Fatty acid synthesis

In biochemistry, fatty acid synthesis is the process by which fatty acids, the fundamental building blocks of fats, are derived from metabolic intermediates through the coordinated actions of enzymes.

Fatty acids (FAs), comprise a large group of chemically heterogeneous compounds. Each fatty acid is composed of a carboxylic acid attached to an aliphatic hydrocarbon chain, of which is either saturated or unsaturated. FAs prove crucial within the cell, as these molecules serve as the indispensable building blocks of cell membranes. FAs also provide dense, long-term energy sources for the cell, and the biosynthetic production of FAs is essential for maintaining cellular homeostasis.

Fatty acid biosynthetic pathways are highly evolutionarily conserved across species, though different enzymes and genetic organizations have evolved to reach similarities about the general pathway. In both animals and fungi, all fatty acid synthetic pathways utilize one multifunctional protein complex, type-I fatty acid synthase (FAS), which is divided into the type-Ia FAS (in fungi) and the type-Ib FAS (in animals). In most prokaryotes and in the plastids of plants, fatty acid synthesis occurs via type-II fatty acid synthase (FAS).

Fatty acid synthesis occurs in the cytosol, where there is a high NADPH/NADP+ ratio available to drive the reactions forward. FAs can be further processed in the endoplasmic reticulum, where they are joined to a glycerol backbone in groups of three to form triacylglycerol (TAG), or in pairs (with the addition of a polar head group on the C1 of glycerol) to form a phospholipid.

Fatty acids are classified according to the number of carbon double bonds present about the aliphatic hydrocarbon chain. Saturated fatty acids have no double bonds. Monounsaturated fatty acids have one double bond, while polyunsaturated fatty acids have two or more double bonds present about the hydrocarbon chain.

Saturated fatty acids are a primary constituent of glycerolipids, as well as the phospholipids and sphingolipids found in cellular membranes. Common saturated fatty acids include palmitic acid, butyric acid, and stearic acid, all of which contribute to LDL cholesterol levels and increase the risk of obesity, heart disease, and stroke. Monounsaturated fatty acids are also primary constituent of glycerolipids and cellular membrane structures. Monounsaturated fatty acids include oleic acid, palmitoleic acid, and vaccenic acid, which help lower LDL cholesterol and reduce the risk of heart disease and stroke. Polyunsaturated fatty acids are found in the phospholipids of cell membranes, and are also known to act as precursors for a variety of lipid signaling molecules. Common polyunsaturated fatty acids include the essential omega-3 and omega-6 fatty acids, which are crucial for brain, heart, and immune health.

While the degree of saturation is used to differentiate fatty acids and their chemical composition, the length of the aliphatic hydrocarbon chain also influences fatty acids and their biological roles. Carbon chain lengths can vary greatly within each class of fatty acids, with some having as few as 12-carbons (ie., dodecanoic acid) and others having as many as 30-carbons (ie., triacontanoic acid). Fatty acid chain length is known to shape several biophysical properties of the cellular membrane, such as membrane fluidity, microdomain formation, and the assembly of membrane-associated signaling platforms. Chain length can also alter cellular susceptibility to death or survival through modulation of membrane properties.

Interestingly, mammals are unable to synthesize polyunsaturated fatty acids de novo. While mammalian cells express the enzymes necessary for the conversion of carbohydrate-derived and protein-derived carbons into saturated and monounsaturated fatty acids, they lack the desaturase enzymes required for production of the limiting-reagent in polyunsaturated fatty acid synthesis. Thus, polyunsaturated fatty acids are considered essential, and must be acquired through dietary consumption.

Thus, for all non-essential fatty acids, FA synthesis occurs de novo, wherein fats are derived from simple precursors like carbohydrates (ie., glucose) via acetyl-CoA. De novo fatty acid synthesis primarily occurs in the cytosol of hepatocytes (ie., in the liver) and adipocytes (ie., in adipose tissue or fat). Fatty acids are also synthesized de novo within tissues with high metabolic demands, such as mammary glands (ie., for milk fat production during lactation), immune cells (ie., macrophages, B cells, T cells), and even within the brain (ie., during neurogenesis). Notably, although saturated and monounsaturated fatty acids are considered non-essential, both saturated and monounsaturated fatty acids can be synthesized de novo alongside polyunsaturated fatty acids.

De novo fatty acid synthesis is separated into two groups based on the compartment wherein fatty acid synthesis takes place: cytosolic fatty acid synthesis (FAS/FASI) and mitochondrial fatty acid synthesis (mtFAS/mtFASII).