Fatty acid synthesis, Inhibition

FIGURE 25.16 Regulation of fatty acid synthesis and fatty acid oxidation are conpled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 

Long-chain fatty acids can slowly cross the mitochondrial membrane by themselves, but this is too slow to keep up with their metabolism. The carnitine shuttle provides a transport mechanism and allows control of (3 oxidation. Malonyl-CoA, a precursor for fatty acid synthesis, inhibits the carnitine shuttle and slows down (3 oxidation (Fig. 13-5). 

Isoniazid (Fab inhibitor) Fatty Acid Synthesis Inhibition... 

Malonyl-CoA, an early intermediate of fatty acid synthesis, inhibits carnitine acyltransferase I, preventing fatty acid entry into mitochondria This blocks fatty acid breakdown while synthesis is occurring. 

In addition to the provision of fatty acids for triacylglycerol synthesis, the low but regulated rates of lipogenesis may be critical for overall control of fatty acid metabolism in humans. As discussed above, malonyl-CoA, which is the product of the ACC reaction and the only free intermediate of fatty acid synthesis, inhibits CPT-1 activity, and thereby prevents transport of fatty acids into mitochondria. Thus, the dual role of malonyl-CoA as an intermediate of fatty acid synthesis and as a regulator of fatty acid oxidation, prevents the operation of the futile cycle, in tissues where both fatty acid synthesis and oxidation can be active. 

The selection of the pathway depends on whether or not the fatty acids enter the mitochondrial matrix, the compartment of (3-oxidation and ketone body formation. When citrate and ATP concentrations are high, as in the fed state, the activity of acetyl CoA carboxylase is stimulated. The resulting malonyl CoA, which is a precursor for fatty acid synthesis, inhibits carnitine acyltransferase 1, which translocates fatty acids from the cytosol into the mitochondria for oxidation. 

Naphthoquiaomycias A (67) and B (68) are isolated from Streptomyces S-1998 (223) and the stmctures for (67) and (68) assigned on the basis of spectral data. Naphthoquiaomycias A and B inhibit fatty acid synthesis ia E. coli. Actamycia (69) is obtaiaed from Streptomyces sp. EJ784 and its stmcture arrived at on the basis of spectral data and degradation studies (224,225). 

Citrate is isomerized to isocitrate by the enzyme aconitase (aconitate hydratase) the reaction occurs in two steps dehydration to r-aconitate, some of which remains bound to the enzyme and rehydration to isocitrate. Although citrate is a symmetric molecule, aconitase reacts with citrate asymmetrically, so that the two carbon atoms that are lost in subsequent reactions of the cycle are not those that were added from acetyl-CoA. This asymmetric behavior is due to channeling— transfer of the product of citrate synthase directly onto the active site of aconitase without entering free solution. This provides integration of citric acid cycle activity and the provision of citrate in the cytosol as a source of acetyl-CoA for fatty acid synthesis. The poison fluo-roacetate is toxic because fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate, which inhibits aconitase, causing citrate to accumulate. 

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... 

Treating mice with 23 led to the inhibition of atherosclerotic progression, whereas macrophage-specific knockout of LXR exacerbates atherosclerosis [111]. In vivo activation of LXR leads to increased fatty acid synthesis, accumulation of TG and the development of hepatic steatosis [109]. Successful LXR agonists will show desirable HDL elevation without these side effects [112]. 

By 1960 it was clear that acetyl CoA provided its two carbon atoms to the to and co—1 positions of palmitate. All the other carbon atoms entered via malonyl CoA (Wakil and Ganguly, 1959 Brady et al. 1960). It was also known that 3H-NADPH donated tritium to palmitate. It had been shown too that fatty acid synthesis was very susceptible to inhibition by p-hydroxy mercuribenzoate, TV-ethyl maleimide, and other thiol reagents. If the system was pre-incubated with acetyl CoA, considerable protection was afforded against the mercuribenzoate. In 1961 Lynen and Tada suggested tightly bound acyl-S-enzyme complexes were intermediates in fatty acid synthesis in the yeast system. The malonyl-S-enzyme complex condensed with acyl CoA and the B-keto-product reduced by NADPH, dehydrated, and reduced again to yield the (acyl+2C)-S-enzyme complex. Lynen and Tada thought the reactions were catalyzed by a multifunctional enzyme system. 

Inhibited by malonyl CoA (increases during fatty acid synthesis)... 

Experiments with chloroplasts showed an apparent inhibition of fatty acid synthesis by PAN (at 72 ppm for 10 min). The result is difficult to interpret the inhibition could be attributed to inactivation of one of the enzymes of the multistep system or to oxidation of the reductant (reduced NADP, or NADPH) required in the chain elongation process. 

Figure 11.3 Mechanism of transfer of acetyl-CoA out of the mitochondrion. In the mitochondrion, acetyl-CoA reacts with oxaloacetate to form citrate, which is transported across the mitochondrial inner membrane. In the cytosol, citrate is split to re-form citrate and oxaloacetate, catalysed by citrate lyase. It has been shown that inhibition of citrate lyase inhibits fatty acid synthesis.

The key enzyme in fatty acid synthesis is acetyl CoA carboxylase (see p. 162), which precedes the synthase and supplies the malonyl-CoA required for elongation. Like all carboxylases, the enzyme contains covalently bound biotin as a prosthetic group and is hormone-dependently inactivated by phosphorylation or activated by dephosphorylation (see p. 120). The precursor citrate (see p. 138) is an allosteric activator, while palmitoyl-CoA inhibits the end product of the synthesis pathway. 

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