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Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism

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Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism
sulfhydryl group of the condensing enzyme (CE, blue) and the phosphopantetheine sulfhydryl group of the acyl carrier
protein (ACP, yellow) lead to the growth of the fatty acid chain. The reactions are repeated until the palmitoyl product is
synthesized.
II. Transducing and Storing Energy
22. Fatty Acid Metabolism
22.4. Fatty Acids Are Synthesized and Degraded by Different Pathways
Figure 22.25. Transfer of Acetyl CoA to the Cytosol. Acetyl CoA is transferred from mitochondria to the cytosol, and
the reducing potential NADH is concomitantly converted into that of NADPH by this series of reactions.
II. Transducing and Storing Energy
22. Fatty Acid Metabolism
22.5. Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid
Metabolism
Fatty acid metabolism is stringently controlled so that synthesis and degradation are highly responsive to physiological
needs. Fatty acid synthesis is maximal when carbohydrate and energy are plentiful and when fatty acids are scarce.
Acetyl CoA carboxylase plays an essential role in regulating fatty acid synthesis and degradation. Recall that this
enzyme catalyzes the committed step in fatty acid synthesis: the production of malonyl CoA (the activated two-carbon
donor). The carboxylase is controlled by three global signals glucagon, epinephrine, and insulin that correspond to
the overall energy status of the organism. Insulin stimulates fatty acid synthesis by activating the carboxylase, whereas
glucagon and epinephrine have the reverse effect. The levels of citrate, palmitoyl CoA, and AMP within a cell also exert
control. Citrate, a signal that building blocks and energy are abundant, activates the carboxylase. Palmitoyl CoA and
AMP, in contrast, lead to the inhibition of the carboxylase. Thus, this important enzyme is subject to both global and
local regulation. We will examine each of these levels of regulation in turn.
Global Regulation.
Global regulation is carried out by means of reversible phosphorylation. Acetyl CoA carboxylase is switched off by
phosphorylation and activated by dephosphorylation (Figure 22.26). Modification of a single serine residue by an AMPdependent protein kinase (AMPK) converts the carboxylase into an inactive form. The phosphoryl group on the inhibited
carboxylase is removed by protein phosphatase 2A. The proportion of carboxylase in the active dephosphorylated form
depends on the relative rates of these opposing enzymes.
How is the formation of the inactive, phosphorylated form of the enzyme regulated? AMPK, the enzyme that
phosphorylates the carboxylase, is essentially a fuel gauge it is activated by AMP and inhibited by ATP. Thus, the
carboxylase is inactivated when the energy charge is low. This kinase is conserved among eukaryotes. Homologs found
in yeast and plants also play roles in sensing the energy status of the cell. The inhibition of phosphatase 2A is necessary
to maintain acetyl CoA carboxylase in the phosphorylated state. Epinephrine and glucagon activate protein kinase A,
which in turn inhibits the phosphatase by phosphorylating it. Hence, these catabolic hormones switch off fatty acid
synthesis by keeping the carboxylase in the inactive phosphorylated state.
How is the enzyme dephosphorylated and activated? Insulin stimulates the carboxylase by causing its
dephosphorylation. It is not clear which of the phosphatases activates the carboxylase in response to insulin. The
hormonal control of acetyl CoA carboxylase is reminiscent of that of glycogen synthase (Section 21.5.2).
Local Regulation.
Acetyl CoA carboxylase is also under local control. This enzyme is allosterically stimulated by citrate. Specifically,
citrate partly reverses the inhibition produced by phosphorylation. It acts in an unusual manner on inactive acetyl CoA
carboxylase, which exists as an octamer (Figure 22.27). Citrate facilitates the polymerization of the inactive octamers
into active filaments (Figure 22.28). The level of citrate is high when both acetyl CoA and ATP are abundant. Recall that
mammalian isocitrate dehydrogenase is inhibited by a high energy charge (Section 17.2.2). Hence, a high level of citrate
signifies that two-carbon units and ATP are available for fatty acid synthesis. The stimulatory effect of citrate on the
carboxylase is antagonized by palmitoyl CoA, which is abundant when there is an excess of fatty acids. Palmitoyl CoA
causes the filaments to disassemble into the inactive octamers. Palmitoyl CoA also inhibits the translocase that transports
citrate from mitochondria to the cytosol, as well as glucose 6-phosphate dehydrogenase, which generates NADPH in the
pentose phosphate pathway.
Response to Diet.
Fatty acid synthesis and degradation are reciprocally regulated so that both are not simultaneously active. In starvation,
the level of free fatty acids rises because hormones such as epinephrine and glucagon stimulate adipose-cell lipase.
Insulin, in contrast, inhibits lipolysis. Acetyl CoA carboxylase also plays a role in the regulation of fatty acid
degradation. Malonyl CoA, the product of the carboxylase reaction, is present at a high level when fuel molecules are
abundant. Malonyl CoA inhibits carnitine acyltransferase I, preventing access of fatty acyl CoAs to the mitochondrial
matrix in times of plenty. Malonyl CoA is an especially effective inhibitor of carnitine acyltransferase I in heart and
muscle, tissues that have little fatty acid synthesis capacity of their own. In these tissues, acetyl CoA carboxylase may be
a purely regulatory enzyme. Finally, two enzymes in the β-oxidation pathway are markedly inhibited when the energy
charge is high. NADH inhibits 3-hydroxyacyl CoA dehydrogenase, and acetyl CoA inhibits thiolase.
Long-term control is mediated by changes in the rates of synthesis and degradation of the enzymes participating in fatty
acid synthesis. Animals that have fasted and are then fed high-carbohydrate, low-fat diets show marked increases in their
amounts of acetyl CoA carboxylase and fatty acid synthase within a few days. This type of regulation is known as
adaptive control.
II. Transducing and Storing Energy
22. Fatty Acid Metabolism
22.5. Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism
Figure 22.26. Control of Acetyl CoA Carboxylase. Acetyl CoA carboxylase is inhibited by phosphorylation and
activated by the binding of citrate.
II. Transducing and Storing Energy
22. Fatty Acid Metabolism
22.5. Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism
Figure 22.27. Dependence of the Catalytic Activity of Acetyl CoA Carboxylase on the Concentration of Citrate.
The dephosphorylated form of the carboxylase is highly active even when citrate is absent. Citrate partly overcomes the
inhibition produced by phosphorylation. [After G. M. Mabrouk, I. M. Helmy, K. G. Thampy, and S. J. Wakil. J. Biol.
Chem. 265(1990):6330.]
II. Transducing and Storing Energy
22. Fatty Acid Metabolism
22.5. Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism
Figure 22.28. Filaments of Acetyl CoA Carboxylase. The electron micrograph shows the enzymatically active
filamentous form of acetyl CoA carboxylase from chicken liver. The inactive form is an octamer of 265-kd subunits.
[Courtesy of Dr. M. Daniel Lane.]
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