De novo synthesis of fatty acids refers to the process by which fatty acids are synthesized from simpler precursors, such as acetyl-CoA and malonyl-CoA. Palmitic acid (C16:0) is the primary product of this synthesis in humans.
The process mainly occurs in the cytosol of hepatocytes (liver cells) and adipocytes (fat cells).
Key Steps in the De Novo Synthesis of Palmitic Acid
1. Formation of Malonyl-CoA:
Process: Acetyl-CoA, derived primarily from glucose metabolism, is converted into malonyl-CoA.
Enzyme: Acetyl-CoA carboxylase (ACC).
Mechanism: ACC adds a carboxyl group to acetyl-CoA using bicarbonate as a source, requiring ATP.
Regulation: Acetyl-CoA carboxylase is the rate-limiting enzyme in fatty acid synthesis and is regulated by allosteric effectors and hormones.
2. Activation of Acetyl-CoA and Malonyl-CoA:
Multi-Enzyme Complex: Fatty acid synthesis is catalyzed by a multi-enzyme complex called fatty acid synthase (FAS).
Components of FAS: Includes acyl carrier protein (ACP) and acyltransferases.
Transfer to ACP: Acetyl-CoA and malonyl-CoA are transferred to the ACP by acetyltransferase and malonyltransferase, respectively. Acetyl-CoA is attached to the cysteine residue of FAS, while malonyl-CoA is attached to the ACP's phosphopantetheine prosthetic group.
3. Elongation of the Fatty Acid Chain:
The elongation occurs through a series of condensation, reduction, dehydration, and reduction reactions, repeated until the desired chain length is achieved.
For palmitic acid, the process is repeated seven times.
Steps in Elongation:
A. Condensation:
Process: The acetyl group on FAS condenses with the malonyl group on ACP, forming a four-carbon molecule (β-ketoacyl-ACP) and releasing one molecule of CO2.
Enzyme: β-Ketoacyl-ACP synthase (KS).
B. Reduction:
Process: The β-ketoacyl-ACP is reduced, converting the keto group to a hydroxyl group, forming β-hydroxyacyl-ACP.
Enzyme: β-Ketoacyl-ACP reductase (KR), which uses NADPH as an electron donor.
C. Dehydration:
Process: The β-hydroxyacyl-ACP is dehydrated to form a trans-2-enoyl-ACP.
Enzyme: β-Hydroxyacyl-ACP dehydratase (DH).
D. Reduction:
Process: The double bond in the trans-2-enoyl-ACP is reduced to form an acyl-ACP molecule with two additional carbons.
Enzyme: Enoyl-ACP reductase (ER), which uses NADPH as an electron donor.
Repetition: The cycle is repeated until the fatty acid chain reaches 16 carbons in length (palmitoyl-ACP).
4. Release of Palmitic Acid:
Process: Once palmitoyl-ACP has been formed, the thioester bond between palmitic acid and ACP is cleaved.
Enzyme: Thioesterase.
Product: Free palmitic acid is released.
Regulation of De Novo Fatty Acid Synthesis
De novo fatty acid synthesis is regulated by various factors, including hormones (such as insulin and glucagon), substrate availability, and cellular energy status.
For example, excess glucose can stimulate fatty acid synthesis, leading to increased production of palmitic acid.