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.de Carvalho, Carla C. C. R.; Caramujo, Maria José (9 October 2018). "The Various Roles of Fatty Acids". Molecules (Basel, Switzerland). 23 (10): 2583. doi:10.3390/molecules23102583. 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).Leibundgut, Marc; Maier, Timm; Jenni, Simon; Ban, Nenad (2008-12). "The multienzyme architecture of eukaryotic fatty acid synthases". Current Opinion in Structural Biology. 18(6): 714–725. doi:10.1016/j.sbi.2008.09.008Schweizer, Eckhart; Hofmann, Jörg (2004-09). "Microbial type I fatty acid synthases (FAS): major players in a network of cellular FAS systems". Microbiology and molecular biology reviews: MMBR. 68 (3): 501–517, table of contents. doi:10.1128/MMBR.68.3.501-517.2004 In most prokaryotes and in the plastids of plants, fatty acid synthesis occurs via type-II fatty acid synthase (FAS).White S.W., Zheng J., Zhang Y.M., Rock C.O. The structural biology of type II fatty acid biosynthesis. Annu. Rev. Biochem. 2005;74:791–831. Doi: 10.1146/annurev.biochem.74.082803.133524.Harwood J.L. Fatty acid metabolism. Annu. Rev. Plant Physiol. Plant Mol. Biol. 1988;39:101–138. doi: 10.1146/annurev.pp.39.060188.000533.Harwood J.L. Recent advances in the biosynthesis of plant fatty acids. Biochim. Biophys. Acta (BBA) Lipids Lipid Metab. 1996;1301:7–56. doi: 10.1016/0005-2760(95)00242-1.
Fatty acid synthesis occurs in the cytosol, where there is a high NADPH/NADP+ ratio available to drive the reactions forward.Chandel, Navdeep S. (1 September 2021). "Lipid Metabolism". Cold Spring Harbor Perspectives in Biology. 13 (9): a040576. doi:10.1101/cshperspect.a040576 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.Suburu, Janel; Gu, Zhennan; Chen, Haiqin; Chen, Wei; Zhang, Hao; Chen, Yong Q. (1 December 2013). "Fatty acid metabolism: Implications for diet, genetic variation, and disease". Food Bioscience. 4: 1–12. doi:10.1016/j.fbio.2013.07.003 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 (i.e., dodecanoic acid) and others having as many as 30-carbons (i.e., 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.Yilmaz, Mustafa; Claiborn, Kathryn C.; Hotamisligil, Gökhan S. (2016-07). "De Novo Lipogenesis Products and Endogenous Lipokines". Diabetes. 65 (7): 1800–1807. doi:10.2337/db16-0251
Thus, for all non-essential fatty acids, FA synthesis occurs de novo, wherein fats are derived from simple precursors like carbohydrates (i.e., glucose) via acetyl-CoA. De novo fatty acid synthesis primarily occurs in the cytosol of hepatocytes (i.e., in the liver) and adipocytes (i.e., in adipose tissue or fat). Fatty acids are also synthesized de novo within tissues with high metabolic demands, such as mammary glands (i.e., for milk fat production during lactation), immune cells (i.e., macrophages, B cells, T cells), and even within the brain (i.e., during neurogenesis).Gonzalez-Bohorquez, Daniel; Gallego López, Isabel M.; Jaeger, Baptiste N.; Pfammatter, Sibylle; Bowers, Megan; Semenkovich, Clay F.; Jessberger, Sebastian (11 January 2022). "FASN-dependent de novo lipogenesis is required for brain development". Proceedings of the National Academy of Sciences of the United States of America. 119(2): e2112040119. doi:10.1073/pnas.2112040119 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).
Fatty Acid Nomenclature
Generally, fatty acids (FAs) can be defined as organic compounds containing a carboxyl group (–COOH) at one end of an aliphatic hydrocarbon chain (also called the "front" end of the molecule), and a methyl group (–CH3) at the opposite end (also called the "methyl" end of the molecule). Fatty acid chains commonly contain anywhere from 4 to 24 carbon atoms, but they are known to reach up to 44 carbon atoms in length. Fatty acid chains typically contain an even number of carbon atoms (i.e., 10, 12, 16) and a linear structure about the acyl chain, though both odd-numbered and branched fatty acids also exist.
Fatty acids can be categorized according to the degree of saturation (number of double bonds) present about the aliphatic hydrocarbon chain. Saturated fatty acids (SFAs) have no double bonds. Monounsaturated fatty acids (MUFAs) have one double bond, while polyunsaturated fatty acids (PUFAs) have two or more double bonds present about the acyl chain.
Two discrete nomenclature systems are used for describing fatty acids: omega (ω–x) nomenclature and delta (Δ) nomenclature, in addition to simple common names. Within the fields of medicine and nutrition, both common names and omega nomenclature are frequently used to discuss fatty acids. In biochemistry and lipids research, fatty acid common names, omega nomenclature, and delta nomenclature are all widely used, but delta nomenclature is more typically seen in discussions on specific fatty acids.
Additionally, common fatty acid names are often denoted alongside a shorthand notation (i.e., palmitic acid (C16:0)). Herein, the total number of carbons about the fatty acid is listed prior to the total number of double bonds present within the molecule, and is generally formatted as is seen in Example 1. for palmitic acid (C16:0) and palmitoleic acid (C16:1).
(ω-x) Nomenclature System
In biochemistry, the most prevalent, internationally accepted system of nomenclature for fatty acids is defined by the International Union of Pure and Applied Chemistry (IUPAC). Herein, the ω-x system (also known as the omega x or n-x system) establishes that fatty acids can be identified through the following formation: C:Dω–x
where C is the total number of carbons, D is the number of double bonds, and ω–x indicates the position of the first double bond, counting from the –CH3 end of the fatty acid. The ω–x system curbs ambiguity regarding SFAs and MUFAs, as it specifically denotes both the carbon and unsaturation numbers, as well as the location of the double bond (i.e., for MUFAs). Equally, ω–x nomenclature is widely used for PUFAs, particularly for those wherein two consecutive double bonds are consistently separated by a methylene group (–CH2–). However, several PUFAs contain double bonds that are not always interrupted by a methylene group, and thus the ω–x system fails to establish the specific position of all double bonds about PUFA chains. As such, these atypical PUFAs are generically referred to as "non-methylene interrupted" (NMI) fatty acids, and are commonly found in lipids from marine invertebrates.
(Δ) Nomenclature System
Using fundamental principles established by IUPAC, the delta (Δ) system for lipid notation was developed by researchers within the mid-20th century, to address the need for distinction between fatty acids with the same acyl chain length but different double bond positions. Thus, the Δ system defines the position of double bonds by virtue of the carboxyl (–COOH) carbon using the general formula: C:DΔy
where C is the total number of carbons, D is the number of double bonds, and Δy indicates the position of each double bond, counting from the –COOH end of the fatty acid. Unlike the omega nomenclature system, each double bond of the fatty acid must be described in the delta system.
Cytosolic Fatty Acid Synthesis
While essential fatty acids (i.e., linoleic acid) are obtained exclusively through diet, all non-essential fatty acids must be synthesized de novo. Acetyl-CoA is the precursor used for fatty acid synthesis in the cytosol; therefore, fatty acid synthesis requires those reactions which produce acetyl-CoA—namely, glycolysis or amino acid metabolism. Regardless of the metabolic source of the product, all de novo lipogenesis relies on the production and availability of cytosolic acetyl-CoA, and thereafter on its conversion into malonyl-CoA.