Acetyl CoA carboxylase regulation

Sufficient evidence has now been accumulated to establish the occurrence of a covalent modification mechanism for acetyl-CoA carboxylase regulation under in vitro eis well as in vivo conditions. Although further... 

As will become obvious later, fatty acid synthesis is constantly modulated by dietary factors and hormones. If fatty acid synthesis is not regulated at the level of acetyl-CoA carboxylase, regulation must affect the synthetase allosteric and adaptive regulation of the synthetase has been described, but these findings will remain difficult to interpret until more is known about the protein involved in the individual steps of fatty acid synthesis in mammalian cells. 

Because this enzyme catalyzes the committed step in fatty acid biosynthesis, it is carefully regulated. Palmitoyl-CoA, the final product of fatty acid biosynthesis, shifts the equilibrium toward the inactive protomers, whereas citrate, an important allosteric activator of this enzyme, shifts the equilibrium toward the active polymeric form of the enzyme. Acetyl-CoA carboxylase shows the kinetic behavior of a Monod-Wyman-Changeux V-system allosteric enzyme (Chapter 15). 

FIGURE 25.17 Hormonal signals regulate fatty acid synthesis, primarily through actions on acetyl-CoA carboxylase. Availability of fatty acids also depends upon hormonal activation of triacylglycerol lipase. 

Based on the information presented in the text and in Figures 25.4 and 25.5, suggest a model for the regulation of acetyl-CoA carboxylase. Consider the possible roles of subunit interactions, phosphorylation, and conformation changes in your model. 

Lopa.schnk, G. D., and Gamble, J., 1994. The 1993 Merck Fro.s.st Award. Acetyl-CoA carboxylase an important regulator of fatty acid oxidation in die heart. Canadian Journal of Physiology and Pharmacology 72 1101 — 1109. 

Acetyl-CoA Carboxylase Is the Most Important Enzyme in the Regulation of Lipogenesis... 

Acetyl-CoA carboxylase is also regulated by hormones such as glucagon, epinephrine, and insulin via... 

Figure 21-6. Regulation of acetyl-CoA carboxylase by phosphorylation/dephosphorylation.The enzyme is inactivated by phosphorylation by AMP-activated protein kinase (AMPK), which in turn is phosphorylated and activated by AMP-activated protein kinase kinase (AMPKK). Glucagon (and epinephrine), after increasing cAMP, activate this latter enzyme via cAMP-dependent protein kinase. The kinase kinase enzyme is also believed to be activated by acyl-CoA. Insulin activates acetyl-CoA carboxylase, probably through an "activator" protein and an insulin-stimulated protein kinase.

Lipogenesis is regulated at the acetyl-CoA carboxylase step by allosteric modifiers, phosphorylation/de-phosphorylation, and induction and repression of enzyme synthesis. Citrate activates the enzyme, and long-chain acyl-CoA inhibits its activity. Insulin activates acetyl-CoA carboxylase whereas glucagon and epinephrine have opposite actions. 

The regulation of fat metabolism is relatively simple. During fasting, the rising glucagon levels inactivate fatty acid synthesis at the level of acetyl-CoA carboxylase and induce the lipolysis of triglycerides in the adipose tissue by stimulation of a hormone-sensitive lipase. This hormone-sensitive lipase is activated by glucagon and epinephrine (via a cAMP mechanism). This releases fatty acids into the blood. These are transported to the various tissues, where they are used. 

Carbonic anhydrase (CA, also called carbonate dehydratase) is an enzyme found in most human tissues. As well as its renal role in regulating pH homeostasis (described below) CA is required in other tissues to generate bicarbonate needed as a co-substrate for carboxylase enzymes, for example pyruvate carboxylase and acetyl-CoA carboxylase, and some synthase enzymes such as carbamoyl phosphate synthases I and II. At least 12 isoenzymes of CA (CA I—XII) have been identified with molecular masses varying between 29 000 and 58 000 some isoenzymes are found free in the cytosol, others are membrane-bound and two are mitochondrial. 

As indicated above, the flux-generating step for fatty acid synthesis is the conversion of acetyl-CoA to malonyl-CoA, catalysed by acetyl-CoA carboxylase. Consequently, regulation of the rate of synthesis is achieved via changes in the activity of this enzyme. The properties of the carboxylase identify three mechanisms for regulation allosteric regulation, reversible phosphorylation (an interconversion cycle) and changes in the concentration of the enzyme. (The principles underlying the first two mechanisms are discussed in Chapter 3.)... 

Figure 8-1. Hormonal regulation of fat metabolism. A Control of fatty acid synthesis by reversible phosphorylation of acetyl CoA carboxylase. B Regulation of tri-acylglycerol degradation by reversible phosphorylation of hormone-sensitive lipase. cAMP, cyclic adenosine monophosphate HS, hormone-sensitive.

Additional information <1> (<1> two other cAMP-independent kinases found, that phosphorylate but do not effect acetyl-CoA carboxylase kinase activity [6] <1> phosphorylation by cAMP-dependent protein kinase has the same effect on acetyl-CoA carboxylase activity then phosphorylation with acetyl-CoA carboxylase kinase-2 [6,7] <1> cAMP-dependent protein kinase identified, that phosphorylates and inactivates acetyl-CoA carboxylase in vitro, but appears not to be involved in regulation in vivo [8]) [6-8]... 

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. 21-1 lb) phosphorylation is accompanied by dissociation into monomeric subunits and loss of activity. 

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. 

Munday, M.R. (2002) Regulation of mammalian acetyl-CoA carboxylase. Biochem. Soc. Trans. 30, 1059-1064. 

Modulation of Acetyl-CoA Carboxylase Acetyl-CoA carboxylase is the principal regulation point in the biosynthesis of fatty acids. Some of the properties of the enzyme are described below. 

One enzyme regulated by AMPK is acetyl-CoA carboxylase, which produces malonyl-CoA, the first intermediate committed to fatty acid synthesis. Malonyl-CoA is a powerful inhibitor of the enzyme carnitine acyl-transferase I, which starts the process of ]3 oxidation by transporting fatty acids into the mitochondrion (see Fig. 17-6). By phosphorylating and inactivating acetyl-CoA carboxylase, AMPK inhibits fatty acid synthesis while relieving the inhibition (by malonyl-CoA) of )3 oxidation (Fig. 23-37). 

FIGURE 23-37 Regulation of fatty acid synthesis and /8 oxidation by AMPK action on acetyl-CoA carboxylase. When... 

Allosteric regulation of malonyl CoA synthesis by acetyl CoA carboxylase. The carboxyl group contributed by dissolved CO2 is shown in blue. 

Hormone-mediated, covalent regulation of acetyl CoA carboxylase. 

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