Fatty Acid Synthesis

Fatty acids are essential components of cell membranes, energy storage molecules, and signaling molecules in living organisms. Fatty acids can be obtained from dietary sources or synthesized endogenously by the cells. The process of synthesizing fatty acids from simple precursors such as sugars or amino acids is called de novo fatty acid synthesis.

De novo fatty acid synthesis occurs mainly in the cytosol of liver and adipose tissue cells, where a multienzyme complex called fatty acid synthase (FAS) catalyzes the sequential addition of two-carbon units to a growing fatty acyl chain. The main product of de novo fatty acid synthesis is palmitate, a 16-carbon saturated fatty acid, which can be further elongated or desaturated to produce other types of fatty acids.

De novo fatty acid synthesis is regulated by two key enzymes: acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). ACC converts acetyl-CoA to malonyl-CoA, which is the substrate for FAS. FAS then combines malonyl-CoA with acetyl-CoA to form a four-carbon unit, and repeats this cycle until palmitate is formed. Each cycle consumes one ATP and two NADPH molecules, which provide the energy and reducing power for the reactions.

De novo fatty acid synthesis is influenced by various hormonal and nutritional factors that modulate the activity and expression of ACC and FAS. For example, insulin stimulates fatty acid synthesis by activating ACC, while glucagon and epinephrine inhibit it by inactivating ACC. De novo fatty acid synthesis is also responsive to the availability of substrates and products. For instance, high levels of glucose or citrate increase fatty acid synthesis by providing more acetyl-CoA and NADPH, while high levels of fatty acids or malonyl-CoA decrease it by inhibiting ACC or FAS.

De novo fatty acid synthesis is important for maintaining cellular lipid homeostasis and fulfilling various physiological functions. Fatty acids synthesized de novo can be incorporated into phospholipids, triglycerides, cholesterol esters, or other lipid derivatives that are essential for membrane structure, energy storage, hormone production, and protein modification. De novo fatty acid synthesis is also involved in cell growth, differentiation, and signaling, as well as in metabolic diseases such as obesity, diabetes, and cancer.

Fatty acid synthesis is a process that occurs in the cytoplasm of the cell, also known as the cytosol. The cytosol is the fluid part of the cell that contains various molecules and organelles. The cytosol provides a suitable environment for fatty acid synthesis because it has a high concentration of substrates and cofactors, such as acetyl CoA, NADPH, ATP, and biotin. The cytosol also contains the enzymes that catalyze the reactions of fatty acid synthesis.

The main enzyme complex that performs fatty acid synthesis is called fatty acid synthase (FAS). FAS is a large multienzyme complex that consists of two identical subunits, each containing seven catalytic domains and one acyl carrier protein (ACP) domain. FAS can be found in the cytosol as a free-floating complex or attached to the endoplasmic reticulum (ER) membrane. The ER is a network of membranes that extends throughout the cytoplasm and is involved in various functions, such as protein synthesis and lipid metabolism.

The attachment of FAS to the ER membrane facilitates the transport of fatty acids to other parts of the cell or to the extracellular space. Fatty acids can be incorporated into phospholipids, which are the main components of cell membranes, or into triglycerides, which are stored in lipid droplets as energy reserves. Fatty acids can also be modified by other enzymes in the ER to produce different types of fatty acids, such as unsaturated, branched-chain, or very-long-chain fatty acids.

Fatty acid synthesis is a highly regulated process that depends on the availability of substrates and cofactors, as well as on the hormonal and nutritional status of the cell. Fatty acid synthesis is stimulated by insulin, which promotes glucose uptake and acetyl CoA production in the cytosol. Fatty acid synthesis is inhibited by glucagon and epinephrine, which activate lipolysis and oxidation of fatty acids in the mitochondria. Fatty acid synthesis is also controlled by feedback inhibition by end products, such as malonyl CoA and palmitate.

Fatty acid synthesis is an essential metabolic pathway for most organisms, as it provides the building blocks for membrane formation, energy storage, and cellular signaling. The location of fatty acid synthesis in the cytosol allows for a rapid and flexible response to changing cellular needs and environmental conditions.

Palmitate is the most common saturated fatty acid in animals and plants. It has 16 carbon atoms and no double bonds. To synthesize one molecule of palmitate, the following substrates are required:

• 8 acetyl CoA: This is the main source of carbon atoms for fatty acid synthesis. Acetyl CoA is derived from various metabolic pathways, such as glycolysis, pyruvate oxidation, and beta-oxidation of fatty acids. Acetyl CoA is transported from the mitochondria to the cytosol by a shuttle system involving citrate and malate.
• 14 NADPH: This is the reducing agent that provides electrons for the reduction reactions in fatty acid synthesis. NADPH is generated from two sources: the pentose phosphate pathway and the malic enzyme reaction. The pentose phosphate pathway converts glucose-6-phosphate to ribose-5-phosphate and produces two NADPH per cycle. The malic enzyme converts malate to pyruvate and produces one NADPH per reaction.
• 7 ATP: This is the energy currency that drives the carboxylation of acetyl CoA to malonyl CoA by acetyl CoA carboxylase. This is the rate-limiting and regulated step of fatty acid synthesis. ATP is also used to activate fatty acids by forming acyl CoA thioesters.

The total energy cost of synthesizing one molecule of palmitate from eight molecules of acetyl CoA is 56 NADPH and 16 ATP. This is equivalent to 112 ATP if NADPH is converted to ATP by oxidative phosphorylation. This shows that fatty acid synthesis is an energy-intensive process that requires a high supply of substrates and cofactors.

The main product of fatty acid synthesis is palmitate, a 16-carbon saturated fatty acid. Palmitate is the most abundant fatty acid in animals and plants, and it serves as a precursor for the synthesis of other fatty acids and lipids. Palmitate can be elongated by adding two-carbon units from malonyl CoA, or desaturated by introducing double bonds at specific positions. These modifications result in a variety of fatty acids with different chain lengths and degrees of unsaturation, such as stearate (18:0), oleate (18:1), linoleate (18:2), and arachidonate (20:4). Some of these fatty acids are essential for humans, meaning that they cannot be synthesized by the body and must be obtained from the diet.

Besides palmitate, another product of fatty acid synthesis is water. Each cycle of fatty acid synthesis consumes one molecule of water in the dehydration step, and produces one molecule of water in the hydrolysis step. Therefore, for every molecule of palmitate synthesized, seven molecules of water are consumed and seven molecules of water are produced. This means that there is no net change in the water balance of the cell during fatty acid synthesis.

A third product of fatty acid synthesis is carbon dioxide. This is generated from the decarboxylation of malonyl CoA in the first step of each cycle. For every molecule of palmitate synthesized, eight molecules of carbon dioxide are released. This carbon dioxide can be used for other biosynthetic pathways, such as the Calvin cycle in plants, or excreted as a waste product.

In summary, the products of fatty acid synthesis are:

• 1 molecule of palmitate (16-carbon fatty acid)
• 7 molecules of water (no net change)
• 8 molecules of carbon dioxide

The fatty acid synthesis pathway is a series of biochemical reactions that convert acetyl CoA into palmitate, a 16-carbon saturated fatty acid. The pathway consists of two main steps: the formation of malonyl CoA from acetyl CoA, and the elongation of the fatty acid chain by repeated addition of two-carbon units from malonyl CoA.

The first step is catalyzed by acetyl CoA carboxylase, an enzyme that uses biotin and bicarbonate as cofactors to add a carboxyl group to acetyl CoA, forming malonyl CoA. This reaction requires one ATP and is the rate-limiting and regulated step of the pathway.

The second step is carried out by a multienzyme complex called fatty acid synthase (FAS), which is located in the cytosol. FAS consists of two identical subunits, each containing seven catalytic domains and an acyl carrier protein (ACP) domain. The ACP domain carries a phosphopantetheine group that acts as a flexible arm to transfer the growing fatty acid chain between different active sites on FAS.

The elongation cycle begins with the transfer of an acetyl group from acetyl CoA to the ACP domain of FAS, forming acetyl-ACP. Then, a malonyl group from malonyl CoA is transferred to another ACP domain of FAS, forming malonyl-ACP. The acetyl group and the malonyl group are then condensed by a condensing enzyme (CE) domain, releasing carbon dioxide and forming acetoacetyl-ACP, a four-carbon intermediate.

The acetoacetyl-ACP is then reduced by a ketoreductase (KR) domain, using NADPH as an electron donor, forming D-3-hydroxybutyryl-ACP. This intermediate is then dehydrated by a dehydratase (DH) domain, forming crotonyl-ACP. Finally, crotonyl-ACP is reduced by an enoyl reductase (ER) domain, using another NADPH as an electron donor, forming butyryl-ACP, a four-carbon saturated fatty acid.

The butyryl group on ACP is then transferred to the CE domain of FAS, where it acts as the new acetyl group for the next cycle. Another malonyl group is transferred to ACP, and the cycle repeats. Each cycle adds two carbons to the fatty acid chain and consumes one ATP, one acetyl CoA, and two NADPH.

After seven cycles, the 16-carbon saturated fatty acid palmitate is formed and released from FAS by a thioesterase (TE) domain. Palmitate can then be further modified by other enzymes or used for various cellular functions.

The following diagram summarizes the fatty acid synthesis pathway:

Acetyl CoA + ATP + HCO3- -> Malonyl CoA + ADP + Pi
Malonyl CoA + Acetyl CoA -> Acetoacetyl-ACP + CO2
Acetoacetyl-ACP + NADPH -> D-3-hydroxybutyryl-ACP + NADP+
D-3-hydroxybutyryl-ACP -> Crotonyl-ACP + H2O
Crotonyl-ACP + NADPH -> Butyryl-ACP + NADP+
Butyryl-ACP + Malonyl CoA -> C6-Fatty acyl-ACP + CO2
...
C14-Fatty acyl-ACP + Malonyl CoA -> C16-Fatty acyl-ACP + CO2
C16-Fatty acyl-ACP -> Palmitate + ACP

Fatty acid synthesis is catalyzed by a multienzyme complex called fatty acid synthase (FAS), which consists of two identical subunits that work together to elongate the fatty acid chain. Each subunit contains seven catalytic domains and one acyl carrier protein (ACP) domain. The catalytic domains are:

• Acetyl/malonyl transferase (MAT): This domain transfers the acetyl group from acetyl-CoA and the malonyl group from malonyl-CoA to the ACP domain of the same subunit. The ACP domain carries a 4`-phosphopantetheine group that acts as a flexible arm to move the acyl groups between different catalytic domains.
• β-Ketoacyl synthase (KS): This domain catalyzes the condensation reaction between the acetyl group on one ACP and the malonyl group on another ACP, releasing CO2 and forming a β-ketoacyl group on the first ACP. This is the rate-limiting step of fatty acid synthesis.
• β-Ketoacyl reductase (KR): This domain reduces the β-ketoacyl group to a β-hydroxyacyl group using NADPH as an electron donor.
• β-Hydroxyacyl dehydratase (DH): This domain dehydrates the β-hydroxyacyl group to an α,β-unsaturated acyl group by eliminating a water molecule.
• Enoyl reductase (ER): This domain reduces the α,β-unsaturated acyl group to a saturated acyl group using NADPH as an electron donor.
• Thioesterase (TE): This domain hydrolyzes the thioester bond between the saturated acyl group and the ACP, releasing the fatty acid product. The TE domain is specific for 16-carbon fatty acids (palmitate), so it terminates the fatty acid synthesis cycle after seven rounds of elongation.
• Acyl carrier protein (ACP): This domain carries the growing fatty acid chain between different catalytic domains. It also interacts with other enzymes involved in fatty acid synthesis, such as acetyl-CoA carboxylase and malonyl-CoA transferase.

Another important enzyme involved in fatty acid synthesis is acetyl-CoA carboxylase (ACC), which converts acetyl-CoA to malonyl-CoA using biotin and bicarbonate as cofactors. ACC requires one ATP for this reaction and is regulated by phosphorylation and allosteric factors. ACC is the main point of control for fatty acid synthesis, as it determines the availability of malonyl-CoA, which is both a substrate and an inhibitor of FAS.

These enzymes are essential for fatty acid synthesis, as they enable the sequential addition of two-carbon units to the growing fatty acid chain using acetyl-CoA, malonyl-CoA, and NADPH as substrates. Fatty acid synthesis is a highly coordinated and regulated process that produces palmitate as the main product, which can then be further modified by other enzymes to produce different types of fatty acids.

Fatty acid synthesis is regulated by the availability of substrates and the hormonal signals that reflect the metabolic state of the organism. The key enzyme that controls the rate of fatty acid synthesis is acetyl CoA carboxylase (ACC), which catalyzes the first committed step of the pathway: the conversion of acetyl CoA to malonyl CoA. ACC is regulated by both allosteric and covalent mechanisms.

Allosteric regulation

ACC is activated by citrate, a product of glycolysis that accumulates in the cytosol when there is excess glucose. Citrate binds to ACC and induces a conformational change that favors the formation of active filaments of the enzyme. Conversely, ACC is inhibited by palmitoyl CoA, the end product of fatty acid synthesis, which binds to ACC and promotes its dissociation into inactive protomers.

Covalent regulation

ACC is also regulated by reversible phosphorylation. In its dephosphorylated state, ACC is active and able to synthesize malonyl CoA. In its phosphorylated state, ACC is inactive and unable to catalyze the carboxylation reaction. The phosphorylation and dephosphorylation of ACC are mediated by different enzymes that respond to hormonal signals.

• Insulin stimulates fatty acid synthesis by activating a phosphatase that dephosphorylates and activates ACC. Insulin is secreted by the pancreas in response to high blood glucose levels, indicating a fed state and a surplus of energy.
• Glucagon and epinephrine inhibit fatty acid synthesis by activating a kinase that phosphorylates and inactivates ACC. Glucagon and epinephrine are hormones that are released during fasting or stress, signaling a low energy state and a need to mobilize stored fuels.

By regulating ACC activity, these hormones modulate the flux of acetyl CoA into fatty acid synthesis or oxidation, depending on the energy needs of the organism.

Fatty acid biosynthesis is a vital anabolic pathway in most organisms. Fatty acids are not only the major components of membranes, but also important energy storage molecules. Moreover, fatty acyl derivatives have various physiological functions, such as post-translational modification of proteins, signaling, and regulation of gene expression.

Fatty acid biosynthesis is essential for cell growth, as it provides the building blocks for membrane expansion and lipid-based signaling molecules. Fatty acids are also required for the synthesis of complex lipids such as phospholipids, sphingolipids, and cholesterol, which are involved in membrane structure and function, cell signaling, and intracellular trafficking.

Fatty acid biosynthesis is also important for cell differentiation, as it modulates the expression and activity of key transcription factors and enzymes that control cell fate and function. For example, fatty acids can regulate the differentiation of adipocytes, myocytes, hepatocytes, and immune cells by influencing the nuclear receptors PPARs (peroxisome proliferator-activated receptors), which are involved in lipid metabolism and inflammation.

Fatty acid biosynthesis is also crucial for maintaining cellular homeostasis, as it balances the supply and demand of energy and nutrients in response to environmental cues. Fatty acids can act as sensors and effectors of cellular stress, such as hypoxia, oxidative stress, nutrient deprivation, and infection. Fatty acids can also modulate the activity of metabolic pathways such as glycolysis, oxidative phosphorylation, and autophagy, which are essential for cellular survival and adaptation.

In summary, fatty acid biosynthesis is a critical process that contributes to various aspects of cellular physiology and pathology. Dysregulation of fatty acid biosynthesis can lead to metabolic disorders such as obesity, diabetes, cardiovascular disease, and cancer. Therefore, understanding the molecular mechanisms and regulation of fatty acid biosynthesis may provide new insights and therapeutic targets for these diseases.

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