Acivicin in 1985

Earhart, Robert H.; Neil, Gary L.

doi:10.1016/0065-2571(85)90076-7

Cited by 52 publications

(30 citation statements)

References 32 publications

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“…As shown in Table 1, at a concentration of 0.1 mM this compound inhibits the investigated reaction by 92 %. Acivicine, a strong inhibitor of glutamine-dependent CPS [26], does not affect the activity present in I? abyssi extracts, which is consistent with the lack of utilisation of glutamine by this enzyme (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Purification and Characterization of Carbamoyl‐Phosphate Synthetase from the Deep‐Sea Hyperthermophilic Archaebacterium Pyrococcus abyssi

Purcarea

Simon

Prieur

et al. 1996

European Journal of Biochemistry

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Carbamoyl-phosphate synthetase was purified from the deep-sea hyperthermophilic archaebacterium Pyrococcus abyssi. This enzyme appears to be monomeric and uses ammonium salts as nitrogen donor. Tts activity is inhibited by some nucleotides that compete with ATP. In contrast with the carbamoylphosphate synthetases investigated so far, this enzyme is very resistant to high temperature. Its low molecular mass (46.6 kDa) and its catalytic properties suggest that the gene coding for this enzyme is a previously postulated ancestor whose duplication gave the genes coding for carbamoyl-phosphate synthetases and carbamate kinases.Keywords : carbamoyl-phosphate synthetase; hyperthermophile; deep-sea vents ; Archae; Pyrococcus.Pyrococcus ahyssi is a hyperthermophilic archaebacterium recently isolated from a deep-sea hydrothermal vent located 2000 m deep in the North-Fiji Basin [I, 21. This microorganism has been characterized as a strict anaerobic, sulfur-metabolizing archaeum, whose optimum temperature for growth is 96°C [3]. Although R abyssi grows at atmospheric pressure, its generation time decreases at high pressure and its maximal temperature for growth is increased when cultured under hydrostatic pressure ; this microorganism is therefore classified as barotolerant to barophilic [3]. Cell growth at such a high temperature raises physiological problems, e.g. the instability of some metabolites, cellular components, and enzymes. For instance, carbamoyl phosphate, the common precursor for the biosynthesis of arginine and pyrimidine nucleotides, is a very unstable compound. At 96"C, its half-life is only a few seconds 14, 51. In all organisms, carbamoyl phosphate is synthesized by carbamoyl-phosphate synthetases (CPS), enzymes which are known for their instability. Most of the eubacteria, plants like pea [6, 71, and mung bean [XI possess a single CPS that provides carbamoyl phosphate for both the arginine and pyrimidine pathways. Eucaryotic organisms, except for plants, possess two CPS enzymes, each specific for one of these two pathways (CPS-A and CPS-P or CPS I and CPS 11, respectively). Some CPS enzymes use NH, as the donor of the amino group of carbamoyl phosphate while others use glutamine. The latter enzymes contain a subunit or domain (glutamine amidotransferase) that binds glutamine, catalyses its deamination, and transfers the NH, to the CPS catalytic site. For instance, Escherichia coli CPS is composed of two subunits, a small subunit (42 kDa), which is the glutamine amidotransferase, and a large subunit (117 kDa) which is CPS [9]. In the absence of the small subunit, the large subunit of CPS, is active and uses NH: as substrate.In a previous study, aspartate transcarbamoylase (ATC), the first enzyme of the pyrimidine pathway, which uses carbamoyl phosphate as substrate, was partially purified from the cell-free extracts of P. abyssi and its catalytic and regulatory properties were determined [lo]. In the present work, the biosynthesis of carbamoyl phosphate was investigated in this hyperthermophilic archae...

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Section: Resultsmentioning

confidence: 99%

Purification and Characterization of Carbamoyl‐Phosphate Synthetase from the Deep‐Sea Hyperthermophilic Archaebacterium Pyrococcus abyssi

Purcarea

Simon

Prieur

et al. 1996

European Journal of Biochemistry

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“…Acivicin is a glutamine analogue. It blocks L-glutamine-requiring enzymes and at high concentrations inhibits de novo synthesis of purine and pyrimidines (65). To determine whether acivicin affected cisplatin nephrotoxicity by inhibiting GGT or through an alternative mechanism, we assessed the nephrotoxicity of cisplatin in GGT knockout mice (7).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Cisplatin to a Nephrotoxin in Proximal Tubule Cells

Townsend

Deng

Zhang

et al. 2003

Journal of the American Society of Nephrology

265

174

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Abstract. Cisplatin, a commonly used chemotherapeutic agent, is nephrotoxic. The mechanism by which cisplatin selectively kills the proximal tubule cells was heretofore unknown. Recent studies in mice and rats have shown that the nephrotoxicity of cisplatin can be blocked by acivicin or (aminooxy)acetic acid, the same enzyme inhibitors that block the metabolic activation of a series of nephrotoxic halogenated alkenes. In this study, it was hypothesized that cisplatin is activated in the kidney to a toxic metabolite through the same pathway that has been shown to activate the halogenated alkenes. This activation begins with the formation of a glutathione-conjugate that is metabolized to a cysteinyl-glycine-conjugate, to a cysteineconjugate, and finally to a reactive thiol. In this study, a protocol was developed in which confluent monolayers of LLC-PK 1 cells were exposed to clinically relevant concentrations of cisplatin or cisplatin-conjugate for 3 h. Cell viability was assayed at 72 h. The role of gamma-glutamyl transpeptidase (GGT) and cysteine-S-conjugate beta-lyase in the metabolism of each of the cisplatin-conjugates was investigated. Pre-incubation of cisplatin with glutathione, cysteinyl-glycine, or N-acetyl-cysteine to allow for the spontaneous formation of cisplatin-conjugates increased the toxicity of cisplatin toward LLC-PK 1 cells. Inhibition of GGT activity showed that GGT was necessary only for the toxicity of the cisplatin-glutathioneconjugate. Inhibition of cysteine-S-conjugate beta-lyase reduced the toxicity of each of the cisplatin-conjugates. These data demonstrate that metabolism of cisplatin in proximal tubule cells is required for its nephrotoxicity. The elucidation of this pathway provides new targets for the inhibition of cisplatin nephrotoxicity.Cisplatin is a potent antitumor agent currently used in the treatment of germ cell tumors, head and neck tumors, cervical cancer, and as a salvage treatment for other solid tumors (1). The dose of cisplatin that can be administered is limited by its nephrotoxicity (2). The mechanism by which cisplatin kills the proximal tubule cells in the kidney has been the focus of intense investigation for many years. In tumors and other dividing cells, cisplatin-DNA crosslinks are thought to be the cytotoxic lesion (3). Nonproliferating cells are less sensitive to the toxicity of DNA-damaging agents, yet the quiescent proximal tubule cells are selectively killed by cisplatin. High concentrations of cisplatin induce necrotic cell death in confluent monolayers of proximal tubule cells, whereas lower concentrations of cisplatin induce apoptosis through a caspase-9 -dependent pathway (4,5). The molecular mechanism by which cisplatin kills these nonproliferating cells has been unclear.Our studies in rats and mice have shown that the nephrotoxicity of cisplatin can be blocked by inhibiting either of two enzymes expressed in the proximal tubules, gamma-glutamyl transpeptidase (GGT) or cysteine-S-conjugate beta-lyase (6 -8). Data from these in vivo studies have lea...

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“…Previous studies have demonstrated that acivicin has a protective effect on cisplatin-induced nephrotoxicity (Hanigan et al, 1994) and suppresses GGT-dependent oxidative damage in ischemic rat kidney (Cutrín et al, 2000). However, acivicin is known to inhibit irreversibly various glutamine amidotransferases, including imidazole glycerol phosphate synthase and guanine monophosphate synthetase, and inactivate a number of biosynthetic enzymes for purine and pyrimidine, amino acids, and amino sugars, which results in a potent cytotoxicity (Earhart and Neil, 1985;Chittur et al, 2001). These findings indicate that GGT is not a natural target of acivicin, but is inhibited fortuitously by acivicin.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, acivicin, a prototype of GGT inhibitor (Capraro and Hughey, 1985), could prevent the ischemia-induced increase in GGT activity, lipid peroxidation enhancement, and morphological alterations (Curtin et al, 2000). However, in addition to inhibiting GGT, acivicin is an antimetabolite and inactivates a number of biosynthetic glutamine amidotransferase enzymes for purine and pyrimidine, amino acids, and amino sugars (Earhart and Neil, 1985). Furthermore, acivicin is known to inhibit other various glutamine amidotransferases, including imidazole glycerol phosphate synthase and guanine monophosphate synthetase (Chittur et al, 2001).…”

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confidence: 99%

Preventive Effect of GGsTop, a Novel and Selective γ-Glutamyl Transpeptidase Inhibitor, on Ischemia/Reperfusion-Induced Renal Injury in Rats

Yamamoto¹,

Watanabe²,

Hiratake³

et al. 2011

J Pharmacol Exp Ther

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GGsTop [2-amino-4-{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid], is a novel, highly selective, and irreversible ␥-glutamyl transpeptidase (GGT) inhibitor with no inhibitory activity on glutamine amidotransferases. In this study, we investigated the effects of treatment with GGsTop on ischemia/reperfusion-induced renal injury in uninephrectomized rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 1 day after reperfusion. Treatment with GGsTop (1 and 10 mg/kg i.v.) 5 min before ischemia attenuated the ischemia/reperfusion-induced renal dysfunction in a dose-dependent manner. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which was significantly suppressed by the GGsTop treatment. In renal tissues exposed to ischemia/reperfusion, GGT activity was markedly increased immediately after reperfusion, whereas renal superoxide production and malondialdehyde level were significantly increased 6 h after reperfusion. These alterations were abolished by the treatment with GGsTop. In addition, renal glutathione content was decreased by the 45-min ischemia, but its level was markedly elevated by the GGsTop treatment. Our results demonstrate that the novel and highly selective GGT inhibitor GGsTop prevents ischemia/ reperfusion-induced AKI. The renoprotective effect of GGsTop seems to be attributed to the suppression of oxidative stress by inhibiting GGT activation, thereby preventing the degradation of glutathione.

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Acivicin in 1985

Cited by 52 publications

References 32 publications

Purification and Characterization of Carbamoyl‐Phosphate Synthetase from the Deep‐Sea Hyperthermophilic Archaebacterium Pyrococcus abyssi

Purification and Characterization of Carbamoyl‐Phosphate Synthetase from the Deep‐Sea Hyperthermophilic Archaebacterium Pyrococcus abyssi

Metabolism of Cisplatin to a Nephrotoxin in Proximal Tubule Cells

Preventive Effect of GGsTop, a Novel and Selective γ-Glutamyl Transpeptidase Inhibitor, on Ischemia/Reperfusion-Induced Renal Injury in Rats

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