Disease relevance of Pcx

• No statistically significant increase in endometriotic lesion size was detected in animals treated with either PCB 126 or with the highest dose of 2,3,7,8-TCDD, possibly due to the effects of histologically observed ovarian toxicity [1].
• Oral administration of a commercial PCB mixture to chickens caused a hepatic-type porphyria characterized by hepatic accumulation and urinary excretion of uroporphyrin [2].
• The activation in vitro of the mutagens isolated from beef extract, when tested with Salmonella typhimurium strain TA1538, requires the presence of S9 fractions from livers of PCB- or 3-methylcholanthrene-induced rats [3].
• Furthermore, the data suggest a potential involvement of an increased body burden of PCB compounds in the etiology of endometriosis in the rhesus [4].
• The outbreak of yusho disease in Japan (which was caused by PCB-contaminated rice oil) and a similar episode of food poisoning in Taiwan (which was also related to PCB contamination) were discussed, particularly with reference to urinary porphyrin levels and clinical response [5].

Psychiatry related information on Pcx

• Since DDT and PCB occur in milk, young animals may ingest these substances during the critical period of neonatal life; For this reason lactating mice were given injections of DDT or PCB, 50 mg/kg body weight, once a week for four weeks, the first injection being administered on the day of delivery [6].

High impact information on Pcx

• In addition to the putative mitochondrial targeting signal, functional domains are readily identifiable in the sequence and are in the following order: biotin carboxylase-carboxyltransferase-biotin carboxyl-carrier protein, as proposed for yeast PC [7].
• Adipose pyruvate carboxylase: amino acid sequence and domain structure deduced from cDNA sequencing [7].
• The complete amino acid sequence of 3T3-L1 adipocyte pyruvate carboxylase (PC) [pyruvate:carbon-dioxide ligase (ADP-forming), EC 6.4.1.1] has been deduced from sequencing overlapping cDNA clones obtained from an adipocyte cDNA library constructed in the lambda Zap vector [7].
• The biotinylated lysine of the encoded PC promoter (1178 amino acids with a calculated M(r) of apocarboxylase = 129,784) is located 35 residues from the COOH-terminal end and, as in most other biotin enzymes, is in the consensus sequence AMKM [7].
• Induction of pyruvate carboxylase apoenzyme and holoenzyme in 3T3-L1 cells during differentiation [8].

Chemical compound and disease context of Pcx

• Procarbazine [N-isoppropyl-alpha-(2-methylhydrazino)-p-toluamide] was tested for mutagenicity with Salmonella typhimurium G46 in the host-mediated assay by using male BALB/c mice pretreated orally with polychlorinated biphenyl (PCB, Aroclor 1254) [9].
• Three PCDEs were also evaluated in outbred (Sprague-Dawley) rats: 2,2',4,5,6'-pentaCDE and 2,3',4',6-tetraCDE, because of their toxicity to mice; 2,2',4,4',5,5'-hexaCDE, because it should exhibit PCB-like toxicity [10].
• We propose that TCDD-mediated reduction in pyruvate carboxylase and lactate dehydrogenase isozyme shifts may represent a major component in TCDD toxicity [11].
• The lactose-fermenting enterobacteria, obligately anaerobic predominantly Gram-negative rods, and total aerobic and anaerobic populations were monitored in the presence and absence of the PCB-degrading pseudomonad [12].

Biological context of Pcx

• Pyruvate carboxylase (PC) plays a crucial role in various metabolic pathways, including gluconeogenesis, lipogenesis, and glucose-induced insulin secretion [13].
• The peroxisome proliferator-activated receptor-gamma regulates murine pyruvate carboxylase gene expression in vivo and in vitro [13].
• Co-transfection studies in 3T3-L1 preadipocytes or HEK293T cells with a 2.3-kb promoter fragment of mouse PC gene linked to a luciferase reporter construct and with plasmids overexpressing retinoid X receptor alpha/PPARgamma1 or retinoid X receptor alpha/PPARgamma2 showed a 6-8-fold increase above the basal promoter activity [13].
• Structural and promoter regions of the murine pyruvate carboxylase gene [14].
• The use of hydrazine sulfate to impede gluconeogenesis through PEP carboxykinase (PEPCK) inhibition heightened the protective effects of energy substrates possibly due to attenuated ATP demands from pyruvate carboxylase (PC) activity and pyruvate mitochondrial transport [15].

Anatomical context of Pcx

• Impaired in vitro differentiation of white adipocytes of PPARgamma2 knock-out mice was also associated with a marked reduction of PC mRNA [13].
• Tumor necrosis factor-alpha, a cytokine that blocks differentiation of 3T3-L1 cells, suppressed PC expression [13].
• Mice with targeted disruption of the PPARgamma2 gene displayed approximately 50-60% reduction of PC mRNA and protein in white adipose tissue [13].
• Southern blot analysis of genomic DNA isolated from human-Chinese hamster somatic cell hybrids localized the pyruvate carboxylase gene on the long arm of human chromosome 11 [16].
• The human cDNA was also used to quantitate pyruvate carboxylase mRNA levels in a differentiating mouse preadipocyte cell line [16].

Associations of Pcx with chemical compounds

• And also the in vitro addition of various concentrations of enfenamic acid (0.25 to 3.0 mM) to the tissue extracts of liver inhibited the activities of important gluconeogenic enzymes such as pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK) and fructose 1,6-diphosphatase (FDPase) [17].
• The effects of postnatal treatment with tumor-promoting agents, including 0.05% sodium barbital in the drinking water until death or a single dose of Aroclor 1254 (a mixture of polychlorinated biphenyls, PCB) given on Postnatal Day 8 or 56, were also examined [18].
• This decrease in pyruvate carboxylase-mediated [14C] carbon fixation was associated with a reduction in fluorometrically determined [citrate] and [malate] [19].
• This suggests that ETZ inhibition of lipogenesis involves an inhibitory effect on pyruvate carboxylase as opposed to acetyl CoA carboxylase, because the incorporation of glutamine into lipids does not involve pyruvate carboxylase [19].
• The limited capacity of NAC to increase GSH synthesis was attributed to impaired glucose metabolism through PC [20].

Regulatory relationships of Pcx

• Prohibitin attenuates insulin-stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxylase [21].

Other interactions of Pcx

• Immunofluorescent localization of acetyl CoA carboxylase, fatty acid synthetase and pyruvate carboxylase during the adipocyte conversion of 3T3 fibroblasts [22].
• Since neurons lack the enzymes glutamine synthetase and pyruvate carboxylase that are expressed only in astrocytes, trafficking of these metabolites must take place between neurons and astrocytes [23].
• The alpha-ketoglutarate/glutamate and malate/alpha-ketoglutarate ratios were higher in CR, in parallel with previously reported increases with CR in pyruvate carboxylase activity and glucagon levels, respectively [24].
• Old mice on CR showed significant increases in the activities of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase when compared with controls, indicating increased gluconeogenesis [25].
• Here we report that PHB-1 has a hitherto undescribed role as an inhibitor of pyruvate carboxylase (PC) [21].

Analytical, diagnostic and therapeutic context of Pcx

• Gel shift and chromatin immunoprecipitation assays demonstrated that endogenous PPARgamma binds to this functional PPAR-response element of the PC promoter [13].
• Nine cDNA clones were isolated and three proved to be pyruvate carboxylase clones based on nucleotide sequencing and Northern blotting [16].
• Molecular cloning of a cDNA for human pyruvate carboxylase. Structural relationship to other biotin-containing carboxylases and regulation of mRNA content in differentiating preadipocytes [16].
• Detection and quantification of nanogram amounts of pyruvate carboxylase (apo and holo forms) in total tissue homogenates by immuno-blotting and by enzyme-linked immunosorbent assay are described [26].
• In maternal and fetal liver, acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and beta-methylcrotonyl-CoA carboxylase abundances were determined by Western blotting; the content of mRNAs for most of these enzymes and holocarboxylase synthetase was determined by real-time RT-PCR [27].

References