Biosynthesis of Fatty Acids and Eicosanoids: -Fatty Acid Biosynthesis Is Tightly Regulated
When a cell or organism has more than enough metabolic fuel to meet its energy needs, the excess is generally converted to fatty acids and stored as lipids such as triacylglycerols. The reaction catalyzed by acetyl-CoA carboxylase is the rate-limiting step in the biosynthesis of fatty acids, and this enzyme is an important site of regulation. In vertebrates, palmitoyl-CoA, the principal product of fatty acid synthesis, is a feedback inhibitor of the enzyme; citrate is an allosteric activator (Fig. 21–11a), increasing Vmax. Citrate plays a central role in diverting cellular metabolism from the consumption (oxidation) of metabolic fuel to the storage of fuel as fatty acids. When the concentrations of mitochondrial acetyl CoA and ATP increase, citrate is transported out of mitochondria; it then becomes both the precursor of cytosolic acetyl-CoA and an allosteric signal for the activation of acetyl-CoA carboxylase. At the same time, citrate inhibits the activity of phosphofructokinase-1 (see Fig. 15–18), reducing the flow of carbon through glycolysis. Acetyl-CoA carboxylase is also regulated by covalent modification. Phosphorylation, triggered by the hormones glucagon and epinephrine, inactivates the enzyme and reduces its sensitivity to activation by citrate, thereby slowing fatty acid synthesis. In its active (dephosphorylated) form, acetyl-CoA carboxylase polymerizes into long filaments (Fig. 21–11b); phosphorylation is accompanied by dissociation into monomeric subunits and loss of activity.
FIGURE 21–10 Shuttle for transfer of acetyl groups from mitochondria to the cytosol. The mitochondrial outer membrane is freely permeable to all these compounds. Pyruvate derived from amino acid catabolism in the mitochondrial matrix, or from glucose by glycolysis in the cytosol, is converted to acetyl-CoA in the matrix. Acetyl groups pass out of the mitochondrion as citrate; in the cytosol they are delivered as acetyl-CoA for fatty acid synthesis. Oxaloacetate is reduced to malate, which returns to the mitochondrial matrix and is converted to oxaloacetate. An alternative fate for cytosolic malate is oxidation by malic enzyme to generate cytosolic NADPH; the pyruvate produced returns to the mitochondrial matrix.
The acetyl-CoA carboxylase of plants and bacteria is not regulated by citrate or by a phosphorylation dephosphorylation cycle. The plant enzyme is activated by an increase in stromal pH and [Mg2+], which occurs on illumination of the plant (see Fig. 20–18). Bacteria do not use triacylglycerols as energy stores. In E. coli, the primary role of fatty acid synthesis is to provide pre cursors for membrane lipids; the regulation of this process is complex, involving guanine nucleotides (such as ppGpp) that coordinate cell growth with membrane formation (see Figs 8–42, 28–24).
In addition to the moment-by-moment regulation of enzymatic activity, these pathways are regulated at the level of gene expression. For example, when animals in gest an excess of certain polyunsaturated fatty acids, the expression of genes encoding a wide range of lipogenic enzymes in the liver is suppressed. The detailed mechanism by which these genes are regulated is not yet clear.
If fatty acid synthesis and β oxidation were to proceed simultaneously, the two processes would constitute a futile cycle, wasting energy. We noted earlier (see Fig. 17–12) that β oxidation is blocked by malonyl-CoA, which inhibits carnitine acyltransferase I. Thus, during fatty acid synthesis, the production of the first inter mediate, malonyl-CoA, shuts down β oxidation at the level of a transport system in the mitochondrial inner membrane. This control mechanism illustrates another advantage of segregating synthetic and degradative pathways in different cellular compartments.
FIGURE 21–11 Regulation of fatty acid synthesis. (a) In the cells of vertebrates, both allosteric regulation and hormone-dependent covalent modification influence the flow of precursors into malonyl-CoA. In plants, acetyl-CoA carboxylase is activated by the changes in [Mg2+] and pH that accompany illumination (not shown here). (b) Filaments of acetyl-CoA carboxylase (the active, dephosphorylated form) as seen with the electron microscope.
