Fatty acid
A fatty acid is an organic molecule consisting of a hydrocarbon chain attached to a terminal carboxylic acid group, typically featuring an even number of carbon atoms ranging from 14 to 24 in biological systems.[1] These compounds serve as the primary structural components of complex lipids such as triglycerides, phospholipids, and sterols, playing essential roles in energy storage, cell membrane integrity, and signaling pathways.[1] In nature, fatty acids are classified based on chain length (short-, medium-, or long-chain), degree of saturation, and the position of double bonds, with most occurring as cis isomers in living organisms.[1] Fatty acids are broadly categorized into saturated and unsaturated types. Saturated fatty acids contain no carbon-carbon double bonds, resulting in a straight chain that allows them to pack tightly, often appearing solid at room temperature; examples include palmitic acid (16:0) and stearic acid (18:0), commonly found in animal fats and tropical oils like coconut oil.[2] Unsaturated fatty acids, in contrast, feature one or more double bonds: monounsaturated types have a single double bond (e.g., oleic acid, 18:1n-9, abundant in olive oil), while polyunsaturated fatty acids (PUFAs) have multiple double bonds (e.g., linoleic acid, 18:2n-6).[2] These double bonds introduce kinks in the chain, making unsaturated fats liquid at room temperature and more fluid in biological membranes.[2] Trans fatty acids, which have trans-configured double bonds, occur rarely in nature but are produced industrially through partial hydrogenation of oils, contributing to adverse health effects like elevated LDL cholesterol.[2] Biologically, fatty acids are indispensable for maintaining cellular homeostasis and physiological functions. They form the backbone of phospholipids in cell membranes, influencing membrane fluidity and permeability, and are stored as triglycerides in adipose tissue for long-term energy reserves.[1] Certain polyunsaturated fatty acids, known as essential fatty acids, cannot be synthesized by humans due to the absence of specific desaturase enzymes and must be obtained through diet; these include omega-6 linoleic acid (LA) and omega-3 alpha-linolenic acid (ALA), which serve as precursors for longer-chain derivatives like arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).[3] These essential fatty acids are critical structural elements in neural tissues (e.g., DHA in the brain and retina) and generate bioactive mediators such as eicosanoids, which regulate inflammation, blood clotting, and immune responses.[3] Deficiencies in essential fatty acids can impair growth, skin integrity, and cardiovascular health, underscoring their role in preventing chronic diseases.[3]History
Early Discovery and Isolation
The early discovery of fatty acids traces back to the work of French chemist Michel Eugène Chevreul in the early 19th century. In 1811, Chevreul began systematic investigations into the composition of soaps derived from animal fats, prompted by his mentor Nicolas-Louis Vauquelin. By acidifying soap solutions, he isolated crystalline substances that displayed acidic properties and could form salts with bases, leading him to coin the term "acides gras" (fatty acids) to describe these compounds extracted from natural fats.[4][5] His observations marked the first recognition of fatty acids as distinct chemical entities separable from the glycerol backbone of fats. Chevreul's experiments in the 1810s and 1820s focused on saponifying various animal and plant lipids to liberate the free fatty acids, followed by purification techniques such as recrystallization of their metal salts (e.g., barium or lead salts) to achieve separation based on solubility differences. From these efforts, he isolated and named several key fatty acids, including stearic acid from mutton fat in 1817, oleic acid from olive and pork fats around 1819, and margaric acid (later identified as a mixture) from various sources in 1816. These isolations revolutionized the understanding of fat chemistry, demonstrating that natural fats were esters of glycerol and these organic acids, and enabling practical applications in soap and candle production through a 1825 patent with Joseph Louis Gay-Lussac for stearic acid-based products.[6][4] Throughout the 19th century, refinements in experimental methods advanced the isolation of individual fatty acids from complex mixtures in animal tallows, plant oils, and other lipids. Saponification—boiling fats with alkali hydroxides to hydrolyze esters into glycerol and fatty acid salts—emerged as the foundational technique, with subsequent acidification yielding the free acids; this process, formalized by Chevreul, allowed scalable extraction from natural sources. Complementary advancements included fractional distillation of the freed acids under reduced pressure to separate them by boiling point differences, particularly effective for liquid unsaturated acids like oleic. These methods facilitated broader access to pure compounds for analysis and industry, with early applications in refining animal fats for margarine production by the mid-century.[7][6] Notable milestones in specific isolations during this period include palmitic acid, obtained in 1840 by French chemist Edmond Frémy through saponification of palm oil, highlighting the diversity of plant-derived fatty acids. Similarly, myristic acid was first isolated in 1841 by British chemist Lyon Playfair from nutmeg (Myristica fragrans) butter via hydrolysis and crystallization. The carboxylic acid nature of these compounds was empirically confirmed through their salt-forming behavior, akin to known acids like acetic, and further validated in the 1840s by oxidation studies conducted by Justus von Liebig and contemporaries, which degraded the acids to carbon dioxide, water, and simpler carboxylates consistent with a -COOH functional group at one end of an aliphatic chain.[8][9][7]Key Milestones in Research and Classification
In 1929, George O. Burr and Mildred Burr demonstrated that rats on a fat-free diet developed severe symptoms, including growth retardation and skin lesions, which could only be alleviated by supplementing with specific unsaturated fats, thereby establishing linoleic acid (an omega-6 polyunsaturated fatty acid) as an essential nutrient that mammals cannot synthesize de novo.[10] Their subsequent work in the early 1930s extended this finding to alpha-linolenic acid (an omega-3 polyunsaturated fatty acid), confirming it as another essential fatty acid required for preventing deficiency symptoms like scaly skin and reproductive failure.[11] This breakthrough shifted the understanding of dietary fats from mere energy sources to vital components for membrane integrity and physiological function. During the 1950s, Eugene P. Kennedy and Albert L. Lehninger elucidated the mitochondrial beta-oxidation pathway, revealing how fatty acids are sequentially shortened by two-carbon units to generate acetyl-CoA for energy production via the citric acid cycle and oxidative phosphorylation.[12] Their experiments with isolated rat liver mitochondria demonstrated that fatty acid oxidation is tightly coupled to ATP synthesis, providing a mechanistic link between lipid catabolism and cellular energy metabolism that explained the high caloric yield of fats.[13] This work built on earlier hypotheses and laid the foundation for studying metabolic disorders involving defective beta-oxidation. In the 1970s, Sune Bergström and Bengt I. Samuelsson identified eicosanoids, a class of bioactive lipids derived from polyunsaturated fatty acids like arachidonic acid, including prostaglandins that mediate inflammation, pain, and vascular regulation.[14] Their structural elucidation of these compounds, showing how they arise from enzymatic oxidation of C20 polyunsaturated fatty acids, highlighted their roles in physiological signaling and disease. This research earned them the 1982 Nobel Prize in Physiology or Medicine (shared with John R. Vane), transforming fatty acids from structural molecules into precursors of potent regulatory mediators.[15] In 2023, researchers at Queensland University of Technology (QUT) employed ozone-enabled mass spectrometry to identify 103 previously unknown unsaturated fatty acids in human plasma, cerebrospinal fluid, and adipose tissue samples, effectively doubling the catalog of known human-derived unsaturated fatty acids.[16] This discovery revealed unexpected structural diversity, including branched and cyclic variants, and underscored the need for advanced lipidomics tools to map the full human lipidome, potentially aiding biomarker discovery for metabolic and neurological conditions.[17] From 2023 to 2025, studies have advanced the understanding of omega-3 polyunsaturated fatty acids' roles in health maintenance, with a comprehensive MDPI review indicating that supplementation preserves muscle strength in older adults by modulating inflammation and supporting protein synthesis, showing small but significant effects in randomized trials.[18] Concurrently, research reported in ScienceDaily highlighted that higher circulating levels of omega-3 fatty acids were associated with better lung function and slower decline in individuals with and without chronic obstructive pulmonary disease (COPD), suggesting benefits for maintaining respiratory health.[19]Definition and Structure
Chemical Composition
Fatty acids are aliphatic carboxylic acids consisting of a hydrocarbon chain attached to a carboxyl group. The general formula for saturated fatty acids is CH_3(CH_2)_nCOOH, where n \geq 2, comprising a polar carboxylic acid head (-COOH) and a nonpolar hydrocarbon tail.[20] Naturally occurring fatty acids typically feature unbranched carbon chains of 4 to 28 atoms in length, with even-numbered chains predominating due to their biosynthesis from successive two-carbon acetyl-CoA units.[21] At physiological pH, the carboxyl group (-COOH) deprotonates to form a carboxylate anion (-COO^-), as exemplified by stearate derived from stearic acid.[22] This combination of a charged, hydrophilic head and a hydrophobic tail renders fatty acids amphipathic.[23]Physical and Chemical Properties
Fatty acids display a range of physical states at room temperature that depend on their carbon chain length. Short-chain fatty acids containing 4 to 6 carbon atoms, such as butyric acid, exist as colorless liquids with melting points below 0°C; for example, butyric acid has a melting point of -7.9°C.[24] Medium-chain fatty acids with 8 to 12 carbons are typically oily liquids or waxy solids with low melting points, while long-chain fatty acids with 14 or more carbons are white solids; stearic acid, for instance, melts at 69.3°C.[25] These trends arise because longer chains enable greater van der Waals interactions, raising melting points progressively with chain length.[26] Regarding solubility, fatty acids are poorly soluble in water due to the hydrophobic nature of their nonpolar alkyl chains, which dominate over the polar carboxylic acid group, leading to insolubility for chains longer than about 10 carbons.[27] In contrast, they dissolve readily in nonpolar organic solvents like chloroform, ethanol, and ether, where the hydrocarbon tails interact favorably.[28] At higher concentrations in aqueous media, fatty acids can function as surfactants, self-assembling into micelles above their critical micelle concentration (CMC), which varies with chain length but typically falls in the millimolar range for medium- to long-chain acids.[29] Chemically, fatty acids behave as weak carboxylic acids with pKa values of approximately 4.5 to 5.0, rendering them weaker than simple carboxylic acids like acetic acid (pKa 4.76) because the extended alkyl chain exerts an electron-donating inductive effect that stabilizes the neutral form.[30][31] This acidity is described by the ionization equilibrium: \ce{R-COOH ⇌ R-COO^- + H^+} where R represents the alkyl chain. Trends in density and viscosity are influenced by saturation level and chain length. Density generally decreases with unsaturation due to looser molecular packing from cis double bonds; for example, oleic acid (C18:1) has a density of 0.89 g/cm³ at 25°C (liquid), while saturated stearic acid (C18:0) has a density of 0.94 g/cm³ at 20°C (solid).[32] Viscosity follows a similar pattern, with unsaturated fatty acids showing reduced values compared to their saturated counterparts owing to decreased intermolecular forces.[33]Classification
By Carbon Chain Length
Fatty acids are classified by the length of their carbon chain, which influences their physical properties, metabolic pathways, and biological roles. Short-chain fatty acids (SCFAs) contain 2 to 6 carbon atoms, medium-chain fatty acids (MCFAs) have 8 to 12 carbons, long-chain fatty acids (LCFAs) range from 14 to 20 carbons, and very long-chain fatty acids (VLCFAs) exceed 20 carbons.[34] This categorization highlights how chain length affects volatility, absorption rates, and incorporation into cellular structures. Short-chain fatty acids (SCFAs), with 2 to 6 carbons, are volatile compounds primarily produced through microbial fermentation of dietary fibers in the gut. Acetic acid (C2:0), a key SCFA, is the main component of vinegar and contributes to its characteristic odor. Butyric acid (C4:0) is found in butter, where it constitutes about 4% of total fatty acids, and plays a role in gut health by serving as an energy source for colonocytes. These SCFAs are rapidly metabolized and influence host physiology, including immune modulation.[35][36][37] Medium-chain fatty acids (MCFAs), spanning 8 to 12 carbons, are distinguished by their rapid absorption and oxidation, bypassing the need for carnitine-dependent transport into mitochondria. Caprylic acid (C8:0), abundant in coconut oil, exemplifies MCFAs and is a primary component of medium-chain triglyceride (MCT) oils used for quick energy provision, particularly in clinical nutrition for malabsorption disorders. MCFAs provide immediate energy due to their efficient hepatic metabolism.[38][39][40] Long-chain fatty acids (LCFAs), with 14 to 20 carbons, predominate in human diets and form the structural backbone of most membrane lipids. Palmitic acid (C16:0) is the most abundant saturated LCFA in the diet, comprising about 55% of dietary saturated fats, and is integral to phospholipids in cell membranes. LCFAs are essential for energy storage and signaling but require specific transport mechanisms for utilization.[41][42] Very long-chain fatty acids (VLCFAs), with more than 20 carbons, are enriched in specialized tissues such as skin and myelin sheaths, where they constitute significant portions of sphingomyelin and glycerophospholipids. Lignoceric acid (C24:0) is a prominent VLCFA in these structures, supporting barrier function and neural insulation. Accumulation of VLCFAs, including lignoceric acid, is a hallmark of X-linked adrenoleukodystrophy, a peroxisomal disorder leading to demyelination and adrenal insufficiency.[34][43] The length of the fatty acid chain critically impacts beta-oxidation, as different enzymes exhibit specificity for chain lengths: short- and medium-chain acyl-CoA dehydrogenases handle SCFAs and MCFAs, while long- and very long-chain variants process LCFAs and VLCFAs, primarily in peroxisomes for the latter. This enzymatic partitioning ensures efficient energy extraction tailored to chain size.[44][45]By Degree of Unsaturation
Fatty acids are classified by degree of unsaturation based on the number of carbon-carbon double bonds in their hydrocarbon chain, which influences their chemical reactivity, physical properties, and biological roles.[46] Saturated fatty acids contain no double bonds, making their chains fully hydrogenated and linear, which allows tight molecular packing and results in higher melting points compared to unsaturated counterparts.[47] A representative example is palmitic acid, denoted as 16:0, with 16 carbon atoms and zero double bonds, commonly found in animal fats and palm oil.[3] Monounsaturated fatty acids feature exactly one carbon-carbon double bond, typically in the cis configuration, introducing a kink in the chain that disrupts packing and lowers the melting point.[47] Oleic acid, or 18:1 Δ9 cis, exemplifies this class, comprising the majority of fatty acids in olive oil and contributing to its liquid state at room temperature.[48] Polyunsaturated fatty acids (PUFAs) possess two or more double bonds, most often cis, leading to multiple kinks that further reduce packing efficiency and increase susceptibility to oxidation due to the reactive allylic positions adjacent to the double bonds.[49] Linoleic acid (18:2 Δ9,12), an omega-6 PUFA, and alpha-linolenic acid (ALA; 18:3 Δ9,12,15), an omega-3 PUFA, illustrate this category, with the omega designation indicating the position of the first double bond from the methyl end of the chain.[3] The standard notation for fatty acids integrates chain length and unsaturation as "total carbons:number of double bonds" (e.g., 18:3 for ALA), often followed by double bond positions using the delta (Δ) system, which numbers from the carboxyl carbon, or the omega (ω) system from the methyl end; cis or trans isomerism is specified, as trans configurations promote straighter chains and better packing similar to saturated acids. This notation also links to chain length classification by specifying total carbons upfront. In 2023, researchers identified 103 previously unknown unsaturated fatty acids in human samples using ozonolysis-mass spectrometry, including novel polyunsaturated variants with unconventional double bond patterns, effectively doubling the cataloged diversity of these lipids in human plasma.[16]By Chain Configuration
Fatty acids are classified by chain configuration into even-chain, odd-chain, branched-chain, and cyclic forms, each arising from distinct biosynthetic pathways and serving specialized roles in organisms. Even-chain fatty acids, such as palmitic acid (C16:0) and stearic acid (C18:0), predominate in most biological systems and are synthesized via the fatty acid synthase complex using acetyl-CoA as the initial primer unit, followed by sequential additions of two-carbon malonyl-CoA units.[50] This process results in chains with an even number of carbon atoms, which form the structural backbone of membrane lipids and energy storage in animals, plants, and microorganisms.[51] In contrast, odd-chain fatty acids, exemplified by pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0), are less common and initiate synthesis with propionyl-CoA as the starter unit instead of acetyl-CoA, leading to chains terminating in an odd number of carbons after malonyl-CoA extensions.[51] These fatty acids occur in minor proportions in most tissues but are more prevalent in ruminant-derived products, such as milk fat and meat, due to microbial fermentation in the rumen that generates propionyl-CoA from dietary fiber and amino acids.[52] For instance, odd-chain fatty acids constitute about 4-6% of total fatty acids in bovine milk, reflecting the unique gut microbiome of ruminants.[53] Branched-chain fatty acids deviate from linear structures through methyl substitutions along the chain, with iso- and anteiso- forms being prominent in bacterial membranes. Iso-branched fatty acids, such as isopalmitic acid (14-methylpentadecanoic acid), feature a methyl group at the penultimate carbon, while anteiso- forms, like anteisoheptadecanoic acid (12-methylhexadecanoic acid), have the branch at the antepenultimate position; both are produced by bacteria using branched-chain acyl-CoA primers derived from amino acid catabolism to adjust membrane fluidity and packing.[54] In ruminants, these bacterial-derived branched chains transfer to host tissues, comprising up to 4% of milk fat.[55] Another notable branched fatty acid is phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a highly branched saturated chain originating from the phytol tail of chlorophyll in plant forages, which ruminant microbes cleave and incorporate into lipids before absorption by the host.[55] Cyclic fatty acids represent a rare configuration, primarily featuring small ring structures integrated into the chain to enhance membrane stability. In bacteria, cyclopropane fatty acids incorporate a three-membered cyclopropane ring adjacent to the carboxyl group or at internal positions, formed post-synthesis by cyclopropane fatty acid synthases that transfer a methylene group from S-adenosylmethionine to an unsaturated precursor double bond.[56] These rings increase membrane rigidity and impermeability, allowing bacteria like Escherichia coli to maintain fluidity under environmental stresses such as low pH or desiccation without altering overall chain length or saturation.[57] Cyclic forms are scarce in eukaryotes but can arise in certain pathological conditions or from dietary sources. The metabolic implications of chain configuration extend beyond biosynthesis, influencing health outcomes in higher organisms. Odd-chain fatty acids, particularly C15:0 and C17:0, have been epidemiologically linked to reduced risk of type 2 diabetes, with higher circulating levels associated with 14-24% lower risk in prospective cohorts, potentially due to their roles in mitochondrial function and anti-inflammatory signaling.[58] Branched-chain fatty acids similarly modulate metabolism through altered lipid peroxidation and membrane dynamics.[54] Cyclic fatty acids, while primarily microbial, underscore how chain variations fine-tune biophysical properties like phase transitions in lipid bilayers.[59]Nomenclature
Systematic Naming Conventions
The systematic nomenclature of fatty acids follows the recommendations of the International Union of Pure and Applied Chemistry (IUPAC) and the International Union of Biochemistry and Molecular Biology (IUPAC-IUBMB), which provide a structured approach based on the carbon chain length, degree of saturation, and configuration of double bonds.[60][61] For saturated fatty acids, the IUPAC name is derived from the corresponding alkane by replacing the "-ane" ending with "-anoic acid," where the carboxyl carbon is designated as carbon 1 (C-1). For example, the 18-carbon saturated fatty acid, commonly known as stearic acid, is systematically named octadecanoic acid.[60][62] Unsaturated fatty acids incorporate the suffix "-enoic acid" for one double bond (or "-dienoic acid" for two, and so on), with locants indicating the positions of the double bonds relative to C-1. The geometry of each double bond is specified using the E/Z designation, where Z corresponds to cis configuration and E to trans. A representative example is oleic acid, named (9Z)-octadec-9-enoic acid, indicating an 18-carbon chain with a cis double bond between carbons 9 and 10.[60][61] Double bond positions can also be denoted using delta (Δ) notation, which marks the lower-numbered carbon of the double bond counting from C-1 (e.g., Δ^9 for a double bond between C-9 and C-10), or omega (ω) notation, which counts from the methyl terminus (e.g., ω-3 for a double bond between C-3 and C-4 from the end). These notations are often used in shorthand alongside the systematic name, such as 18:2(Δ^9,Δ^{12}) for linoleic acid. For polyunsaturated acids with multiple double bonds, all positions and configurations are listed in ascending order, as in (9Z,12Z)-octadeca-9,12-dienoic acid for linoleic acid.[61][60] Trivial names for fatty acids often originate from their natural sources or historical isolation contexts. For instance, oleic acid derives its name from the Latin oleum, meaning oil, reflecting its abundance in olive and other plant oils. Similarly, arachidonic acid's name stems from arachidic acid, which was first isolated from peanut oil (Arachis hypogaea), with the prefix "arach-" adapted from the genus name.[32][63]Common Names and Shorthand Notations
Fatty acids are frequently referred to by common names derived from their primary natural sources, facilitating their identification in nutritional, biochemical, and industrial contexts. For instance, palmitic acid is named after palm oil, where it constitutes about 40% of the fatty acids; stearic acid derives from suet or animal fat, comprising 5-40% in ruminant fats; oleic acid from olive oil, its major constituent; and linoleic acid from linseed oil, present in virtually all seed oils.[64] These names provide a practical bridge to their systematic IUPAC equivalents, such as hexadecanoic acid for palmitic acid, as detailed in formal nomenclature conventions. In biochemical and nutritional literature, fatty acids are commonly denoted using shorthand notations that indicate chain length and degree of unsaturation. The general format is C_n:m, where n represents the number of carbon atoms and m the number of double bonds; for example, linoleic acid is abbreviated as 18:2, signifying 18 carbons and 2 double bonds. Double bond positions can be specified using Δ notation from the carboxyl end, such as 18:2(Δ9,12) for linoleic acid, or omitted when contextually clear. In biological systems, unsaturated fatty acids are typically assumed to have all-cis configurations unless otherwise stated. An alternative notation, particularly useful in nutrition and physiology, is the omega (ω) or n- system, which counts the position of the first double bond from the methyl (ω) end of the chain. This highlights the family classification, such as ω-3 for alpha-linolenic acid (ALA, 18:3 n-3), where the double bonds begin at the third carbon from the methyl terminus.[65] Similarly, linoleic acid is classified as 18:2 n-6. This system is essential for distinguishing essential fatty acid families like n-3 and n-6 polyunsaturated fatty acids (PUFAs).[65] The following table summarizes major dietary fatty acids, categorized by saturation, with representative examples, their shorthand notations, and primary sources:| Category | Common Name | Shorthand Notation | Primary Dietary Sources |
|---|---|---|---|
| Saturated (SFA) | Lauric acid | 12:0 | Coconut and palm kernel oils[64] |
| Saturated (SFA) | Palmitic acid | 16:0 | Palm oil, meat, dairy[64] |
| Saturated (SFA) | Stearic acid | 18:0 | Animal fats, cocoa butter[64] |
| Monounsaturated (MUFA) | Oleic acid | 18:1 n-9 | Olive oil, avocados, nuts[64] |
| Polyunsaturated (PUFA) | Linoleic acid | 18:2 n-6 | Seed oils (e.g., soybean, sunflower)[64] |
| Polyunsaturated (PUFA) | Alpha-linolenic acid (ALA) | 18:3 n-3 | Flaxseed, chia seeds, walnuts[65] |
| Polyunsaturated (PUFA) | Docosahexaenoic acid (DHA) | 22:6 n-3 | Fatty fish (e.g., salmon), algae oils[65] |
Sources and Production
Biological Biosynthesis in Organisms
In eukaryotic organisms, the primary site of de novo fatty acid biosynthesis is the cytosol, where the multifunctional fatty acid synthase (FAS) complex catalyzes the iterative assembly of saturated fatty acids from acetyl-CoA and malonyl-CoA precursors.[50] This type I FAS system operates through seven cycles of condensation, reduction, dehydration, and further reduction, starting with the priming of acetyl-CoA and incorporating seven malonyl-CoA units to yield palmitate (16:0), the most common product.[50] The overall reaction is: $8 \text{ acetyl-CoA} + 7 \text{ ATP} + 14 \text{ NADPH} \rightarrow \text{palmitate} + 14 \text{ NADP}^+ + 8 \text{ CoA} + 7 \text{ ADP} + 7 \text{ P}_i + 7 \text{ CO}_2 This process requires energy input from ATP for malonyl-CoA formation via acetyl-CoA carboxylase and reducing equivalents from NADPH, primarily generated by the pentose phosphate pathway.[50] Post-synthesis modifications occur in the endoplasmic reticulum (ER) or mitochondria, where elongases add two-carbon units from malonyl-CoA to the growing acyl chain, extending palmitate to longer fatty acids such as stearate (18:0).[66] These elongases, including ELOVL family members in animals and plants, facilitate the production of very-long-chain fatty acids essential for membrane structure and signaling.[66] Desaturation introduces double bonds via desaturase enzymes, which are oxygen-dependent and cytochrome b5-supported in eukaryotes. Plants possess Δ12 and Δ15 desaturases that enable synthesis of polyunsaturated fatty acids (PUFAs) like linoleic (18:2 ω-6) and α-linolenic (18:3 ω-3) acids from oleate and linoleate precursors, respectively, contributing to their high ω-3 content.[67] In contrast, animals lack Δ12 and Δ15 desaturases, limiting de novo PUFA production and rendering ω-6 and ω-3 fatty acids essential in their diets.[67] Microbial fatty acid biosynthesis exhibits diversity, with bacteria employing a dissociated type II FAS system comprising individual enzymes in the cytosol to produce primarily straight-chain saturated and monounsaturated fatty acids.[68] Many bacteria, such as those in the genus Bacillus, generate branched-chain fatty acids (e.g., iso- and anteiso-forms) by initiating synthesis with branched primers like isobutyryl-CoA derived from valine catabolism, which enhances membrane fluidity under stress.[69] In microalgae like Schizochytrium species, a polyketide synthase-like PUFA synthase pathway enables efficient de novo production of docosahexaenoic acid (DHA, 22:6 ω-3), serving as a rich natural source for this long-chain ω-3 PUFA.[70] Species-specific variations further diversify fatty acid profiles; for instance, plants accumulate abundant ω-3 PUFAs due to their desaturase repertoire, supporting chloroplast membrane integrity.[67] In ruminants, rumen microbial biohydrogenation converts dietary unsaturated fatty acids to even-chain saturated forms, such as transforming linoleic acid to stearic acid via isomerization and hydrogenation by bacteria like Butyrivibrio fibrisolvens, thereby altering the fatty acid composition absorbed in the small intestine.[71]Industrial Production Methods
Industrial production of fatty acids primarily involves the hydrolysis of triglycerides from natural fats and oils, yielding mixtures of saturated and unsaturated fatty acids alongside glycerol as a byproduct. Alkaline hydrolysis, or saponification, reacts triglycerides with sodium or potassium hydroxide under heat to form fatty acid salts (soaps) and glycerol; subsequent acidification liberates the free fatty acids. This method is commonly applied to vegetable sources like palm and soy oils, which provide high volumes of mixed fatty acids for oleochemical applications.[72][73] Acid hydrolysis, often catalyzed by sulfuric acid or conducted via high-pressure steam splitting, directly cleaves triglycerides into free fatty acids and glycerol without soap intermediates, achieving near-complete conversion (up to 99% yield) and is favored for large-scale production due to its efficiency.[74][75] Raw materials include animal tallow, rich in saturated fatty acids like palmitic and stearic acids, and vegetable oils such as soy and palm, which yield unsaturated fatty acids including oleic and linoleic acids. Following hydrolysis, fatty acids are purified via fractional distillation under vacuum, separating components by boiling point; for instance, tall oil fatty acids—comprising oleic and linoleic acids—are isolated from crude tall oil, a pine wood pulping byproduct, through this process.[76][77] Synthetic routes complement natural extraction for specialized fatty acids. Oxidation of hydrocarbons, such as n-paraffins with air or oxygen, produces linear fatty acids used in detergents, while the Koch reaction carbonylaates olefins with carbon monoxide and water under acidic conditions to yield branched carboxylic acids. Olefin metathesis, particularly cross-metathesis of natural unsaturated fatty acids with terminal alkenes, enables production of tailored polyunsaturated fatty acids (PUFAs) for nutraceuticals and polymers.[78][79] Recent advances emphasize sustainability, with enzymatic hydrolysis using immobilized lipases catalyzing triglyceride breakdown under mild conditions (40–60°C, pH 7–8), achieving 90–95% yields from waste oils while minimizing energy use and wastewater compared to chemical methods. The global fatty acids market is estimated at USD 33.8 billion in 2025 (as of September 2025), propelled by biofuel demand where fatty acids serve as precursors for biodiesel production.[80][81][82]Metabolism and Physiology
Digestion, Absorption, and Transport
The digestion of dietary fatty acids primarily occurs through the hydrolysis of triglycerides, the main form in which fats are ingested. In the oral cavity and stomach, lingual and gastric lipases initiate the process by partially hydrolyzing triglycerides into diglycerides and free fatty acids, though this step accounts for only about 10-30% of total lipid digestion.[83] The majority of hydrolysis takes place in the small intestine, where pancreatic lipase, in conjunction with colipase, efficiently cleaves triglycerides at the sn-1 and sn-3 positions, yielding free fatty acids and 2-monoglycerides.[83] Colipase anchors the lipase to the lipid-water interface, counteracting the inhibitory effects of bile salts.[83] Following hydrolysis, the lipolytic products—free fatty acids and 2-monoglycerides—are rendered soluble by bile salts secreted from the liver and stored in the gallbladder. These amphipathic bile salts form mixed micelles (approximately 4-8 nm in diameter) that incorporate the hydrophobic fatty acids and monoglycerides, along with cholesterol and other lipids, facilitating their transport to the brush border of enterocytes in the jejunum.[83][84] Absorption into enterocytes occurs primarily via passive diffusion across the unstirred water layer, with contributions from transmembrane proteins such as CD36/FAT and fatty acid transport protein 4 (FATP4).[83] Within the enterocytes, absorbed fatty acids and 2-monoglycerides are rapidly re-esterified into triglycerides via the monoacylglycerol pathway, involving enzymes like monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT).[83] These triglycerides are then packaged with apolipoprotein B-48 (apoB-48), phospholipids, and cholesterol esters into chylomicrons in the endoplasmic reticulum and Golgi apparatus, a process dependent on microsomal triglyceride transfer protein (MTP).[83] Chylomicrons are exocytosed from enterocytes into the lacteals of the villi and enter the lymphatic system (thoracic duct), bypassing the portal vein to deliver lipids directly into the systemic bloodstream.[83][84] In contrast, short- and medium-chain fatty acids (typically 2-12 carbons) do not require micelle formation; they are absorbed directly by enterocytes and transported via the portal vein to the liver bound to albumin, due to their higher water solubility.[83] The process is regulated by enteroendocrine hormones, notably cholecystokinin (CCK), which is released from I-cells in the duodenum and jejunum in response to fatty acids and amino acids in the chyme. CCK stimulates gallbladder contraction for bile release and pancreatic secretion of lipase and colipase, optimizing lipid emulsification and hydrolysis.[85][86]Catabolic Pathways
Fatty acids are activated in the cytosol by acyl-CoA synthetases, which catalyze the reaction between the fatty acid, coenzyme A (CoA), and ATP to form acyl-CoA, AMP, and pyrophosphate; this activation step consumes the equivalent of two ATP molecules due to the subsequent hydrolysis of pyrophosphate to two inorganic phosphates.[87] Following activation, long-chain acyl-CoA esters are transported into the mitochondrial matrix via the carnitine shuttle system, a prerequisite detailed in fatty acid absorption and transport processes.[87] The principal catabolic pathway for fatty acids is β-oxidation, a repetitive four-step cycle that sequentially removes two-carbon units as acetyl-CoA, primarily occurring in the mitochondrial matrix for long-chain fatty acids (LCFA, 12–20 carbons) and in peroxisomes for very long-chain fatty acids (VLCFA, >20 carbons).[87] The cycle begins with dehydrogenation of acyl-CoA to form trans-Δ²-enoyl-CoA, catalyzed by acyl-CoA dehydrogenases (e.g., very long-chain, medium-chain, or short-chain variants) and producing FADH₂.[87] This is followed by hydration to L-3-hydroxyacyl-CoA via enoyl-CoA hydratase (crotonase), oxidation to 3-ketoacyl-CoA by 3-hydroxyacyl-CoA dehydrogenase using NAD⁺ to yield NADH and H⁺, and finally thiolysis by thiolase (e.g., mitochondrial trifunctional protein or β-ketothiolase) to produce acetyl-CoA and a shortened acyl-CoA that re-enters the cycle.[87] Each turn of the β-oxidation cycle generates one FADH₂ and one NADH, which yield a net of 4 ATP upon oxidation in the electron transport chain (assuming P/O ratios of 1.5 for FADH₂ and 2.5 for NADH).[87] For the saturated even-chain fatty acid palmitate (C16:0), complete β-oxidation requires seven cycles, yielding eight acetyl-CoA units that can enter the citric acid cycle for further energy production.[87] The overall reaction is: \ce{C15H31COOH + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O -> 8 acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+} This process, minus the 2 ATP equivalents for activation, provides a net energy yield of approximately 106 ATP molecules when accounting for the oxidation of reduced coenzymes and acetyl-CoA through oxidative phosphorylation.[87] Unsaturated fatty acids require additional enzymatic steps during β-oxidation to handle double bonds: for monounsaturated fatty acids like oleate, Δ³-cis-enoyl-CoA is isomerized to trans-Δ²-enoyl-CoA by 2,4-dienoyl-CoA Δ³,Δ²-isomerase (DCI), allowing continuation of the cycle; polyunsaturated fatty acids, such as linoleate, additionally involve reduction by 2,4-dienoyl-CoA reductase (DECR1) to remove conjugated double bonds.[87] Odd-chain fatty acids, less common in diets but present in some microbial lipids, undergo β-oxidation to yield propionyl-CoA as the final three-carbon unit, which is carboxylated to D-methylmalonyl-CoA by propionyl-CoA carboxylase (using biotin and ATP), racemized to L-methylmalonyl-CoA, and rearranged to succinyl-CoA by methylmalonyl-CoA mutase (vitamin B12-dependent), entering the citric acid cycle as a gluconeogenic precursor.[87] When β-oxidation produces excess acetyl-CoA beyond the liver's citric acid cycle capacity, particularly during fasting or prolonged exercise, it is diverted to ketogenesis in hepatic mitochondria to generate ketone bodies (acetoacetate and β-hydroxybutyrate) for export to extrahepatic tissues as an alternative fuel source.[88] This pathway begins with the reversible condensation of two acetyl-CoA to acetoacetyl-CoA by acetoacetyl-CoA thiolase, followed by addition of another acetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) via HMG-CoA synthase (the rate-limiting enzyme, induced by fasting), and cleavage by HMG-CoA lyase to acetoacetate, which is partially reduced to β-hydroxybutyrate by β-hydroxybutyrate dehydrogenase.[88]Anabolic Pathways and Essential Fatty Acids
In anabolic pathways, fatty acids serve as building blocks for the synthesis of more complex lipids, including longer-chain polyunsaturated fatty acids (PUFAs) through processes like elongation and desaturation. These pathways occur primarily in the endoplasmic reticulum and peroxisomes of mammalian cells, where enzymes add carbon atoms via elongation or introduce double bonds via desaturation. Following the initial biosynthesis of saturated fatty acids like palmitate, further modification of essential PUFAs—linoleic acid (LA, 18:2 ω-6) and α-linolenic acid (ALA, 18:3 ω-3)—relies on alternating cycles of desaturation and elongation to produce bioactive longer-chain PUFAs such as arachidonic acid (AA, 20:4 ω-6) and docosahexaenoic acid (DHA, 22:6 ω-3). The key rate-limiting enzymes include Δ6-desaturase (FADS2), which initiates the conversion by introducing a double bond at the Δ6 position, and Δ5-desaturase (FADS1), which acts later in the pathway; elongases such as ELOVL2 and ELOVL5 add two-carbon units between these steps.[89][90][91] Humans and other mammals lack the Δ12- and Δ15-desaturases needed to insert double bonds at the ω-6 and ω-3 positions, respectively, making LA and ALA essential fatty acids that must be obtained from the diet. These precursors are then metabolized into longer-chain PUFAs critical for eicosanoid production, membrane fluidity, and neural development. Deficiency in essential fatty acids arises from inadequate dietary intake, leading to symptoms such as scaly dermatitis, poor wound healing, and growth retardation in children, as observed in cases of prolonged parenteral nutrition without lipid supplementation.[3][92][93] The conversion pathways from LA and ALA highlight the competitive nature of these anabolic processes, as both ω-6 and ω-3 substrates vie for the same desaturase and elongase enzymes, often favoring ω-6 metabolism due to higher dietary availability. The ω-6 pathway proceeds as follows:- LA (18:2 ω-6) → γ-linolenic acid (GLA, 18:3 ω-6) via Δ6-desaturase
- GLA → dihomo-γ-linolenic acid (DGLA, 20:3 ω-6) via elongation
- DGLA → AA (20:4 ω-6) via Δ5-desaturase
- ALA (18:3 ω-3) → stearidonic acid (SDA, 18:4 ω-3) via Δ6-desaturase
- SDA → eicosatetraenoic acid (ETA, 20:4 ω-3) via elongation
- ETA → eicosapentaenoic acid (EPA, 20:5 ω-3) via Δ5-desaturase
- EPA → docosapentaenoic acid (DPA, 22:5 ω-3) via elongation
- DPA → DHA (22:6 ω-3) via peroxisomal Δ4-desaturase or further elongation/desaturation