Lipid Biosynthesis Inhibitors

Lipids are essential plant components as they are constituents of membranes and cuticular waxes as well as being major seed storage 

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E,Z) Ajoene antithrombotic, inhibition of platelet aggregation, lipid biosynthesis inhibitor, antibacterial, antimycotic, antifungal, antimutagenic, protection of immune cells. 13,35,86.94-98,100. 

Ajoene was shown to have potent antiproliferative activity against epimastigotes and amastigotes of Trypanosoma cruzi in vitro this activity was associated with a significant alteration of the phospholipid composition of the cells with no significant effects on the sterol content. This shows the potential of lipid biosynthesis inhibitors as useful therapeutic agents in the treatment of leishmaniasis and Chagas disease [96]... 

Owing to its mode of action as lipid biosynthesis inhibitor, juvenile stages of aphids are particularly affected by spirotetramat 32, whereas adults are strongly affected in their fecundity (unpublished results), which from an applied point of view will drastically reduce population development under fidd conditions. Spirotetramat 32 applied foliarly exhibited excellent systemic efficacy against aphids and whiteffies, whereas its contact efficacy against these pests is rather limited (Fig. 28.4.6). 

E.L. Mercer, Sterol Biosynthesis Inhibitors their current status and modes of action , Lipids, 1991,26, 584-597. 

Is a specific Inhibitor of type II fatty acid synthetase In higher plants and . coll 12401. The acetyl-CoA ACP S-acety1-transferase Is the apparent specific site of Inhibition 12411. Another antibiotic, cerulenin (structure not shown) Inhbits -ketococy1-ACP synthetase I In bacteria, fungi, and plants, but also Is Inhibitory to other sites such as polyketide and sterol biosynthesis 1242-2441. Cerulenin and thiolactomycin Inhibited CQ14W-acetate Incorporation Into fatty acids at 150 values of 50 and 4 uM, respectively 12451. Recently cydohexanedlone herbicides have been shown to Inhibit lipid biosynthesis by Inhibition of acetyl-CoA carboxylase 12461. 

Etoxazole and flufenoxuron are inhibitors of chitin biosynthesis. Spirodiclofen and spiromesifen are inhibitors of lipid biosynthesis. Spirodiclofen blocks the enzyme acetyl-coenzyme A carboxylase, which allows mites to synthesize important fatty acids. 

These compounds are inhibitors of lipid biosynthesis and auxin activity. 

Bieberich E, Freischutz B, Suzuki M, Yu RK. Differential effects of glycolipid biosynthesis inhibitors on ceramide-induced cell death in neuroblastoma cells. J. Neurochem. 1999 72 1040-1049. Makino A, Ishii K, Murate M, Hayakawa T, et al. D-threo-1-Phenyl-2-decanoylamino-3-morpholino-l-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains. Biochemistry 2006 45 4530-4541. 

Disaccharides have also been synthesized as potential cell wall biosynthesis inhibitors, including analogs of the arabinogalactan linkage disaccharide (O Fig. 22e) [286], and small lipid disaccharides containing arabinose and galactose [287]. Some of these have exhibited moderate in vitro activity against TB. 

Recently Kerkenaar and Kaars Sijpesteijn (1979) demonstrated that inhibition of respiration cannot be the primary cause of growth inhibition, and that the action of tridemorph is similar to that of known sterol biosynthesis inhibitors. Their study seems to favour in lipid biosynthesis, possibly ergosterol biosynthesis, as a primary mode of action of tridemorph, and would agree with the rather late interference of this compound with protein and RNA synthesis (Kerkenaar et al., 1979, 1981). 

Of the (13 0), (15 1), (17 1), and (17 2)-anacardic acids, the (17 2) is the most active inhibitor [280] of glycerol 3-phosphate dehydrogenase (GPDH) and nearly comparable in action to the adipostatins [201,281 ][72], (15 0)-cardol derivatives, potentially of interest in human obesity studies. Inhibition of lipid biosynthesis in bacteria, yeast and animal cells by anacardic acids from Ginkgo biloba has also been reported by the same authors [282]. 

A number of workers have had difficulty in detecting acetyl-CoA carboxylase in certain plant tissues, e.g., developing soybean seeds. Although there is no doubt that under in vivo conditions it functions in generating malonyl-CoA for lipid biosynthesis, the enzyme appears to be an unusually labile system. As already indicated, an inhibitor in chloroplasts combines with the transcarboxylase, thereby markedly inhibiting carboxylase activity. Presumably, the same inactivating process may occur in other tissues therefore, it is important to identify this inhibitor and correlate its appearance with observed low activities of the carboxylase. The possible regulatory implications under in vivo conditions are obvious, particularly since no metabolite allosteric effectors have as yet been observed for plant carboxylases. 

The best characterized extraneous site ir bitors are the many chemical classes of herbicidal inhibitors of acetolactate synthase. These have been extensively reviewed elsewhere (i, 8,9,52,56,81,92). Extraneous site inhibitors are also exemplified by four classes of grass selective herbicides the aryloxyphenoxypropionic acids represented by diclofop, the cyclohexanediones typified by clethc m (for a recent review see (57)), the triazinediones (82) and the perhydroindolizinediones (83) (Figure 7). The following discussion is limited to the first two classes. Both classes of herbicides are potent, reversible inhibitors of acetyl-CoA carboxylase (ACC) from susceptible plants, the putative rate limiting enzyme in lipid biosynthesis. With wheat... 

Modulation of epidermal lipid biosynthesis has been reported to boost drag delivery. It has also been suggested that it is both the hydrophobic nature of the lipids as well as their tortuous, extracellular localization that are responsible for the restriction in the transport of most molecules across the stratum comeum. The function of this barrier depends on three key lipids cholesterol, fatty acid, or ceramides. Delays of synthesis ceramides in the epidermis have been reported as means of barrier perturbation. Inhibitors of lipid synthesis were used to enhance the trans-A cmaV dehvery of hdocaine or caffeine. Alteration of barrier function was produced by the fatty acid synthesis inhibitor S-(tetradecyloxy)-2-furancarboxylic acid, the cholesterol synthesis inhibitor fluvastatin, or the cholesterol sulfate, which resulted in a further increase in lidocaine absorption (38). The major components of sebaceous lipids in the skin are 45-60% TAGs, 25% wax and sterol esters, 12-15% squalene and 10% free fatty acids (39). Some fatty acids, especially unsaturated fatty acids, are well-known skin penetration enhancers. The addition of PC to dermal dosage forms has been reported to increase percutaneous absorption. Lipid disperse systems (LDSs) containing polar lipids, such as PC and glycosylceramide, are also useful for... 

The research on potential inhibitors, herbicides and xenobiotics of plant lipid biosynthesis is not only a matter of general interest for agronomists and those concerned with crop protection but also for the plant biochemist, since active inhibitors represent essential tools for the characterization and better understanding of those metabolic processes and pathways which are involved in the biosynthesis of plant lipids. Theoretically all steps in plant lipid biosynthesis could be a target of inhibitors. However, only a few herbicide groups of plant lipid biosynthesis are known today. This review summarizes our present knowledge of the different types of xenobiotica and their mode of interaction with plant lipid biosynthesis. 

Today several xenobiotics, either natural antibiotics (cerulenin, thiolactomycin) or active herbicides are known to interfere with acetyl-CoA formation, de novo fatty acid biosynthesis, desaturation of fatty acids, biosynthesis of long chain fatty acids and glycerolipid formation. This is summarized in Fig. 9. Certainly other new herbicides which interfere with the same or other particular parts of plant lipid biosynthesis will be developed in the future. From the study of the mode of action of these inhibitors in sensitive and tolerant species, one will not only be able to efficiently control weeds in crop plants and guarantee a better food production but also obtain a new and better understanding of the function of plant lipids and the regulation of plant lipid biosynthesis. 

Several lines of evidence point to a connection between lipid metabolism and scaly skin. Inhibitors of cholesterol biosynthesis such as triparanol and nicotinic acid can produce scaly lesions superficially resembling ichthyosis. A disturbance of cutaneous sterol ester biosynthesis accompanies the hyperkeratosis of essential fatty acid deficiency, and increased ratios of free sterol to sterol esters have been reported in psoriasis and atopic eczema . We have recently shown that epidermal lipid biosynthesis is increased in lesions of psoriasis and lichen simplex, with the free sterol fraction affected more than other lipid classes. 

Bach TJ, Lichtenthaler HK. Plant growth regulation by mevinolin and otherr sterol biosynthesis inhibitors. In Fuller G, Nes WD, editors. Ecology and Metabolism of Plant Lipids, Am Chem Soc Symposium Series 325, American Chemical Society, Washington, 1987 109-139. 

I have previously noted the minimal impact of basic lipid research on chemotherapeutic approaches to atherosclerosis. In order to close on a hopeful and somewhat more positive note, I would like to call attention to three substances which interfere with specific events in lipid biosynthesis and do so by well understood mechanisms, 3-Decynoyl-N-acetyl-cysteamine, developed in our laboratory as a substrate analogue, has been shown to block the formation of unsaturated fatty acids in certain bacteria in a highly specific manner ( 2). The compound itself is not an inhibitor but a pseudosubstrate, converted by the target enzyme into the allenic isomer,... 

In Section II (on the biosynthesis of oligosaccharides), emphasis is placed on the biosynthesis of the dolichol-linked sugars, because the inhibitors mainly interfere with steps in the dolichol cycle of protein glycosylation. Modification of the oligosaccharide side-chain, once it has been transferred from the carrier lipid to the protein, is not discussed in any great detail. 

An article by Li and Li (Tnlane University, LA) on the biosynthesis and catabolism of glycosphingolipids serves to extend that by Kiss (Vol. 24), which dealt mainly with the chemistry of these compounds. Schwarz and Datema (Giessen) provide a detailed account of the lipid pathway of protein glyeosylation and of its inhibitors, and then discuss the biological significance of protein-bound carbohydrates, thereby... 

Figs. 12—16 to 12—22) and prevent the progressive course of Alzheimer s disease. Direct inhibition of gene expression for the biosynthesis of these proteins is not currently possible and is currently not a very feasible therapeutic possibility. Perhaps a more realistic therapeutic possibility would be to inhibit the synthesis of beta amyloid, in much the same way that lipid-lowering agents act to inhibit the biosynthesis of cholesterol in order to prevent atherosclerosis. This could be done by means of enzyme inhibitors, such as protease inhibitors, which are at least a theoretical possibility. 

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