The short-term regulation of Acetyl CoA carboxylase involves both its rate-limiting and regulated step in fatty acid synthesis. The inactive form of ACC consists of complex polypeptides. Citrate activates the enzyme by causing the protomers to polymerize, while palmitoyl CoA inactivates it by causing depolymerization. Phosphorylation also plays a role in the short-term regulation, with AMPK phosphorylating and inactivating ACC. AMPK itself is activated by AMP and cyclic AMP-dependent protein kinase A (PKA). When counterregulatory hormones like epinephrine and glucagon are present, ACC is phosphorylated and inactive. In the presence of insulin, ACC is dephosphorylated and active.

The long-term regulation of Acetyl CoA carboxylase is influenced by the consumption of a diet with excess calories. Diets high in carbohydrates and low in fat lead to an increase in ACC synthesis, resulting in increased fatty acid synthesis. On the other hand, low-calorie or high-fat, low-carbohydrate diets have the opposite effect. Carbohydrate, specifically glucose, activates ACC synthesis through the transcription factor carbohydrate response element-binding protein (ChREBP), while insulin activates it through sterol regulatory element-binding protein-1c (SREBP-1c). Metformin, used to treat type 2 diabetes, lowers plasma TAG levels by activating AMPK, which inhibits ACC activity and expression of ACC and fatty acid synthase. Metformin also increases AMPK-mediated glucose uptake by muscle, thereby lowering blood glucose levels.

In eukaryotes, fatty acid synthesis is catalyzed by the multifunctional enzyme fatty acid synthase (FAS). This process involves adding two carbons from malonyl CoA to acyl acceptors. FAS is a homodimeric enzyme with six different enzymic domains and an acyl carrier protein (ACP) domain that contains 4'-phosphopantetheine. This derivative of pantothenic acid carries acyl units on its terminal thiol (–SH) group and presents them to the catalytic domains of FAS during fatty acid synthesis. It is also a component of CoA. In prokaryotes, FAS is a multienzyme complex.


1. Acetyl CoA carboxylase short-term regulation: This carboxylation is both the rate-limiting and the regulated step in fatty acid synthesis (see Fig. 16.7). The inactive form of ACC is a protomer (complex of ≥2 polypeptides). The enzyme is allosterically activated by citrate, which causes protomers to polymerize, and allosterically inactivated by palmitoyl CoA (the end product of the pathway), which causes depolymerization. A second mechanism of short-term regulation is by reversible phosphorylation. Adenosine monophosphate–activated protein kinase (AMPK) phosphorylates and inactivates ACC. AMPK itself is activated allosterically by AMP and covalently by phosphorylation via several kinases. At least one of these AMPK kinases is activated by cyclic AMP (cAMP)–dependent protein kinase A (PKA). Thus, in the presence of counterregulatory hormones, such as epinephrine and glucagon, ACC is phosphorylated and inactive (Fig. 16.8). In the presence of insulin, ACC is dephosphorylated and active. [Note: This is analogous to the regulation of glycogen synthase (see p. 131).] itself is regulated both covalently and allosterically. CoA = coenzyme A; ADP phosphate.
2. Acetyl CoA carboxylase long-term regulation: Prolonged consumption of a diet containing excess calories (particularly high-carbohydrate, low-fat diets) causes an increase in ACC synthesis, thereby increasing fatty acid synthesis. A low-calorie or a high-fat, low-carbohydrate diet has the opposite effect. [Note: ACC synthesis is upregulated by carbohydrate (specifically glucose) via the transcription factor carbohydrate response element–binding protein (ChREBP) and by insulin via the transcription factor sterol regulatory element–binding protein-1c (SREBP-1c). Fatty acid synthase (see C. below) is similarly regulated. The function and regulation of SREBP are described on p. 222.] Metformin, used in the treatment of type 2 diabetes, lowers plasma TAG through activation of AMPK, resulting in inhibition of ACC activity (by phosphorylation) and inhibition of ACC and fatty acid synthase expression (by decreasing SREBP-1c). Metformin lowers blood glucose by increasing AMPK-mediated glucose uptake by muscle.
C. Eukaryotic fatty acid synthase
The remaining series of reactions of fatty acid synthesis in eukaryotes is catalyzed by the multifunctional, homodimeric enzyme fatty acid synthase (FAS). The process involves the addition of two carbons from malonyl CoA to the carboxyl end of a series of acyl acceptors. Each FAS monomer is a multicatalytic polypeptide with six different enzymic domains plus a 4ʹphosphopantetheine-containing acyl carrier protein (ACP) domain. 4ʹ-Phosphopantetheine, a derivative of pantothenic acid (vitamin B5, see p.
385), carries acyl units on its terminal thiol (–SH) group and presents them to the catalytic domains of FAS during fatty acid synthesis. It also is a component of CoA. [Note: In prokaryotes, FAS is a multienzyme complex.] The reaction numbers in brackets below refer to Figure 16.9.
adenine dinucleotide phosphate.
1.
An acetyl group is transferred from acetyl CoA to the –SH group of the ACP. Domain: Malonyl/acetyl CoA–ACP transacylase.
2.
Next, this two-carbon fragment is transferred to a temporary holding site, the –SH group of a cysteine residue on the condensing enzyme domain (see [4] below).