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饱和脂肪酸的生物合成

已有 8048 次阅读 2007-11-10 15:31 |个人分类:微生物生理学专栏

以下材料来自:脂类数据库(The Lipid library)http://www.lipidlibrary.co.uk/Lipids/fa_sat/index.htm

The lipid library是一个很好的有关脂类基础知识、分析方法及最新进展的好网站,由脂类分析专家Dr Christie负责维护,他现已退休,但对脂类研究有着深厚的兴趣。他还有自己的Blog.

The biosynthesis of saturated fatty acids

The biosynthesis of saturated fatty acids requires a primer molecule, usually acetic acid in the form of its Coenzyme A ester, and a chain extender, malonyl-CoA. The latter is formed from acetyl CoA by the activity of the enzyme acetyl-CoA carboxylase in which biotin is the prosthetic group (and thus can be inhibited by avidin). In the first step of the reaction, carbon dioxide is linked to the biotin moiety, and this is subsequently transferred to acetyl-CoA to form malonyl-CoA. In microorganisms such as Escherichia coli, the enzyme complex comprises three dissociable proteins, but in plants and animals, the enzyme is a single multifunctional complex that exists in two main isoforms. Malonyl-CoA is also involved in the regulation of fatty acid oxidation by inhibiting carnitine palmitoyl-CoA transferase-1.

Successive molecules of malonyl-CoA are added to the single primer molecule of acetyl-CoA in a sequence of reactions catalysed by a multifunctional enzyme complex, the fatty acid synthetase, which can be of three types. In the Type I enzyme (FAS I) found in animals, the various sub-units carrying out each step of the reaction are discrete domains of a single protein that is the product of one gene. In yeast and fungi, there are two genes that produce polypeptide products, which then coalesce to form a multifunctional Type I fatty acid synthase complex. Type II enzymes (FAS II) consist of separate proteins encoded by different genes that each catalyse a separate step and can be dissociated and purified, although they normally operate in concert; they are found in bacteria (e.g. E. coli - considered the model system), parasites and plants. Type III fatty acid synthetases are also termed 'elongases' and catalyse the addition of C2 units to preformed fatty acids.

As a first step, both the primer and extender substrates are attached to acyl carrier protein (ACP), which has the same prosthetic group as Coenzyme A. A sequence of reactions follows in which the chain is extended and butanoate is formed, as illustrated. First, 3-oxobutanoate is formed by a reaction catalysed by β-ketoacyl-ACP synthetase, this is reduced to 3-hydroxy-butanoate by β-ketoacyl-ACP reductase, which is in turn dehydrated to trans-2-butenoate by β-hydroxyacyl-ACP hydratase before it is reduced to butanoate by enoyl-ACP reductase. The process then continues with the addition of a further six units of malonyl-ACP by successive cycles of these reactions until palmityl-ACP is formed. At this point, a thioesterase removes the fatty acyl product as the free acid (with the mammalian enzyme), and it must be converted to the CoA-ester before it can enter into the various biosynthetic pathways for the production of specific lipids. Medium-chain fatty acids are produced by enzymes in which the specificity of the thioesterase component differs from normal, i.e. the chain-elongation cycle is terminated prematurely. With the fungal fatty acid synthase, the finished acid is attached directly to CoA using a malonoyl/palmitoyl transacylase domain.  

Palmityl-CoA can be further elongated by C2 units to form long- or very-long-chain fatty acids by Type III fatty acid synthetases (elongases). Based on the presence of similar motifs in their gene structure, six enzymes, that have been termed ELOVL 1 to 6 (Elongation of very-long-chain fatty acid) and are believed to perform the condensation reaction in the elongation cycle, are recognized. Three of these (ELOVL 1, 3 and 6) are involved in the production of saturated and monoenoic fatty acids, while the remainder are elongases of polyunsaturated fatty acids. Some parasitic organisms produce all their fatty acids by using elongases. For example, Trypanosoma brucei, the human parasite that causes sleeping sickness, uses three elongases the first converting C4 to C10, the second extending C10 to C14, and the third elongating C14 to C18.

With odd-chain fatty acids, the primer molecule can be propanyl-CoA, but these can also be produced from even-numbered components by alpha-oxidation. Similarly, short- and medium-chain fatty acids can be produced as by-products of oxidative processes.

Type I fatty acid synthases are generally considered to be more efficient, because all the enzymatic activities are linked in a single polypeptide template from which the intermediates cannot easily diffuse. The product is largely the single fatty acid palmitate. In contrast, type II fatty acid synthases can produce many different products for cellular metabolism, including fatty acids of different chain lengths, and unsaturated, iso- and anteiso-methyl-branched, and hydroxy fatty acids. In addition, ACP-intermediates from the process, which are diffusible entities, can be used for production of other important cellular constituents, such as lipoic acid.

It has long been known that for activity the mammalian fatty acid synthases exists as a dimer, while the fungal isomer is hexameric, but the exact nature and requirement for the polymeric states were not known until X-ray crystal structures of the enzymes were obtained. With the mammalian enzyme, the two monomers are in a head-to-head arrangement (not head-to-tail as previously believed) and dimerization seems to be dictated by the structure of the β-ketoacyl synthase domain, i.e. the component responsible for the key chain-elongation step. Although the structure of the fungal isomer is very different, it appears that the β-ketoacyl synthase domain is again the dominant factor controlling polymerization.

Of course, this account presents the basic details of the biosynthetic process only. Those requiring more detailed information are referred to the reading list below.

While saturated fatty acids obviously provide desirable properties to lipids in membranes by conferring rigidity where this is required, their nutritional value is a matter for debate, especially for those of medium chain-length. Most nutritionists recommend keeping dietary intakes of saturated fatty acids as low as possible, but detailed discussion of this topic is not possible here.



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