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).