity

Bauer

Büki

Hakam

et al. 1990

Biochemical Journal

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“…To induce a systemic inflammatory response, we applied endotoxin (LPS 0111:B4 from Escherichia coli; Sigma) to the animals of the LPS group [100 g as bolus and 20 g/(h ⅐ kg ⅐ body wt) per infusionem]. The rabbits of the 3-AB group received the PARS inhibitor 3-AB (Sigma) [10 mg as bolus and 5 mg/(h ⅐ kg ⅐ body wt) per infusionem] (1,31,36,39). The LPS ϩ 3-AB group consisted of rabbits treated with the combination of LPS and 3-AB.…”

Section: Animalsmentioning

confidence: 99%

Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Kiefmann

Heckel²,

Dörger³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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During systemic inflammation, recruitment and activation of leukocytes in the pulmonary microcirculation may result in a potentially life-threatening acute lung injury. We elucidated the role of the poly(ADP-ribose) synthetase (PARS), a nucleotide-polymerizing enzyme, in the regulation of leukocyte recruitment within the lung with regard to the localization in the pulmonary microcirculation and in correlation to hemodynamics in the respective vascular segments and expression of intercellular adhesion molecule 1 during endotoxemia. Inhibition of PARS by 3-aminobenzamide reduced the endotoxin-induced leukocyte recruitment within pulmonary arterioles, capillaries, and venules in rabbits as quantified by in vivo fluorescence microscopy. Microhemodynamics and thus shear rates in all pulmonary microvascular segments remained constant. Simultaneously, inhibition of PARS with 3-aminobenzamide suppressed the endotoxin-induced adhesion molecules expression as demonstrated for intercellular adhesion molecule 1 by immunohistochemistry and Western blot analysis. We confirmed this result with the use of PARS knockout mice. The inhibitory effect of 3-aminobenzamide on leukocyte recruitment was associated with a reduction of pulmonary capillary leakage and edema formation. We first provide evidence that PARS activation mediates the leukocyte sequestration in pulmonary microvessels through upregulation of adhesion molecules. As reactive oxygen species released from leukocyte are supposed to cause an upregulation of adhesion molecules we conclude that PARS inhibition contributes to termination of this vicious cycle and inhibits the inflammatory process.

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“…In the 3AB control group (n = 4), to examine whether administration of 3AB itself might affect the CAP thresholds, 10 mg/kg of 3AB was given intravenously and the CAP threshold was measured before and 4 hours after administration. In the physiological saline solution (PSS) ischemia group (n =15), each animal was subjected to IS, 30, or 60 minutes of ischemia (5 in each subgroup) and intravenously received PSS at 2 mL/kg of body weight 1 minute before the onset of reperfu- )---TV 12 16…”

Section: Resultsmentioning

confidence: 99%

Poly(Adenosine Diphosphate-Ribose) Synthetase Inhibitor 3-Aminobenzamide Alleviates Cochlear Dysfunction Induced by Transient Ischemia

Tabuchi¹,

Ito²,

Tsuji³

et al. 2001

Ann Otol Rhinol Laryngol

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The present study was undertaken to determine the possible deleterious role played by poly(adenosine diphosphate-ribose) synthetase (PARS) in cochlear ischemia-reperfusion injury. Transient ischemia of the cochlea was induced in albino guinea pigs for 15, 30, or 60 minutes by pressing the labyrinthine artery at the porus acusticus internus. The animals were given intravenous 3-aminobenzamide (a PARS inhibitor) or physiological saline solution I minute before the onset of reperfusion. The compound action potential thresholds were measured before the onset of ischemia and 4 hours after the onset of reperfusion. A statistically significant reduction in the postischemic compound action potential threshold shift was observed in the animals treated with 3-aminobenzamide after 15 or 30 minutes of ischemia, whereas no statistical difference was found after 60 minutes of ischemia. These results suggest that excessive activation of PARS exerts deleterious effects on the cochlear injury induced by transient ischemia.

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Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo

Cited by 236 publications

References 28 publications

Macromolecular association of ADP-ribosyltransferase and its correlation with enzymic activity

Macromolecular association of ADP-ribosyltransferase and its correlation with enzymic activity

Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Poly(Adenosine Diphosphate-Ribose) Synthetase Inhibitor 3-Aminobenzamide Alleviates Cochlear Dysfunction Induced by Transient Ischemia

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