4.4: Fatty acid synthesis

The synthesis of fatty acids is an anabolic pathway that occurs in the cytosol under fed conditions. As glucose is taken up by the liver and the flux through the TCA cycle increases, excess citrate is removed via the citrate shuttle. Once in the cytosol, citrate is cleaved by citrate lyase back into oxaloacetate (OAA) and acetyl-CoA. The OAA can be reduced to malate by cytosolic malate dehydrogenase and decarboxylated by malic enzyme producing pyruvate and NADPH (figure 4.15).

Figure 4.15: Citrate shuttle reaction moves citrate from the mitochondria to the cytosol for fatty acid synthesis.

The NADPH generated through this process is necessary for fatty acid synthesis. This is one of the primary pathways that produces NADPH, and the other is the oxidative portion of the pentose pathway.

The process of fatty acid synthesis starts with the carboxylation of acetyl-CoA to form malonyl-CoA (figures 4.16 and 4.17). The enzyme involved, acetyl-CoA carboxylase, is the regulatory enzyme for this pathway and requires biotin as a cofactor. After the initial priming of fatty acid synthase with acetyl-CoA, all other carbon units are added to the elongating fatty acid chain in the form of malonyl-CoA. You will see later that this intermediate is also a key inhibitor of \(\beta\)-oxidation.

Figure 4.16: Fatty acid synthesis is an iterative process that begins with the transfer of an acetyl moiety from acetyl-CoA to fatty acid synthase; following this activation, carbons are added to the growing chain in the form of malonyl-CoA.

The synthesis of fatty acids by fatty acid synthase initially starts with the transfer of an acetyl moiety from acetyl-CoA to the acyl carrier protein within fatty acid synthase. Malonyl-CoA is added to the acetyl group and decarboxylated to form a four-carbon \(\beta\)-keto chain. From here, the fatty acid chain is elongated through a series of dehydration and reduction reactions, which use NADPH as a reducing agent. The final product is palmitate, a C-16 molecule (figure 4.16). Fatty acids are not stored in the liver and must be packaged into VLDL particles for transport to peripheral tissues for storage. To produce VLDL particles, the newly synthesized fatty acids are packaged into triacylglycerols (TAGs). TAG synthesis can take place in both the liver and adipose tissue. Synthesis requires glycerol 3-phosphate, which can be derived from glycolysis or from the phosphorylation of glycerol using glycerol kinase in the liver. Three fatty acyl-CoA groups react with the glycerol 3-phosphate to form a TAG. TAGs, along with cholesterol, are packaged into VLDLs distributed into circulation (section 6.2).

Regulation of fatty acid synthesis

Acetyl-CoA carboxylase is the regulatory enzyme for fatty acid synthesis. This enzyme is regulated both allosterically and through covalent modification. It is allosterically activated by high levels of citrate and inhibited by its product, fatty acyl-CoA. It can also be inhibited by elevated levels of glucagon, epinephrine, and adenosine monophosphate (AMP)-activated protein kinase phosphorylation. Insulin will stimulate the dephosphorylation and activation of the enzyme such that it can be active in the fed state (figure 4.17).

Figure 4.17: Regulatory reaction of fatty acid synthesis. The synthesis of malonyl-CoA by acetyl-CoA carboxylase is highly regulated within the cytosol.

Summary of pathway regulation

Metabolic pathway	Major regulatory enzyme(s)	Allosteric effectors	Hormonal effects
Fatty acid synthesis	Acetyl-CoA carboxylase	Citrate (+) Palmitate (-)	Insulin \(\uparrow\) Glucagon \(\downarrow\)

Table 4.3: Summary of pathway regulation.

References and resources

Text

Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 6: Bioenergetics and Oxidative Phosphorylation: Section V, VI, Chapter 8: Introduction to Metabolism and Glycolysis, Chapter 9: TCA Cycle and Pyruvate Dehydrogenase Complex: Section IIA, IIB, Chapter 11: Glycogen Metabolism: Section V, VI, Chapter 16: Fatty Acid Ketone Body and TAG Metabolism: Section II, IV, V, Chapter 23: Metabolic Effect of Insulin and Glucagon, Chapter 25: Diabetes Mellitus.

Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 72–78, 85–89.

Lieberman, M., and A. Peet, eds. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 2: The Fed or Absorptive State, Chapter 19: Basic Concepts of Regulation: Section IV.A.1.2, Chapter 20: Cellular Bioenergetics, Chapter 22: Generation of ATP from Glucose: Section I.A.B.C, III, Chapter 24: Oxidative Phosphorylation and the ETC: Section I.E, II, III, Chapter 31: Synthesis of Fatty Acids: Section I.A.B, IV, V.

Figures

Grey, Kindred, Figure 4.15 Citrate shuttle reaction moves citrate from the mitochondria to the cytosol for fatty acid synthesis. 2021. https://archive.org/details/4.15-new. CC BY 4.0.

Grey, Kindred, Figure 4.16 Fatty acid synthesis is an iterative process which begins with the transfer of an acetyl moiety from acetyl-CoA to fatty acid synthase, following this activation, carbons are added to the growing chain in the form of malonyl-CoA. 2021. https://archive.org/details/4.16_20210924. CC BY 4.0.

Grey, Kindred, Figure 4.17 Regulatory reaction of fatty acid synthesis. The synthesis of malonyl-CoA by acetyl-CoA carboxylase is highly regulated within the cytosol. 2021. https://archive.org/details/4.17-new. CC BY 4.0.