Inhibition of fatty acid synthesis

Experiments with chloroplasts showed an apparent inhibition of fatty acid synthesis by PAN (at 72 ppm for 10 min). The result is difficult to interpret the inhibition could be attributed to inactivation of one of the enzymes of the multistep system or to oxidation of the reductant (reduced NADP, or NADPH) required in the chain elongation process. 

Cerulenin inhibits formation of polyisoprenol, probably by uncom-petitively inhibiting HMG-CoA synthetase.250 It strongly inhibited production of Rous-sarcoma virus by infected, chick-embryo cells, but an effect on the viral glycoproteins was not observed.251 Other effects of cerulenin, such as its inhibition of fatty acid synthesis, may have caused inhibition of virus production. The inhibition, by cerulenin, of secretion of proteins by bacilli has been noted for some time, but no satisfactory explanation has as yet been offered (see Ref. 252, and ref-... 

G D Agnolo, IS Rosenfeld, J Awaya, S Omura, PR Vagelos. Inhibition of fatty acid synthesis by the antibiotic cerulenin specific inactivation of P-ketoacyl-acyl carrier protein synthase. Biochem Biophys Acta 236 155-166, 1973. 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

Quizalofop or 2-[4-[(6-chloro-2-quinoxalinyl)oxyphenoxy] propanoic acid Aryloxyphenoxy acid Inhibition of fatty acid synthesis selective for grass weeds Potatoes, soy beans, cotton, flax 11-5... 

Neurological complications also are associated with vitamin B-12 deficiency and result from a progressive demyelination of nerve cells. The demyelination is thought to result from the increase in methylmalonyl-CoA that result from vitamin B-12 deficiency. Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in fatty acid biosynthesis as well as being able to substitute for malonyl-CoA in any fatty acid biosynthesis that may occur. Since the myelin sheath is in continual flux the methylmalonyl-CoA-induced inhibition of fatty acid synthesis results in the eventual destruction of the sheath. The incorporation methylmalonyl-CoA into fatty acid biosynthesis results in branched-chain fatty acids being produced that may severely alter the architecture of the normal membrane structure of nerve cells... 

Furuya, Y., Akimoto, S., Yasuda, K. and Ito, H., Apoptosis of androgen-independent prostate cell line induced by inhibition of fatty acid synthesis. Anticancer Res 17 (1997) 4589-4593. 

Pizer, E. S., Jackisch, C., Wood, F. D., Pasternack, G. R., Davidson, N. E. and Kuhajda, F. P., Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res 56 (1996a) 2745-2747. 

The polyketide synthesis chemically and biochemically resembles that of fatty acids. The reaction of fatty acid synthesis is inhibited by the fungal product ceru-lenin [9]. It inhibits all known types of fatty acid synthases, both multifunctional enzyme complex and unassociated enzyme from different sources like that of some bacteria, yeast, plants, and mammalians [10]. Cerulenin also blocks synthesis of polyketides in a wide variety of organisms, including actinomycetes, fungi, and plants [11, 12]. The inhibition of fatty acid synthesis by cerulenin is based on binding to the cysteine residue in the condensation reaction domain [13]. Synthesis of both polyketide and fatty acids is initiated by a Claisen condensation reaction between a starter carboxylic acid and a dicarboxylic acid such as malonic or methylmalonic acid. An example of this type of synthesis is shown in Fig. 1. An acetate and malonate as enzyme-linked thioesters are used as starter and extender, respectively. The starter unit is linked through a thioester linkage to the cysteine residue in the active site of the enzymatic unit, p-ketoacyl ACP synthase (KS), which catalyzes the condensation reaction. On the other hand, the extender... 

Structure-activity studies are an indirect method to investigate a possible interaction of AKH peptides with their receptor proteins. For various members of the AKH family a vast body of literature has accumulated, employing bioassays such as lipid mobilization in locusts and the tobacco hommoth Manduca sexta, carbohydrate mobilization in various cockroach species, the activation of phosphorylase in the larvae of M. sexta, or the inhibition of fatty acid synthesis in the fat body of locusts [10, 33, 37, 53]. Contrary to most other invertebrate neuropeptides, the insect members of the AKH family do not have a core sequence which is essential for potency, however, the N-terminal pGlu residue and the C-terminal amide are important, as well as the aromatics at position 4 and 8. To achieve full efficacy, all amino acids are apparently important. There is also no superagonist found and also no inhibitor. 

Pizer ES, Wood FD, Heine HS, Romantsev FE, Pasternack GR, Kuhajda EP. (1996) Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res 56 1189-1193. 

Acetyl-CoA carboxylase is also inhibited by long-chain fatty acyl-CoA, and such inhibition is accompanied by enzyme depolymerization (91, 92, 95). Binding of 1 mole of palmityl-CoA per mole of rat liver acetyl-CoA carboxylase inhibits the enzyme (95). The Ti for palmityl-CoA, about 5 nM, is far lower than the critical micellar concentration of the thioester this indicates that the inhibition may be physiologically significant. If the allosteric control mechanisms of citrate promoted "substrate activation or fatty acyl-CoA mediated "feed back inhibition of fatty acid synthesis function at all under in vivo conditions, they must function as a dual mechanism (90). 

The decrease of 4 0-14 0 and 16 0 concentrations in milk caused by CLA or soy oil supplementation (77) is consistent with the decrease reported by others (80). Because almost all milk 4 0-14 0 and about half of 16 0 is synthesized de novo by the mammary epithelial cells, these changes suggest that the mechanism of milk fat depression caused by CLA involves inhibition of de novo fatty acid synthesis, which cannot be attributed simply to the shortage of substrates for fatty acid synthesis because the addition of CLA to the diet did not change volatile fatty acid concentrations in the rumen. The possible mechanism of inhibition of fatty acid synthesis warrants further study, but it is likely related to inhibition of acetyl-CoA carboxylase because long-chain fatty acids inhibit activity of this enzyme (83) and expression of its gene (84). 

Sethoxydim (IpM) inhibited the biosynthesis of fatty acids in isolated oat chloroplasts (measured via [14C]acetate incorporation into the total fatty acid fraction) to ca. 60 %, whereas in the isolated chloroplasts of the dicotyledonous pea plants their synthesis was not affected by sethoxydim. About 50 % inhibition of fatty acid synthesis by IpM sethoxydim was detected in experiments with chloroplasts isolated from Poa pratensis, a herbicide-sensitive grass. In chloroplasts isolated from Poa annua, which as a whole plant is tolerant against sethoxydim [7], fatty acid biosynthesis was also blocked (to ca. 45 %) by IpM sethoxydim (Fig. 2). This indicates a basic difference in the mechanism of tolerance for Pisum sativum and Poa annua, respectively. In Poa annua, the tolerance is apparently based on... 

CHLOROACETAMIDE INHIBITION OF FATTY ACID SYNTHESIS IN THE GREEN ALGA SCENEDESMUS ACUTUS... 

DAgnolo G, Rosenfeld IS, Awaya J, Omura S, Vagelos PR. Inhibition of fatty acid synthesis by the antibiotic cerulenin. Specific inactivation of B-ketoacyl-acyl carrier protein synthetase. Biochim Biophys Acta 1973 326 155-166. 

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