Fatty acid metabolism saturated

Fatty acid saturation metabolism, so called biohydrogenation, is considered to be a detoxif ting metabolism of gut bacteria to transform toxic-free polyunsaturated fatty acids to less toxic-free saturated fatty acids. We have revealed the complex metabolic... 

Takeuchi, M., Kishino, S., Hirata, A., Park, S. B., Kitamura, N., Ogawa, J. (2015). Characterization of the linoleic acid A9 hydratase catalyzing the first step of polyunsaturated fatty acid saturation metabolism in Lactobacillus plantarum AKU 1009a. /. Biosci. Bioeng., 119,636-641. 

Certain long-chain unsaturated fatty acids of metabolic significance in mammals are shown in Figure 23-1. Other C20, C22, and C24 polyenoic fatty acids may be derived from oleic, linoleic, and a-flnolenic acids by chain elongation. Palmitoleic and oleic acids are not essential in the diet because the tissues can introduce a double bond at the position of a saturated fatty acid. 

Glycerol provides a minor source of energy, in that it can be modified readily to glyceraldehyde 3-phosphate, one of the intermediates in the glycolytic pathway. The fatty acids are metabolized by a process termed P-oxidation, which involves the sequential removal of two-carbon units via oxidation at the P-position. The process for saturated fatty acids will now be described. 

The conversion of a monounsaturated fatty acid to acetyl-GoA requires a reaction that is not encountered in the oxidation of saturated acids, a cis-trans isomerization (Figure 21.9). Successive rounds of P-oxidation of oleic acid (18 1) provide an example of these reactions. The process of P-oxidation gives rise to unsaturated fatty acids in which the double bond is in the trans arrangement, whereas the double bonds in most naturally occurring fatty acids are in the cis arrangement. In the case of oleic acid, there is a cis double bond between carbons 9 and 10. Three rounds of P-oxidation produce a 12-carbon unsaturated fatty acid with a cis double bond between carbons 3 and 4. The hydratase of the P-oxidation cycle requires a trans double bond between carbon atoms 2 and 3 as a substrate. A cis-trans isomerase produces a trans double bond between carbons 2 and 3 from the cis double bond between carbons 3 and 4. From this point forward, the fatty acid is metabolized the same as for saturated fatty acids. When oleic acid is P-oxidized, the first step (fatty acyl-GoA dehydrogenase) is skipped, and the isomerase deals with the cis double bond, putting it into the proper position and orientation to continue the pathway. 

Linoleic acid A9 hydratase, which is involved in the linoleic acid saturation metabolism of Lactobacillus plantarum AKU 1009a, was cloned as his-tagged recombinant enz une, purified with affinity column, and characterized [30]. The enzyme required FAD as a cofactor for its activity, and the activity was enhanced by NADH. The maximum activities for hydration of linoleic acid and for dehydration of lO-hydroxy-czs-12-octadecenoic acid (HYA) were observed at 37°C, pH5.5, with 0.5M NaCl. C16 and CIS free fatty acids with cis-9 double bond served as substrates for hydration with CIO regiospecificity and (S) stereospecificity (Figure 22.9). 10-Hydroxy fatty acids served as substrates for dehydration reactions. The apparent value for linoleic acid was estimated to be 92 irM with its values at 2.6 x 10 s and Hill factor was 3.3. The apparent K value for HYA was estimated to be 98 iM with its values at 1.2 x 10 s ... 

Uptake of LCFAs across the lipid-bilayer of most mammalian cells occurs through both a passive diffusion of LCFAs and a protein-mediated LCFA uptake mechanism. At physiological LCFA concentrations (7.5 nM) the protein-mediated, saturable, substrate-specific, and hormonally regulated mechanism of fatty acids accounts for the majority (>90%) of fatty acid uptake by tissues with high LCFA metabolism and storage such as skeletal muscle, adipose tissue, liver,... 

LPA, i.e. monoacyl-glycerol-3-phosphate, can be formed and degraded by multiple metabolic pathways (Fig. 1). Depending on the precursor molecule and respective pathway, the fatty acid chain in LPA differs in length, degree of saturation and position (sn-1 or sn-2), which has an influence on biological activity. LPA... 

After the extraction of lipid and nonlipid components from the leaves of mandarin orange Citrus reticulata, the lipid fraction was further separated by PTLC to determine different lipid classes that affect the chemical deterrence of C. reticulata to the leaf cutting ecat Acromyrmex octopinosus. These lipids seem to be less attractive to the ants [81a]. The metabolism of palmitate in the peripheral nerves of normal and Trembler mice was studied, and the polar lipid fraction purified by PTLC was used to determine the fatty acid composition. It was found that the fatty acid composition of the polar fraction was abnormal, correlating with the decreased overall palmitate elongation and severely decreased synthesis of saturated long-chain fatty acids (in mutant nerves) [81b]. 

Manco, M., Mingrone, G., Greco, A. V., Capristo, E., Gniuli, D., De Gaetano, A., Gasbarrini, G. Metabolism 49, 2000, 220-224. Insulin resistance directly correlates with increased saturated fatty acids in skeletal muscle triglycerides. 

Most of our fat intake will consist of fatty acids with an even number of carbon atoms, but not all dietary fatty acids nor all those synthesized in the liver are saturated. A variable, but probably not inconsiderable, proportion of dietary fatty acids are unsaturated, partly perhaps because a high intake of unsaturated fat is recommended to help reduce the risk for diseases of the heart and vascular system. Unsaturated and odd-numbered fatty acids pose particular chemical problems to the 3-oxidation pathway and additional enzymes are required for their metabolism. 

The resynthesized triglycerides invariably contain saturated and unsaturated fatty acids in an approximate 2 1 ratio. Typically, nearly all of the fatty acid content of adipose tissue can be accounted for by just six different types of molecule with palmitate (06 0) and oleate (08 1) together contributing over 75% of the total. Turnover studies suggest that for most people, much of the fat is metabolically relatively inert acting as depot with a long half-life, and only a smaller component of the stored fat being readily accessible. 

This finding has been replicated several times in clinical studies. Let me cite one example. In a careful metabolic study carried out in 1990, Mensink and Katan determined the plasma LDL/HDL ratio when 10% of the energy from oleic acid was replaced in the diet by either the corresponding trans fat or the corresponding saturated fatty acid, stearic acid. The resulting LDL/HDL ratios were 2.02 on the oleic acid diet, 2.34 on the stearic acid diet, and 2.58 on the trans fatty acid diet. This is one more example of the impact of small structural changes in molecules on their biological properties. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Metabolism of unsaturated fatty acids is similar to that of the saturated compounds just described, but additional enzymic reactions are necessary. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

Oxidation of fatty acids with an odd number of carbons The (3-oxidation of a saturated fatty acid with an odd number of carbon atoms proceeds by the same reaction steps as that of fatty acids with an even number, until the final three carbons are reached. This com pound, propionyl CoA, is metabolized by a three-step pathway (Figure 16.21). [Note Propionyl CoA is also produced during the metabolism of certain amino acids (see Figure 20.10, p. 264).]... 

Particular saturated fatty acids in the diet. Metabolism 14, 776-787. 

---