Fatty acid synthesis is the process by which fatty acids are synthesized from acetyl-CoA and NADPH using enzymes known as fatty acid synthases. This procedure occurs in the cell's cytoplasm. The glycolytic process provides the majority of the acetyl-CoA that is transformed into fatty acids. However, some of this acetyl-CoA may also be derived from the citric acid cycle through enzymatic reactions that transfer acetate groups onto alpha-ketoglutarate. Alternatively, it has been suggested that acetyl-CoA can be generated directly from glucose by means of gluconeogenesis.
In addition to its role in fatty acid biosynthesis, acetyl-CoA is also required for the formation of many other cellular compounds including sterols, neurotransmitters, ubiquinones, and collagen. Thus, cells need efficient pathways to convert acetyl-CoA into these various products.
Acetyl-CoA can be converted into fatty acids by two different pathways: the fatty acid synthase (FAS) pathway and the polyketide synthase (PKS) pathway. Both pathways use similar steps to produce a carbon chain of variable length between acetyl-CoA and a terminal methyl group donated by S-adenosyl methionine. The difference is that FAS uses repetitive cycles of enzyme activities to add several carbons at a time, while PKS typically adds one carbon at a time.
Acetyl-CoA is solely the direct precursor of the methyl end of the developing fatty acid chain in fatty acid synthesis. Malonyl-CoA formation is the commitment step for fatty acid synthesis since malonyl-CoA serves no metabolic function other than as a precursor to fatty acids. The conversion of acetyl-CoA to malonyl-CoA is catalyzed by the enzyme acetyl-CoA carboxylase.
Fatty acids are activated by the addition of an alcohol group to their carboxylic acid tail. This reaction is called "esterification". Fatty acids are also oxidized to generate energy under conditions of oxygen deprivation or when this process is beneficial instead of using energy directly from food. This reaction is called "beta-oxidation". Both reactions occur in the cell membrane and require enzymes called lipases for activation. Acetyl-CoA can also be converted into ketone bodies used as an alternative fuel source for brain cells during periods of starvation or when glucose levels in the blood are low. Ketone bodies are also used as an energy source by some cancer cells.
The body uses fatty acids for structural integrity of cellular membranes, for storage, and for signaling functions. The amount of fatty acid present in cells is regulated by hormones such as insulin and glucagon which stimulate or inhibit their uptake into cells. Cellular uptake of fatty acids occurs through specific protein receptors located on the cell surface.
Fatty acids are broken down to acetyl-CoA inside the mitochondria by beta oxidation, whereas fatty acids are generated from acetyl-CoA outside the mitochondria, in the cytoplasm. Instead, acetyl-CoA generated by fatty acid beta-oxidation condenses with oxaloacetate to enter the citric acid cycle. The entry point is controlled by a protein complex called ACSS2, which activates the synthesis of this enzyme by binding to its promoter region.
There are three enzymes in the citric acid cycle that are involved in converting glucose into carbon dioxide and water using oxygen as a byproduct: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and succinate dehydrogenase. These enzymes are present in all cells except for red blood cells which lack an electron transport system. Glucose enters the cell through membrane channels or via glycolysis, which is why many tumors use up all their glucose via anaerobic metabolism resulting in increased levels of lactate in the blood. This phenomenon is known as aerobic glycolysis or the "Warburg effect" after the scientist who first described it in 1956. Tumors also produce large amounts of lactic acid because they don't have enough oxygen to remove it efficiently. Thus, inhibiting any of these enzymes would block conversion of glucose into carbon dioxide and water, leading to death of the cell.
In most organisms, fatty acid production is an important anabolic process. Fatty acids are key energy-storage molecules in addition to being a major component of membranes, and fatty acid derivatives have a number of physiological activities, including post-translational modification of various proteins. The main function of fatty acid synthesis is to provide cells with carbon sources for biomass formation and membrane expansion. In prokaryotes, the anabolic role of fatty acid synthesis is replaced by that of membrane biogenesis. However, some bacteria use fatty acid synthase to produce conjugated linoleic acid, which is a polyunsaturated fatty acid with potential health benefits.
In eukaryotes, fatty acid synthesis occurs in the cytoplasm and involves approximately 10 steps. Fatty acid synthases are large multienzymatic complexes that catalyze the elongation of acetyl-CoA units derived from either glucose or pyruvate. They have a molecular mass of about 100 kD and contain both large and small subunits. The large subunit contains all of the activity required for initiating chain elongation and transferring the acyl group from its substrate to the C-1 position of CoA, whereas the small subunit provides additional enzymatic activities that terminate chain elongation and that alter the substrate specificity of the enzyme.
The only source of fatty acids for these processes is the uptake of lipids from the blood.
Acetyl-CoA can also be formed from pyruvate, which occurs during glucose metabolism via glycolysis or the pentose phosphate pathway. Pyruvate also contributes to the synthesis of alanine and aspartate.
The conversion of fatty acids into ketone bodies occurs mainly in the liver. Fatty acid oxidation produces more reactive oxygen species than does glucose oxidation (which instead yields water). Thus, increased lipid peroxidation has been observed in obese individuals compared with normal-weight individuals. Oxidative stress may play a role in the development of obesity-related diseases such as type 2 diabetes and cardiovascular disease.
Ketones reduce the effectiveness of chemotherapy by binding to serum albumin, preventing it from reaching cancer cells. However, this effect is not seen with glucose deprivation therapy, indicating that it is specifically due to the action of ketones rather than being a general property of depleted nutrients.
When ATP is plentiful, acetyl-CoA can be redirected to other uses, such as energy storage in the form of fatty acids. However, fatty acid biosynthesis cannot proceed directly from this acetyl-CoA since it is synthesized inside the mitochondria whereas fatty acid biosynthesis happens in the cytoplasm.
Fatty acids are degraded by gradually cleaving two carbon atoms and turning them to acetyl coenzyme A. The citric acid cycle, which is also involved in the metabolism of glucose, oxidizes acetyl CoA. Carbon dioxide and water are released as waste products.
Acetyl CoA can be used to make other molecules such as cholesterol, hormones, and neurotransmitters. It is converted into oxalacetate by oxaloacetate decarboxylase. Oxalacetate is then converted into pyruvate and ammonia by enzymes called oxalacetate transaminases. Pyruvate can then be converted into alanine or lactate. Lactate is removed from cells through transport proteins and discharged into the blood stream. Alanine is removed through a protein called alanine aminotransferase (ALT). When ALT is present in higher concentrations in the blood, this means that more alanine is being removed from cells.
Alanine can be converted back into pyruvate and glutamate by enzymes called alanine transaminases. Glutamate can then be converted into alpha-ketoglutarate (α-KG) and removed from the cell through membrane transporters for amino acids. Α-KG can also be converted into succinyl CoA and removed from the cell.