Fatty acid metabolism catabolism

The 3-ketothiolase has been purified and investigated from several poly(3HB)-synthesizing bacteria including Azotobacter beijerinckii [10], Ral-stonia eutropha [11], Zoogloea ramigera [12], Rhodococcus ruber [13], and Methylobacterium rhodesianum [14]. In R. eutropha the 3-ketothiolase occurs in two different forms, called A and B, which have different substrate specificities [11,15]. In the thiolytic reaction, enzyme A is only active with C4 and C5 3-ketoacyl-CoA whereas the substrate spectrum of enzyme B is much broader, since it is active with C4 to C10 substrates [11]. Enzyme A seems to be the main biosynthetic enzyme acting in the poly(3HB) synthesis pathway, while enzyme B should rather have a catabolic function in fatty-acid metabolism. However, in vitro studies with reconstituted purified enzyme systems have demonstrated that enzyme B can also contribute to poly(3HB) synthesis [15]. 

The level of a particular enzyme involved in xenobiotic metabolism can obviously affect the extent of metabolism by that enzyme. Again, competition may play a part if endogenous and exogenous substrates are both metabolized by an enzyme, as is the case with some of the forms of cytochromes P-450, which metabolize steroids, or NADPH cytochrome P-450 reductase and cytochrome b5 reductase, which are also involved in heme catabolism and fatty acid metabolism, respectively. 

Additionally, the study demonstrated that there are fatty acid metabolism genes that were positively associated with lovastatin production and tended to encode catabolic enzymes that are predicted to promote formation of the polyketide precursors acetyl-CoA and malonyl-CoA, whereas fatty acid metabolism genes that are negatively associated with secondary metabolite production encode anabolic enzymes, i.e., acyl-CoA oxidase, fatty acid desaturase, and fatty acid synthases. 

The stigma of the emcic acid (C22 ln - 9) in rapeseed oil has lingered despite firm evidence that this fatty acid was more of a threat to rats than to humans. It is sufficient to say that the discovery of chain shortening of emcic acid to oleic acid by peroxisomes was one of the most fundamental breakthroughs in understanding fatty acid metabolism in the last few decades. Once in the oleic acid form, the emcic acid residue is as readily catabolized by mitochondria, as are palmitic and other fatty acids (4). The reduction of emcic acid in rapeseed oil resulted in a marked increase in octadecanoic acids, and their contribution in canola oil is around 95% of all fatty acids present (Table 2). 

FIGURE 21.18 A portion of an animal cell, showing the sites of various aspects of fatty-acid metabolism. The cytosol is the site of fatty-acid anabolism. It is also the site of formation of acyl-CoA, which is transported to the mitochondrion for catabolism by the P-oxidation process. Some chainlengthening reactions (beyond Cjg) take place in the mitochondria. Other chain-lengthening reactions take place in the endoplasmic reticulum (ER), as do reactions that introduce double bonds. 

Although humans store most of their energy as fatty acids within triglycerides, metabolic machinery to convert these into carbohydrates is not present. Fatty acids are catabolized to acetyl-CoA via P-oxidation (Sec. 10.5), and the overall reaction of the pyravate dehydrogenase complex is irreversible. 

Figure 2. Diagram representing anaplerotic (solid lines and shapes) and cataplerotic (dashed lines and shapes) sequences connecting the Krebs cycle to gluconeogenesis, fatty acid metabolism, and dispensible AA synthesis. Some sequences can serve both anaplerotic and cataplerotic roles, thus linked metabolites (bold) can be catabolized or synthesized. a-KG, a-ketoglutarate OAA, oxaloacetate PEP, phosphoenolpyruvate.

The ability of an enzyme to respond to concentrations of metabolites other than its substrate and product adds a new dimension to metabolic regulation. It allows the end product of the metabolic pathway to bring about feedback inhibition on earlier steps (Yates and Pardee, 1956). Such feedback control may be exerted by a metabolite several steps removed in a pathway or by metabolites from a different pathway which share a common intermediate with the first pathway. This regul-ability in strategically located enzymes can have profound effects on cellular metabolism. It allows certain key intermediates in one pathway to act as switches for another pathway for example, citric acid can act as the switch for fatty acid metabolism. Regulation by central intermediates—e.g., adenine and pyridine nucleotides—may in fact determine the resultant direction of metabolism as anabolic or catabolic, depending on the energy reserves or redox state of the cell (see metabolite ratios below). 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

The clearance of labeled chylomicrons from the blood is rapid, the half-time of disappearance being under 1 hour in humans. Larger particles are catabolized more quickly than smaller ones. Fatty acids originating from chylomicron triacylglycerol are delivered mainly to adipose tissue, heart, and muscle (80%), while about 20% goes to the liver. However, the liver does not metabolize native chylomicrons or VLDL significantly thus, the fatty acids in the liver must be secondary to their metabolism in extrahepatic tissues. 

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

During catabolic and anabolic processes, a renovation of the molecular cellular components takes place. It should be emphasized that the catabolic and anabolic pathways are independent of each other. Be these pathways coincident and differing in the cycle direction only, the metabolism would have been side-tracked to the so-called useless, or futile, cycles. Such cycles arise in pathology, where a useless turnover of metabolites may occur. To avoid this undesirable contingency, the synthetic and degradative routes in the cell are most commonly separated in space. For example, the oxidation of fatty acids occurs in the mitochondria, while the synthesis thereof proceeds extramitochondrially, in the microsomes. 

Gerhard B (1993) Catabolism of fatty acid acids. In Moore TS (ed) Lipid metabolism in plants. CRS Press, Baton Rouge, p 527... 

Examples of such intra cellular membrane transport mechanisms include the transfer of pyruvate, the symport (exchange) mechanism of ADP and ATP and the malate-oxaloacetate shuttle, all of which operate across the mitochondrial membranes. Compartmentalization also allows the physical separation of metabolically opposed pathways. For example, in eukaryotes, the synthesis of fatty acids (anabolic) occurs in the cytosol whilst [3 oxidation (catabolic) occurs within the mitochondria. 

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

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