Disease relevance of Ccbl1

• The possibility is discussed that the spontaneous hypertension in rats carrying the GTK/KAT I mutation may be due in part to disruption of glutamine transamination [1].
• The enzyme exists in a cytosolic and in a mitochondrial form because of the presence of two different KATI mRNAs coding for a protein respectively with and without leader sequence targeting the protein into mitochondria.We have cloned from a phage library of rat kidney cDNA four new KATI cDNAs containing different 5' untranslated regions (UTRs) [2].
• Aminooxyacetic acid and probenecid protected against DCVC toxicity, indicating a role for metabolism by cysteine conjugate beta-lyase and organic anion transport, respectively [3].
• Since energy-dependent secondary excitotoxic mechanisms also account for the pathogenesis of neurodegenerative diseases, a study was made of the effects of sodium azide on the immunohistochemical localization of kynurenine aminotransferase-I [4].
• Leukotriene E4 was incubated with cysteine-conjugate beta-lyase isolated from the intestinal bacterium Eubacterium limosum [5].

High impact information on Ccbl1

• In the rat, one of the described KAT isoforms has been found to correspond to glutamine transaminase K. In addition, rat kidney alpha-aminoadipate aminotransferase (AadAT) also shows KAT activity [6].
• Nephrotoxic cysteine conjugates kill cells after they are metabolized by the enzyme cysteine conjugate beta-lyase to reactive fragments which bind to cellular macromolecules [7].
• The purified mitochondrial enzyme is similar to the cytosolic glutamine transaminase K whose beta-lyase activity with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is regulated by concurrent transamination (Stevens, J. L., Robbins, J. D., and Byrd, R. A. (1986) J. Biol. Chem. 261, 15529-15537) [8].
• S-(2-Benzothiazolyl)-L-cysteine (BTC) is a poor substrate for purified glutamine transaminase K from mitochondria and cytosol, but BTC is as active as DCVC in crude mitochondrial matrix suggesting that other enzymes may be present [8].
• S-(1,2-Dichlorovinyl)-L-cysteinylglycine, a putative metabolite of DCVG, also produced cell death, which was prevented by 1,10-phenanthroline, phenylalanylglycine, and aminooxyacetic acid, inhibitors of aminopeptidase M, cysteinylglycine dipeptidase, and cysteine conjugate beta-lyase, respectively [3].

Chemical compound and disease context of Ccbl1

• Although the toxicity of this compound was originally hypothesized to result from the biotransformation of its cysteine conjugates into toxic thionoacyl halide metabolites by renal cysteine conjugate beta-lyase, recent evidence suggests that alternative mechanisms may be responsible for compound A nephrotoxicity [9].
• Aminooxyacetic acid, an inhibitor of renal cysteine conjugate beta-lyase, did not inhibit the toxicity of the mercapturates, whereas acivicin, an inhibitor of gamma-glutamyltranspeptidase, potentiated the toxicity of both classes of conjugates [9].
• Pretreatment of animals with aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase (beta-lyase), had no effect on the toxicity of 2-Br-(diCYS)HQ, partially inhibited the toxicity of 2-Br-5&6-(CYS)HQ, and almost completely protected against the toxicity of both 2-Br-6-(NAC)HQ and 2-Br-(diNAC)HQ [10].
• Aminooxyacetic acid, a competitive inhibitor of renal cysteine conjugate beta-lyase, partially protected against Compound A-induced diuresis and proteinuria [11].
• The current study analysed kynurenine aminotransferase I (KAT I) activity and kynurenic acid (KYNA) concentrations in human senile cataractous lenses and in experimentally induced cataracts in diabetic rats treated with streptozotocin (STZ) [12].

Biological context of Ccbl1

• As an approach to this we have isolated a cDNA for cysteine conjugate beta-lyase from a rat kidney cDNA library, using a combination of immunological and hybridization screening [13].
• The roles of GTK in (a) brain nitrogen, sulfur, and aromatic amino acid/kynurenine metabolism, (b) brain alpha-keto acid metabolism, (c) bioactivation of certain electrophiles in brain, (d) prodrug targeting, and (e) maintenance of normal blood pressure deserve further study [1].
• Preliminary mapping of the gene for human cysteine conjugate beta-lyase by PCR analysis of genomic DNA from human-rodent hybrid cells indicated that it is located on human chromosome 9 [14].
• Evidence that the isolated cDNA encoded for mitochondrial KAT/GTK was obtained after transfection of HEK-293 cells with the cDNA coding for this new KAT/GTK isoenzyme [15].
• Cloning and expression of a rat kidney cytosolic glutamine transaminase K that has strong sequence homology to kynurenine pyruvate aminotransferase [16].

Anatomical context of Ccbl1

• Expression of the cDNA in Cos-1 cells resulted in the production of a cytosolic enzyme which showed both cysteine conjugate beta-lyase and glutamine transminase K activity [14].
• Cultured cells transfected with the cDNA for KAT also showed glutamine transaminase K activity [17].
• Thus, rat kidney cytosol possesses at least two distinct enzymes that catalyze glutamine transaminase K/cysteine S-conjugate beta-lyase/kynurenine pyruvate aminotransferase reactions [16].
• The existence of multiple enzymes is also supported by the observation that alpha-keto acids which are not substrates for purified glutamine transaminase K from mitochondria and cytosol do stimulate beta-lyase activity in the mitochondrial matrix fraction [8].
• Cysteine conjugate beta-lyase activity from rat kidney cortex was found in the cystosolic and mitochondrial fractions [18].

Associations of Ccbl1 with chemical compounds

• The role of rat kidney cysteine conjugate beta-lyase in the production of nephrotoxic thiols from S-cysteine conjugates of xenobiotics has been well established [13].
• On the other hand, the beta-lyase reaction catalyzed by GTK may be useful in the conversion of some cysteine S-conjugate prodrugs to active components in vivo [1].
• Identification of a mitochondrial form of kynurenine aminotransferase/glutamine transaminase K from rat brain [15].
• GTK is one of several pyridoxal 5'-phosphate (PLP)-containing enzymes that can catalyze non-physiological beta-elimination reactions with cysteine S-conjugates containing a good leaving group attached at the sulfur [1].
• However, owing to strong competition from other amino acid substrates, the turnover of kynurenine to kynurenate by GTK/KAT I in nervous tissue must be slow unless kynurenine and GTK are sequestered in a compartment distinct from the major amino acid pools [1].

Regulatory relationships of Ccbl1

• These findings indicate that the reactive thiol moiety formed by cysteine conjugate beta-lyase cleavage of PCBC can inhibit both glutathione reductase and lipoyl dehydrogenase activities in vivo following HCBD administration [19].

Other interactions of Ccbl1

• This investigation demonstrates that rat hepatic cysteine conjugate beta-lyase is the same enzyme as kynureninase [20].
• The data presented support the hypothesis that the nephrotoxicity of chlorotrifluoroethene is due to the enzymatic formation of a glutathione conjugate, which is metabolized to the ultimate nephrotoxin by the sequential action of renal gamma-glutamyltransferase, cysteinylglycine dipeptidase and cysteine conjugate beta-lyase [21].
• Evidence is presented that a major enzyme responsible for the cysteine S-conjugate beta-lyase reactions in the rat liver cytosol is gamma-cystathionase [22].
• Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, and bis-p-nitrophenyl phosphate, an amidase inhibitor, blocked the effect of N-acetyl PCBC on glutathione reductase, indicating that metabolism by the cytosol is required to produce enzyme inhibition [19].

Analytical, diagnostic and therapeutic context of Ccbl1

• Molecular cloning and expression of a cDNA for human kidney cysteine conjugate beta-lyase [14].
• Using a combination of hybridisation screening and PCR techniques we have isolated a full-length cDNA for human kidney cysteine conjugate beta-lyase [14].
• We show here by in situ hybridization that KATI mRNA is widely expressed throughout the adult rat brain [23].
• An activity stain to detect glutamine transaminase K subjected to nondenaturing polyacrylamide gel electrophoresis (ND-PAGE) was developed [24].
• Neuronal expression of KATI mRNA was further confirmed by RT-PCR and in a model of transient cerebral ischemia [23].

References