Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat liver acetyl-CoA carboxylase activity was inhibited by the free as well as the CoA monothioester of beta, beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) (Bar-Tana, J., Rose-Kahn, G. and Srebnik, M. (1985) J. Biol. Chem. 260, 8404-8410 (1985). (1) The CoA monothioester of MEDICA 16 served as a dead-end inhibitor with an apparent Ki of 2 microM and 58 microM for the biotin-carboxylated and noncarboxylated enzyme forms, respectively. MEDICA 16-CoA binding was not mutually exclusive with that of citrate and did not affect the avidin-resistance of rat liver acetyl-CoA carboxylase. (2) The free dioic acid of MEDICA 16 was competitive to citrate, having an apparent Ki of about 70 microM, as compared to a Ka of 2-8 mM for the citrate activator. Inhibition of the carboxylase by the free dioic acid of MEDICA 16 was accompanied by an increase in its avidin resistance. The resultant inhibition of acetyl-CoA carboxylase by MEDICA 16 and its CoA thioester, together with the previously reported citrate-competitive inhibition of ATP-citrate lyase by MEDICA 16, may account for the observed hypolipidemic effect of MEDICA 16 under dietary conditions where liver lipogenesis constitutes a major flux of liver lipid synthesis.
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PMID:Inhibition of rat liver acetyl-CoA carboxylase by beta, beta'-tetramethyl-substituted hexadecanedioic acid (MEDICA 16). 196 52

The interaction between acetyl-CoA fragments and rat liver acetyl-CoA carboxylase was studied. It was found that the 3'-phosphate group did not interfere with the enzyme interaction since the substrate properties of acetyl-dephospho-CoA and acetyl-CoA are nearly identical. The non-nucleotide substrate analogs S-acetyl-pantethin and its 4'-phosphate) also displayed substrate properties (V = 1.5% and 15% of the V for acetyl-CoA carboxylation respectively). The nucleotide fragment of the acetyl-CoA molecule produced an appreciable effect on the thermodynamics of this substrate interaction with the enzyme. Its physiological role consists in all probability, in the activation and propes orientation of the acetyl group in the enzyme active center. The far more pronounced substrate properties of S-acetyl pantethin 4'-phosphate and the inhibitory properties of pantethin 4'-phosphate (compared to non-phosphorylated analogs) suggest the essential role of the beta-phosphate residue of ADP in the acetyl-CoA binding to the enzyme. The data obtained suggest also that the hydrophobic region responsible for the acyl radical binding, has a site which specifically recognizes the beta-mercaptoethyl residue of the CoA pantethin fragment. The pivotal role in the acetyl-CoA carboxylase interaction with the substrate is ascribed to the productive binding of the acetyl radical; the contribution of individual fragment of the CoA molecule is variable.
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PMID:[Substrate specificity of acetyl-CoA-carboxylase from the rat liver]. 197 87

Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (approximately 2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 micrograms TNF/200 g body wt, and the half-maximal effect is observed with 5 micrograms TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride t 1/2; diabetic vs. TNF-administered diabetic, 3.5 +/- 0.7 vs. 4.0 +/- 0.6 min, respectively; NS). The production of triglyceride, measured by the Triton WR-1339 technique, is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl-CoA carboxylase, a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA, an allosteric inhibitor of acetyl-CoA carboxylase. However, there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase, and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor-increased hepatic very-low-density lipoprotein production and increased serum triglyceride levels in diabetic rats. 197 29

Acetyl-CoA carboxylase, the rate-limiting enzyme in the biogenesis of long-chain fatty acids, is regulated by phosphorylation and dephosphorylation. The major phosphorylation sites that affect carboxylase activity and the specific protein kinases responsible for phosphorylation of different sites have been identified. A form of acetyl-CoA carboxylase that is independent of citrate for activity occurs in vivo. This active form of carboxylase becomes citrate-dependent upon phosphorylation under conditions of reduced lipogenesis. Therefore, phosphorylation-dephosphorylation of acetyl-CoA carboxylase is the enzyme's primary short-term regulatory mechanism; this control mechanism together with cellular metabolites such as CoA, citrate, and palmitoyl-CoA serves to fine-tune the synthesis of long-chain fatty acids under different physiological conditions.
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PMID:Role of reversible phosphorylation of acetyl-CoA carboxylase in long-chain fatty acid synthesis. 257 Jul 25

When 400 mg/rat/day of secondary autoxidation products of linoleic acid was orally administered 3 times to rats, they died at 30-40 h after the third dose. To search the markers of the toxicity of secondary products in vivo, the rats were killed at 24h after the third dose, and conditions of their digestive tracts and liver were analyzed. In the stomach, macroscopically, inflation, retention of undigested food, and edema were seen. Slight congestions were detected in the small intestines. It was considered that these injuries led to reduction in food consumption and then depression of the growth, but did not lead to the death of the animals. The lipid peroxide levels in the liver and the activities of its detoxifying enzymes were increased as compared to those in the control groups. The hepatic lipid contents and unsaturated fatty acid compositions were also not changed. The endogenous lipid peroxidation, therefore, did not give the rats a severe stress. The activities of hepatic acetyl-CoA carboxylase and carnitine palmitoyltransferase were 20 and 35% lower than those of control, respectively. The levels of CoASH, acetyl-CoA, and long-chain acyl-CoA were 1/9, 1/2, and 1/4 of those in control, respectively. Thus, one of the markers of the toxicity of secondary products was the depletion of hepatic CoA derivatives. In rat, bio-energy was reduced by the decrease in the intestinal absorption of nutrients, and the depletion of hepatic CoA derivatives also failed to supply energy with beta-oxidation.
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PMID:Depletion of hepatic coenzyme A derivatives is one of the markers of the toxicity of orally administered secondary autoxidation products of linoleic acid in rat. 273 13

The effects of the hypoketonaemic and hypoglycaemic compound 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA) on fatty acid synthesis and fatty acid oxidation in rat hepatocytes were examined. Two microM-POCA caused a small stimulation of fatty acid synthesis which might be due to an increased flux through pyruvate dehydrogenase. Ten to one hundred microM-POCA inhibited (40-70%) fatty acid synthesis. At low concentrations (less than or equal to 5 microM) POCA was a more powerful inhibitor of fatty acid oxidation than of synthesis, but at higher concentrations (10-100 microM) the inhibition of synthesis and oxidation was similar. One hundred microM POCA-CoA inhibited acetyl-CoA carboxylase by about 22% and 100 microM-palmitoyl-CoA by about 33%. Since POCA was a more potent inhibitor of fatty acid synthesis than palmitate, but POCA-CoA did not inhibit acetyl-CoA carboxylase more strongly than palmitoyl-CoA, it is suggested that POCA-CoA may inhibit fatty acid synthase directly.
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PMID:Effects of 2[5(4-chlorphenyl)pentyl]oxirane-2-carboxylate on fatty acid synthesis and fatty acid oxidation in isolated rat hepatocytes. 286 21

1. The effect of nutritional status on fatty acid synthesis in brown adipose tissue was compared with the effect of cold-exposure. Fatty acid synthesis was measured in vivo by 3H2O incorporation into tissue lipids. The activities of acetyl-CoA carboxylase and fatty acid synthetase and the tissue concentrations of malonyl-CoA and citrate were assayed. 2. In brown adipose tissue of control mice, the tissue content of malonyl-CoA was 13 nmol/g wet wt., higher than values reported in other tissues. From the total tissue water content, the minimum possible concentration was estimated to be 30 microM 3. There were parallel changes in fatty acid synthesis, malonyl-CoA content and acetyl-CoA carboxylase activity in response to starvation and re-feeding. 4. There was no correlation between measured rates of fatty acid synthesis and malonyl-CoA content and acetyl-CoA carboxylase activity in acute cold-exposure. The results suggest there is simultaneous fatty acid synthesis and oxidation in brown adipose tissue of cold-exposed mice. This is probably effected not by decreases in the malonyl-CoA content, but by increases in the concentration of free long-chain fatty acyl-CoA or enhanced peroxisomal oxidation, allowing shorter-chain fatty acids to enter the mitochondria independent of carnitine acyltransferase (overt form) activity.
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PMID:Regulation of fatty acid synthesis and malonyl-CoA content in mouse brown adipose tissue in response to cold-exposure, starvation or re-feeding. 288 57

9-Oxononanoic acid, which is one of the major products of the autoxidation of linoleic acid, was administered orally to rats and its effect on hepatic lipid metabolism was investigated. The de novo synthesis of fatty acids was strongly reduced 30 h after the administration of 100 mg of 9-oxononanoic acid as compared to that in the saline-administered group. Activity of acetyl-CoA carboxylase decreased by 60% and the activity of carnitine palmitoyltransferase increased by 35% in the test group. The level of triacylglycerols in serum was low and the level of free fatty acids remained unchanged. Thus, the administration of 9-oxononanoic acid decreased hepatic lipogenesis. It is generally believed that the reduction in lipogenesis is facilitated by a decrease in the NADPH level. The ratio of NADPH/NADP in the test group, however, became high as compared to that in the control group, and the activities of glucose 6-phosphate and isocitrate dehydrogenases increased. On the other hand, the levels of CoA derivatives, especially long-chain acyl-CoA, were higher in the test group than in the control. Therefore, the reduction of hepatic lipogenesis in the 9-oxononanoic acid group could be attributed to the inhibition of acetyl-CoA carboxylase by the accumulated long-chain acyl-CoA.
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PMID:Effect of orally administered 9-oxononanoic acid on lipogenesis in rat liver. 289 34

A high rate of lipogenesis in obese mice plays a major role in their excessive deposition of body lipid. Inhibition of lipogenesis may decrease their obesity. Therefore, we have investigated the effects of sodium 2-n-pentadecyl-benzimidazole-5-carboxylate (M & B 35347B), an inhibitor of acetyl-CoA carboxylase, on in-vivo lipogenesis in obese and lean mice. It significantly inhibited hepatic cholesterol and fatty acid synthesis, measured using 3H2O, in both lean and obese mice, with or without a glucose load. Brown adipose tissue (scapular) lipogenesis was decreased by M & B 35347B in obese mice but not in lean mice. In white adipose tissue, M & B 35347B did not affect the rates of lipogenesis in either scapular white, inguinal or epididymal depots of obese mice, or the inguinal and scapular white depot of lean mice. However, it doubled lipogenesis in the epididymal fat pad of lean mice. After a glucose load, lipogenesis in the lean epididymal fat pad was not inhibited but that in the inguinal depot was. M & B 35347B inhibited acetyl CoA carboxylase of adipose tissue in vitro but only a small inhibition was detected after in-vivo treatment. These different responses according to type of mouse, treatment and tissue site appear to stem from differences in inhibitor concentration and the importance of acetyl CoA carboxylase as the rate-limiting enzyme of lipogenesis. The weight gain of obese mice dosed orally (200 mg M & B 35347B/kg daily) for 60 days was unaffected and they continued to deposit excess body fat. This presumably occurred because of the lack of inhibition of fatty acid synthesis in white adipose tissue.
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PMID:Effect of sodium 2-n-pentadecyl-benzimidazole-5-carboxylate (M & B 35347B), an inhibitor of acetyl-CoA carboxylase, on lipogenesis and fat deposition in obese hyperglycaemic (ob/ob) and lean mice. 289 66

Exogenous 1-oleoyl-2-acetylglycerol (OAG) is known to mimic the action of tumour-promoting phorbol esters in various cell types. However, in isolated rat hepatocytes OAG depressed the rate of de novo fatty acid synthesis and the activity of the key enzyme acetyl-CoA carboxylase (EC 6.4.1.2), in contrast to the pronounced stimulation of both parameters by phorbol 12-myristate 13-acetate (PMA). The inhibition by OAG appeared to be dose- and time-dependent. On the other hand, medium-chain 1,2-diacylglycerols like 1,2-dioctanoyl-sn-glycerol did mimic the stimulatory action of PMA. The anomalous effect of OAG may well be explained by its metabolic breakdown leading to liberation of oleate and subsequent inhibition of acetyl-CoA carboxylase activity by endogenously formed oleoyl-CoA. The stimulatory effects of both PMA and medium-chain diacylglycerols are likely to be mediated by protein kinase C.
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PMID:Dissimilar effects of 1-oleoyl-2-acetylglycerol and phorbol 12-myristate 13-acetate on fatty acid synthesis in isolated rat-liver cells. 289 28


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