Fatty acid activation mechanism

Desbois, A. P. Smith, V. J. (2010). Antibacterial free fatty acids activities, mechanisms of action and biotechnological potential. Appl. Microbiol. Biotechnol, 85, 1629-1642. 

Some drugs impair mitochondrial function through a combination of mechanisms. A good example is valproic acid, which inhibits mitochondrial fatty acid oxidation by sequestering coenzyme A (a cofactor necessary for fatty acid activation and... 

Kansanen, E., G. Bonacci, F. J. Schopfer et al. 2011. Electrophilic nitro-fatty acids activate NRF2 by a KEAPl cysteine 151-independent mechanism. iolCh 286 (16) 14019-27. 

Like mitochondria, peroxisomes contain pathways for the /3-oxidation of fatty acids. The mechanism by which fatty acids enter peroxisomes is unclear but does not appear to involve the CPTl-CACT-CPT2 pathway. Long-chain and very-long-chain acyl-CoA synthetase activities are associated with peroxisomes, but it has not been established whether fatty acids or fatty acyl-CoAs traverse the peroxisomal membrane. The basic reactions of peroxisomal /3-oxidation resemble those found in mitochondria, but the peroxisomal and mitochondrial enzymes are distinct proteins (Figure 4). In fact, peroxisomes contain two sets of yS-oxidation enzymes, which appear to function with distinct substrates. 

Figure 3.7 Model of intermolecular fatty acid synthetase mechanism in the a2 2 protomer of yeast. A, acetyl transferase E, enoyl reductase D, dehydratase P, palmitoyl transferase M, malonyl transferase C, 5-ketoacyl synthase R. )5-ketoacyl reductase ACP, acyl carrier protein. Dotted lines and arrows delineate the route taken by intermediates when sequentially processed on different FAS domains. Numbers indicate the reaction sequence. Catalytically active dohnains, at a specific moment, are marked by bold lines. Shaded areas on E and P domains potentially interact by hydrophobic attraction in the presence of palmitate (b). On the protomer depicted in (a) fatty acyl chain elongation occurs in one half of the a2 2 protomer. In (b) chain termination is induced by hydrophobic interaction between E> bound palmitate and P. Subsequently, palmitate Is transferred to Its O-ester binding site on P. Inactivation of the left half of simultaneously activates its right half (b). Redrawn from Schweizer (1984) with permission of the author and Elsevier Science Publishers, BV. From Fatty Acid Metabolism and its Regulation (1984) (ed. S. Numa), p. 73, Figure 7.

FIGURE 25.2 (a) The acetyl-CoA carboxylase reaction produces malonyl-CoA for fatty acid synthesis, (b) A mechanism for the acetyl-CoA carboxylase reaction. Bicarbonate is activated for carboxylation reactions by formation of N-carboxybiotin. ATP drives the reaction forward, with transient formation of a carbonylphosphate intermediate (Step 1). In a typical biotin-dependent reaction, nncleophilic attack by the acetyl-CoA carbanion on the carboxyl carbon of N-carboxybiotin—a transcarboxylation—yields the carboxylated product (Step 2). 

The metabolic breakdown of triacylglycerols begins with their hydrolysis to yield glycerol plus fatty acids. The reaction is catalyzed by a lipase, whose mechanism of action is shown in Figure 29.2. The active site of the enzyme contains a catalytic triad of aspartic acid, histidine, and serine residues, which act cooperatively to provide the necessary acid and base catalysis for the individual steps. Hydrolysis is accomplished by two sequential nucleophilic acyl substitution reactions, one that covalently binds an acyl group to the side chain -OH of a serine residue on the enzyme and a second that frees the fatty acid from the enzyme. 

Step 1 of Figure 29.13 Carboxylation Gluconeogenesis begins with the carboxyl-afion of pyruvate to yield oxaloacetate. The reaction is catalyzed by pyruvate carboxylase and requires ATP, bicarbonate ion, and the coenzyme biotin, which acts as a carrier to transport CO2 to the enzyme active site. The mechanism is analogous to that of step 3 in fatty-acid biosynthesis (Figure 29.6), in which acetyl CoA is carboxylated to yield malonyl CoA. 

Smith and Stirton applied this mechanism to the sulfonation of long-chain fatty acid esters [31]. Instead of forming the well-defined mixed anhydride during the reaction of fatty acids with S03, the acid esters form a complex less defined in structure and composition. In this complex the a-hydrogen is activated, so that a second molecule of S03 can react. These two addition steps are fast. The final step is again a slow rearrangement of the intermediate with a loss of one molecule of S03. 

Nagayama et al. [36] studied a-sulfonation using nuclear magnetic resonance (NMR). They reported the presence of two intermediates. The first intermediate is the adduct of S03 to the carbonyl oxygen formed at low temperatures. In contrast to the mechanism of Stein et al., they did not propose a rearrangement of this intermediate but a second addition of S03 to the activated a-hydrogen to give the second intermediate. The reaction of the intermediate with sodium hydroxide can lead to the disodium salt if the neutralization is immediate or to the sodium a-sulfo fatty acid ester if the neutralization is delayed. 

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Figure 2.1 Mechanism for the oxygenation of iipids by iipoxygenase under aerobic conditions. LH, fatty acid LOOM, fatty-acid hydroperoxide Fe, the redox active centre of the enzyme.

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