Fatty Acids: Straight-Chain Saturated

1. Structure, Nomenclature and Occurrence

Most natural lipids contain esterified straight- or normal-chain, saturated fatty acids that are even-numbered in general and comprise up 10 to 40% of the total. The most abundant of these in animal and plant tissues are straight-chain compounds with 14, 16 and 18 carbon atoms, but all the possible odd- and even-numbered homologues with 2 to 36 carbon atoms have been found in nature in esterified form. They are named systematically from the saturated hydrocarbon with the same number of carbon atoms, the final 'e' being changed to 'oic'. Thus, the fatty acid with 16 carbon atoms and the structural formula -

Stuctural formula of hexadecanoic acid

   - is systematically named 'hexadecanoic acid', although it is more usual to see the trivial name 'palmitic acid' in the scientific literature. It can be termed a 'C16' fatty acid or with greater precision - '16:0', the number before the colon specifying the number of carbon atoms and that after the colon, the number of double bonds. A list of saturated fatty acids together with their trivial names and shorthand designations is given in the table below. Trivial names are best avoided, and I have not listed the more obscure of these, but this advice is perhaps too pedantic for the more common ones.

Table 1. Systematic and trivial names for saturated fatty acids.
Systematic
name		 Trivial name Shorthand
designation		 Systematic
name		 Trivial name Shorthand
designation
 
ethanoic acetic 2:0 octadecanoic stearic 18:0
propanoic propionic 3:0 nonadecanoic 19:0
butanoic butyric 4:0 eicosanoic arachidic 20:0
pentanoic valeric 5:0 heneicosanoic 21:0
hexanoic caproic 6:0 docosanoic behenic 22:0
heptanoic 7:0 tricosanoic 23:0
octanoic caprylic 8:0 tetracosanoic lignoceric 24:0
nonanoic 9:0 pentacosanoic 25:0
decanoic capric 10:0 hexacosanoic cerotic 26:0
undecanoic 11:0 heptacosanoic 27:0
dodecanoic lauric 12:0 octacosanoic montanic 28:0
tridecanoic 13:0 nonacosanoic 29:0
tetradecanoic myristic 14:0 triacontanoic 30:0
pentadecanoic 15:0 hentriacontanoic 31:0
hexadecanoic palmitic 16:0 dotriacontanoic 32:0
heptadecanoic margaric 17:0
 

Although there is no internationally accepted definition, short-chain fatty acids are usually considered to be C1 to C6 in chain-length, while medium-chain are C7 to C12. Long-chain saturated fatty acids are C14 to C20 (or C22), while those with even longer chains are designated very-long-chain fatty acids. As saturated long-chain fatty acids have relatively high melting points, they increase the rigidity of membranes in esterified form, while animal fats and seed oils such as palm oil in which these components are abundant tend to be solids at room temperature. Short- and medium chain fatty acids are weakly acidic with pKa values around 4.8, and they have relatively high solubilities in water.

Not everyone would consider formic or methanoic acid (HCOOH or 1:0) to be a fatty acid, not least because of its solubility in water, but it has been identified in esterified form in phosphatidylcholine from human neutrophils, with 16:0, 18:0 or 18:1 as the other fatty acid, and linked to aliphatic alcohols in acarid mites. It is utilized in post-translational modication of certain proteins, such as histones, where it is linked to lysine or arginnine residues and modifies gene expression.

Formula of acetic acidAcetic or ethanoic acid (2:0) is of great importance in living tissues, as a source of energy and as the biosynthetic precursor of fatty acids and innumerable other lipids and organic molecules. It is only occasionally found in association with fatty acids of higher molecular weight in esterified form in lipid molecules, although it does occur esterified to glycerol in ruminant milk fats (presumably in position sn-3). Acetylated triacylglycerols accumulate in the pupae of a type of insect, the goldenrod gall fly, and these remain liquid during winter when the pupa of the insect is frozen so can serve as a source of energy to maintain life. It is linked to position sn-2 of the phospholipid mediator platelet-activating factor in animals. In seed oils, acetic acid occurs in position sn-3 of triacylglycerols of Euonymus verrucosus and related species and in position sn-2 in Polygala virgata, while in others, it has been detected in linkage to the hydroxyl group of a hydroxy fatty acid, which is in turn esterified to glycerol, i.e., as an estolide.

Acetates of long-chain alcohols are found in plant and insect waxes and as insect pheromones. A novel sphingomyelin species isolated from a cyanobacterium, Scytonema julianum, contains acetate in an estolide linkage, i.e., with the acetyl group esterified to an ω-1 hydroxyl group of a long-chain fatty acid. An acetylated cerebroside derivative has been found in rat brain myelin, i.e., with an acetyl group linked at the C3 hydroxyl of the sphingosine base, and indeed, acetate is a common constituent of complex glycosphingolipids, usually in amide linkage to glucosamine, galactosamine, neuraminic acid or even sphingosine. It takes part in post-translational modification of many proteins as does propionate and butyrate.

Propanoic acid (3:0) from the diet is rapidly metabolized in the liver, but it is the primer molecule for biosynthesis of odd-chain fatty acids (see below), and it is a precursor of some amino acids and a component of the tricarboxylic acid cycle during gluconeogenesis. It is rarely found in esterified form in natural lipids, and to my knowledge, the only exception is for molecules related to platelet-activating factor.

Butanoic or butyric acid (4:0) comprises 3-4% by weight (much more in molar terms) of the total fatty acids in cow's milk, where it is found exclusively in position 3 of the triacyl-sn-glycerols, and it is found in milk fats of other ruminants but not in the lipids of other tissues of these species (it is a major product of rumen fermentation in these animals). In most animals, including humans, it is produced to some extent by microbial fermentation of the carbohydrate components of dietary fibres, together with acetate and propionate, in the lower intestinal tract, where it is absorbed for transport to other tissues. It is reported to have a role in signalling with effects upon epithelial cell proliferation, apoptosis and differentiation by activation of G-protein coupled receptors and inhibition of histone deacetylase, and it is the main energy source for colonocytes. As an anti-inflammatory agent, it inhibits activation of the transcription factor NF-κB primarily, and signals by binding to Free Fatty Acid Receptor 2 (FFAR2, GPR43) and FFAR3 (GPR41) (see our web page on unesterified fatty acids). It may even affect the brain as it is reported to be an antidepressant in animal models of depression and chronic mild stress, and it is reported to have therapeutic potential in some cancers, lung, rheumatoid arthritis and neurodegenerative diseases.

Odd-chain fatty acids from 5:0 to 11:0 have been detected at trace levels in the triacylglycerols of ruminant milks, but not elsewhere in conventional esterified form in these species. More generally, they are found as oxidation products of long-chain fatty acids, together with a range of even-numbered components (2:0 to 12:0) as urinary acylcarnitines.

Hexanoic acid (6:0) comprises 1-2% of the total fatty acids in ruminant milk triacylglycerols, where most of it is esterified to position 3 of the triacyl-sn-glycerols, and it is found as a minor component of certain seed oils rich in medium-chain saturated fatty acids. Other than these, the commonest source of short-chain fatty acids (3:0 to 8:0) in humans is microbial metabolism in the gut.

Formula of lipoic acid.Medium-chain fatty acids, such as octanoic (8:0), decanoic (10:0) and dodecanoic (lauric - 12:0), are found in esterified form in most milk fats, including those of non-ruminants, though usually as minor components, but not elsewhere in animal tissues in significant amounts. They are never detected in membrane lipids, for example. They are absent from most vegetable fats, but with the exception of coconut oil, palm kernel oil and oils from Cuphea species. Octanoic acid is esterified to a serine residue in the peptide hormone ghrelin, as discussed in our web page on proteolipids. It is also the biosynthetic precursor of lipoic acid (5R-(1,2-dithiolan-3-yl)pentanoic acid), i.e., with two sulfur atoms (at C6 and C8) connected by a disulfide bond, which is synthesised in mitochondria as a cofactor for bioenergetic mitochondrial enzymes and as a natural antioxidant (among many important metabolic properties - see also below). Medium-chain fatty acids have antibacterial properties and are sometimes added as adjuvants to topical antibiotic preparations. Dodecanoic acid in the vasculature of Arabidopsis deters insect predation.

Odd-chain fatty acids from 13:0 to 19:0 are found in esterified form in the lipids of many bacterial species, and they can usually be detected at trace levels in most animal tissues, where they may have originated in the intestinal microbiome, or as part of the diet, or as minor metabolites within cells. They occur in appreciable amounts (5% or more) in the tissues of ruminant animals where a high proportion is derived from the rumen microflora.

Myristic acid (14:0) is a ubiquitous component of lipids in most living organisms, but usually at levels of 1 to 2% only. It is more abundant in cow's milk fat, some fish oils and those seed oils enriched in medium-chain fatty acids (e.g., coconut and palm kernel, and of course those of the family Myristicaceae, e.g., nutmeg oil). This fatty acid is a characteristic component of certain proteolipids, where it is linked via an amide bond to an N‑terminal glycine residue and is essential to the function of the protein components.

Palmitic acid (16:0) is usually considered the most abundant saturated fatty acid in nature, and it is found in appreciable amounts in the lipids of animals, plants and lower organisms. It is the primary product of the fatty acid synthase and comprises 20 to 30% of the lipids in most animal tissues and lipid classes. In seed oils, it is present in amounts that vary from 10 to 40%, and among commercial sources, it is most abundant in palm oil (40% or more). It is the biosynthetic precursor of sphingoid bases and thence of all sphingolipids, and it is a vital component of a family of proteolipids, where it is linked to internal cysteine residues via thioester bonds. In contrast, many negative effects as a nutrient upon health have been reported, although usually only when it is consumed in excess as it can be pro-inflammatory as an agonist for the toll-like receptors TLR2 and TLR4.

Stearic acid (18:0) is the second most abundant saturated fatty acid in nature, and again it is found in the lipids of most living organisms. In lipids of some commercial importance, it occurs in the highest concentrations in ruminant fats (milk fat and tallow) or in vegetable oils such as cocoa butter and of course in industrially hydrogenated fats. It can comprise 80% of the total fatty acids in gangliosides. Relatively high proportions of stearic acid in comparison to other saturated fatty acids are subjected to enzymatic desaturation in animal tissues with oleic acid (9-18:1) as the main product.

Eicosanoic acid (20:0) can be detected at low levels in most lipids of animals and often in those of plants and microorganisms. Saturated fatty acids from 20:0 to 26:0 in amide linkage to long-chain bases are major constituents of sphingolipids in animals, plants and fungi. While very-long-chain saturated fatty acids (22:0 to 32:0) are not usually considered to be common constituents of lipids, they do occur in many plant waxes, which by some estimates are the most abundant lipids in living tissues on earth, and they are found in some animal waxes such as wool and meibum waxes.

Dicarboxylic long-chain fatty acids are abundant in the cuticular layer of plants, where they are mainly saturated, although mono- and dienoic components do occur. Shorter-chain dicarboxylic acids are formed by peroxisomal omega-oxidation in animal tissues, and in hepatocytes, they may influence fatty acid oxidation and triacylglycerol accumulation.

2. Biosynthesis of Saturated Fatty Acids - Acetyl-CoA Carboxylase

Animals obtain fatty acids both from the diet and from synthesis de novo, and some parasitic organisms acquire them from their hosts, but most other forms of life must synthesise all their fatty acids from short-chain precursors. As fatty acids are even numbered, it was easily deduced that a two-carbon precursor then shown to be acetate or more accurately its coenzyme A ester was involved, but when it was found that the reaction required carbon dioxide, the experimental evidence soon pointed to malonyl-CoA as the chain-extender. In animals, most of this acetate is derived from glucose metabolism via pyruvate. In some plants, it may be formed in the same way in the plastids, but in others acetate is formed from pyruvate in mitochondria and must diffuse to the plastids before conversion to the CoA ester. The following account presents the basic details only of the biosynthetic processes in different organisms.

Malonyl-CoA is formed from acetyl CoA by the enzyme acetyl-CoA carboxylase in which biotin is the prosthetic group (and thus can be inhibited by avidin). There are three main functional domains: a biotin carboxylase domain (BC), a carboxyl transferase domain (CT) and a biotin carboxyl carrier protein domain (BCCP), which links the BC and CT domains. The BC domain consumes ATP and bicarbonate to catalyse the carboxylation of biotin with bicarbonate donating the carboxyl moiety, which is transferred by the BCCP domain to the CT domain, where it is added to acetyl-CoA to convert it into malonyl-CoA.

Reaction of acetyl-CoA carboxylase to produce malonyl-CoA
Figure 1. Reaction of acetyl-CoA carboxylase to produce malonyl-CoA.

In animals, the enzyme is a single multifunctional complex that exists in two main isoforms (ACC1 and ACC2), which are structurally related, differing in an extended ACC2 N-terminus containing a mitochondrial targeting sequence, but they are spacially separate and form dimers in the active state. ACC1 is expressed mostly in the cytosol of lipogenic tissues, such as liver, adipose tissue and lactating mammary gland, and the malonyl-CoA produced is used for fatty acid synthesis. The ACC2 isoform is expressed more in oxidative organs such as skeletal muscle and heart, where it is anchored to the outer mitochondrial membrane by its hydrophobic N‑terminal region; the malonyl-CoA produced takes part in the regulation of fatty acid oxidation by allosterically inhibiting the carnitine palmitoyl-CoA transferase-1 (see our web page on β-oxidation). The two pools of malonyl-CoA are highly segregated within cells and do not mix. As acetyl-CoA carboxylase is the first committed step in lipid biosynthesis, its acute regulation is especially important. ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein–protein interactions, which is further linked to filament formation. When there is increased energy demand, the protein kinase AMPK is stimulated and phosphorylates both ACC1 and ACC2 to de-activate them; ACC2 inhibition tends to increase fatty acid β-oxidation, while ACC1 inhibition decreases fatty acid biosynthesis. Apart from transcription and phosphorylation, ACC is promoted by citrate from the Krebs cycle (not in yeasts), and it is inhibited by the long-chain acyl-CoAs formed by the fatty acid synthases.

In prokaryotes and primitive plants, the enzyme complex comprises four dissociable proteins, i.e., it is heteromeric with three catalytic subunits now called AccA, AccD and AccC plus a carrier protein (AccB) in bacteria such as Escherichia coli. In higher plants, although there are some differences among plant genera, acetyl-CoA carboxylase exists in two molecular forms, i.e., multi-protein complexes (heteromeric) in the plastids and multifunctional proteins in the cytosol. The latter are homomeric and are large single polypeptides comprised of three fused domains, namely biotin carboxylase, biotin carboxylase carrier protein and carboxyltransferase.

3. Biosynthesis of Saturated Fatty Acids - Synthases

Successive molecules of malonyl-CoA are added to the single primer molecule of acetyl-CoA in a sequence of reactions catalysed by multifunctional enzyme complexes, fatty acid synthases (FAS), which can be of three main types. In addition, some fatty acids can be produced by polyketide synthases, which have some similarities with FAS systems, and this is discussed in our web page on polyunsaturated fatty acids.

Type I fatty acid synthases (FAS I): In this enzyme complex found in animals, the various sub-units carrying out each step of the reaction are discrete domains of a single protein entity that is the product of one gene, i.e., a homodimeric multi-enzyme with a molecular weight of about 0.5 MDa and with seven different active sites per dimer, including a carrier protein that transfers the intermediates from one catalytic site to the next. In yeast and fungi, there are two genes that produce polypeptide products, which then coalesce to form a multifunctional Type I fatty acid synthase complex as a dodecamer with six pairs of non-identical subunits of about 2.6 MDa. Type I fatty acid synthases are generally considered to be more efficient than type II, because all the enzymes are linked in a single polypeptide template from which the intermediates cannot easily diffuse. In animals, FAS I is most active in adipose tissue, liver and muscle, but it is present in most peripheral tissues, including the brain.

As a first step, both the primer and extender substrates are attached to acyl carrier protein (ACP), which has the same prosthetic group as coenzyme A. The ACPs in this instance are tethered covalently to the megasynthase by flexible linkers in the peptide chain, allowing them to carry their cargo from one enzyme or enzymatic domain to another during the iterative cycles of fatty acid biosynthesis. This enables the sequence of reactions in which the chain is extended to form butanoate in the first turn of the cycle, as illustrated. First, 3-oxobutanoate is produced by a reaction catalysed by β‑ketoacyl-ACP synthetase, this is reduced by β‑ketoacyl-ACP reductase to 3‑hydroxy-butanoate, which is dehydrated to trans-2-butenoate by β‑hydroxyacyl-ACP hydratase before reduction to butanoate by enoyl-ACP reductase with NADPH providing the reducing power. The process then continues with the addition of a further six units of malonyl-ACP by successive cycles of these reactions until palmitoyl-ACP is formed. At this point, a thioesterase removes the fatty acyl product as the free acid (with the animal enzyme), and it must be converted to the CoA-ester before it can enter the biosynthetic pathways for the production of the various lipid classes. With the fungal fatty acid synthase, the finished acid is attached directly to CoA using a malonoyl/palmitoyl transacylase domain.

Biosynthesis of saturated fatty acids
Figure 2. Biosynthesis of saturated fatty acids by a type I fatty acid synthase.

To summarize, carbons 15 and 16 of the palmitate molecule are derived directly from acetyl-CoA as primer for the reaction, while malonyl-CoA, produced from acetyl-CoA by acetyl-CoA carboxylase, provides carbons 14 to 1. The overall equation for the biosynthesis of palmitic acid is -

Equation for the biosynthesis of saturated fatty acids

The chain-length of the final product is believed to be controlled by two factors. Firstly, the condensing enzymes have a limited space available for the growing chain, so elongation is inhibited when the chain reaches an appropriate length, and secondly, the lengthening hydrophobic tail of the growing chain has an affinity for the enzymes that terminate the reaction to release the acyl chain as CoA esters or unesterified fatty acids. Medium-chain fatty acids are usually produced by enzymes in which the specificity of the thioesterase component differs from normal, i.e., the chain-elongation cycle is terminated prematurely. In some tissues, such as the mammary gland, shorter chain fatty acids can be produced by a separate chain-termination enzyme, thioesterase II, which is able to modify the fatty acids synthase.

For synthesis of odd-chain fatty acids, the primer molecule can be propanyl-CoA, but these can also be produced from even-numbered components by alpha-oxidation. Similarly, short- and medium-chain fatty acids can be by-products of oxidative processes.

It has long been known that the mammalian fatty acid synthases exist and act as a dimer while the fungal forms are hexameric, but the exact nature and requirement for the polymeric states were not known until X-ray crystal structures of the enzymes were obtained. With the mammalian enzyme, the two monomers are in a head-to-head arrangement (not head-to-tail as previously believed), and dimerization seems to be dictated by the structure of the β‑ketoacyl synthase domain, i.e., the component responsible for the chain-elongation step. The mammalian fatty acid synthase is primarily a cytoplasmic enzyme complex, but it can be located on intracellular membranes. It is phosphorylated by kinases and this regulation may be required for both the activity of the enzyme and its subcellular location. The amazing dodecameric enzyme complex of the fungal FAD I contains 48 catalytic centres held together by linkage units in a single barrel shaped structure. Although the structure is very different, it appears that the β‑ketoacyl synthase domain is again the dominant factor controlling polymerization.

This pathway is under the control of sterol regulatory element-binding protein 1, SREBP-1 in three forms of which SREBP-1c is relevant here, a master transcription factor for lipogenesis that regulates the expression of both the fatty acid synthase and the desaturase SCD1. SREBP-1 are synthesised as inactive precursors in the ER and require SREBP cleavage-activation protein (SCAP) to transport them from the ER to the Golgi for sequential cleavage to release the N-terminal isoforms, permitting them to enter the nucleus to initiate the expression of lipogenic genes.

Type II fatty acid synthases (FAS II) have been characterized in bacteria (e.g., E. coli), parasites, algae, higher plants and perhaps surprisingly mitochondria in animals. They consist of separate proteins encoded by different genes that each catalyse a single step analogous to those by FAS I enzymes, and these proteins can be dissociated and purified although they normally operate in concert. The ACPs are discrete proteins that transport the growing fatty acyl chain to the reaction partners while sequestering the intermediates within a hydrophobic core to protect against possible side reactions.

In plastids of plants, three types of β-ketoacyl-ACP synthases (KASs) catalyse the elongation of malonyl-ACP to fatty acids, i.e., KAS III (FabH) catalyses the initial condensation reaction to generate butyryl-ACP, while KAS I (FabB) catalyses the condensation of butyroyl and subsequent intermediate ACPs to myristoyl-ACP (C14). KAS II (FabF) catalyses a range of chain-elongation reactions but notably the condensation of C14 and C16‑ACPs with malonyl-ACP, and it determines the ratio of 16:0 to 18:0. The reaction is terminated by a thioesterase in two isoforms, FATA and FATB, with distinct substrate specificities (FATA prefers C18:1-ACP). Variant FabB forms in selected species, including those in Cuphea species, can release fatty acids earlier to generate seed oils enriched in medium-chain fatty acids, although variant forms of the acyltransferases are then required to insert these into triacylglycerols.

In prokaryotes, the synthases in general differ in that they do not use thioesterases, and instead acyltransferases terminate the reaction by esterifying new fatty acids directly to a lipid. The E. coli FAS II is not in fact typical of bacterial enzymes in that it is able to produce unsaturated fatty acids as well as saturated (see our web page on monoenoic fatty acids), and it has only recently been recognized that the Archaea have a non-typical fatty acid synthase. Mycobacteria contain both FAS 1 and FAS II systems.

Scottish thistleIn contrast to type I, type II fatty acid synthases can produce many different products for cellular metabolism, including fatty acids of different chain lengths, and unsaturated, iso- and anteiso-methyl-branched and hydroxy fatty acids. ACP-intermediates from the process, which are diffusible discrete proteins that must deliver their acyl groups to independent catalytic partners, such as for complex lipid synthesis, can be used for production of other cellular constituents, e.g., lipoic acid, and assembly of the electron transport chain complex. The β-ketoacyl-ACP synthase FabF has a bimodal catalytic pattern to factilitate this by stabilizing C6 and C10 acyl substrates for preferential catalysis. These enzymes in bacteria are considered targets for the development of novel antibiotics.

Mitochondrial fatty acid synthases (FAS II): Mitochondria in animals, plants and yeasts contain FAS II enzymes, related to those in prokaryotes and entirely distinct from the cytoplasmic FAS I. Indeed, the components of this, such as malonyl-CoA:ACP transferase, β-ketoacyl synthase and 2-enoyl-ACP reductase, were first identified by their similarity to the corresponding bacterial and yeast proteins and can be regarded as orthologs. There does not appear to be a mitochondrial acetyl-CoA carboxylase in mammals, although variants have been described in plants and yeasts. While propionyl-CoA carboxylase, a mitochondrial enzyme in mammals, can catalyse carboxylation of acetyl-CoA also in vitro, the efficiency is low, and it is possible that mitochondria import the required malonate. There are fewer proteins in the fatty acid synthase in mitochondria than in bacteria, and as an example a single KAS is responsible for all the condensation steps. To date, five components of the mitochondrial enzyme complex have been characterized from Arabidopsis, namely a β‑ketoacyl-ACP synthase, 3‑hydroxyacyl-ACP dehydratase, enoyl‑ACP reductase, phosphopantetheinyl transferase, and malonyl-CoA synthetase.

There are believed to be some specific requirements for long-chain fatty acids produced as ACP esters for mitochondrial metabolism, and although many questions remain, it has been established that mitochondrial fatty acid synthesis is essential for cellular respiration and mitochondrial biogenesis. During β‑oxidation of fatty acids, CoA acts as acyl-group carrier whereas ACP does this in synthesis, an arrangement that separates the two metabolic pathways and prevents futile cycling. Links between mitochondrial type II fatty acid synthases and RNA processing have been uncovered in vertebrates and yeast, and this pathway may be involved in the coordination of intermediary metabolism in eukaryotic cells.

A major product of the mitochondrial fatty acid synthase is octanoyl-ACP for biosynthesis of lipoic acid, which essential for aerobic metabolism and for photorespiration in plants. By binding via its carboxyl group to lysine residues of proteins, this is a cofactor for five enzymes or classes of enzymes, i.e., pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (part of the citric acid cycle), together with the glycine cleavage system, branched-chain keto acid dehydrogenase, and the α-oxo-adipate dehydrogenase.

Type III fatty acid synthases - elongases: the latter term is more often used for enzymes present on the cytosolic side of the endoplasmic reticulum that catalyse the addition of C2 units from malonyl-coA to preformed fatty acids. By this means, palmitoyl-CoA can be further elongated by C2 units to form long- or very-long-chain fatty acids by such enzymes. Based on the presence of similar motifs in their gene structure, seven enzymes are recognized in mammals that have been termed ELOVL 1 to 7 (Elongation of very-long-chain fatty acid (VLCFA)) and are believed to perform the condensation reaction in the elongation cycle. Four of these (ELOVL 1, 3, 6 and 7) produce longer-chain saturated and monoenoic fatty acids, while the remainder (ELOVL 2, 4 and 5) are elongases of polyunsaturated fatty acids of the essential n-6 and n-3 families. An ELOV8 has been characterized in fish. These enzymes are integral proteins of the endoplasmic reticulum and consist of transmembrane domains that anchor them to the membrane and catalytic domains containing conserved motifs and residues essential for substrate binding to carry out the enzymatic reactions.

Of these, ELOVL1 is expressed ubiquitously in tissues and has been linked to the production of C20 to C24 fatty acids for sphingolipid biosynthesis, especially in the brain. In the epidermis, it is regulated by ceramide synthases to produce C26 fatty acids, which can be further elongated up to C36 by ELOV4, which differs in that it is also utilized in docosahexaenoic acid metabolism in the retina. ELOV3 is expressed in sebaceous glands and brown adipose tissue, and ELOVL6 appears to be the only enzyme capable of elongating palmitate (and 12:0 and 14:0) to a significant extent. Activation of peroxisome proliferator-activated receptor alpha (PPARα) induces the expression of ELOVL1, ELOVL3, ELOVL5, and ELOVL6 but not of ELOVL2 and ELOVL4, which are regulated by PPARγ, while ELOVL3 expression requires glucocorticoids additionally.

The cycle of fatty acid elongation is composed of four steps, the first of which is rate-limiting, i.e., condensation, reduction, dehydration and reduction again, to increase the chain-length of an acyl-CoA ester by two, with each step being carried out by distinct membrane-embedded enzymes. In the initial step, the CoA ester is condensed with malonyl-CoA in a reaction catalysed by the ELOVL enzyme (or β-ketoacyl-CoA synthase). The product is a 3-keto-acyl-CoA, which is converted to 3‑hydroxyacyl-CoA by the action of a β-ketoacyl-CoA reductase that requires NADPH as the source of reducing equivalents. The elements of water are removed by a β-hydroxyacyl-CoA dehydratase to produce a trans-2,3-acyl-CoA, which is then reduced by enoyl-CoA reductase to yield a fatty acid two methylene groups longer than the starting molecule. Depending on the requirement of the organism at any given time, the product can be incorporated into lipids or undergo additional cycles of elongation. A separate enzyme system that uses acetate as chain extender is present in mitochondria.

Chain elongation of fatty acids
Figure 3. Biosynthesis of very-long-chain fatty acids (VLCFA) by type III fatty acid synthases (elongases).

Three elongases (Elo1-3) are present in yeasts such Saccharomyces cerevisiae; Elo1 extends C12-C16 fatty acyl-CoAs to C16-C18 fatty acids, Elo2 elongates these up to C22, while Elo3 elongates C18 fatty acids to C20 to C26. In higher plants such as Arabidopsis thaliana, the four components of the elongation system have been identified, but they share little homology with the animal and yeast equivalents; they are believed to be organized in a single complex on the cytosolic side of the endoplasmic reticulum, but this requires confirmation. The condensing enzyme provides the substrate specificity and determines the amount of product synthesised.

Some parasitic organisms produce all their fatty acids by using elongases, and Trypanosoma brucei, the human parasite that causes sleeping sickness, uses three elongases (ELO1-3), the first of which converts C4 to C10, the second extends C10 to C14, and the third elongates C14 to C18. In T. cruzi, ELO2 and ELO3 are required for global lipid homeostasis while ELO1 is needed to sustain mitochondrial viability.

4. Further Metabolism

Desaturation: In animal cells, most saturated fatty acids from 12:0 to 18:0 can be converted to monounsaturated products through the action of Δ9‑desaturases, with the activity increasing the greater the chain-length (see our web page on monoenoic fatty acids). In human sebaceous glands, palmitic acid can be desaturated by a Δ6-desaturase to produce sapienic acid (6-16:1), which may be bactericidal, as well as to 9‑16:1, while in plants stearoyl-CoA can be desaturated to oleoyl-coA (or other isomers) in the endoplasmic reticulum and then enter metabolic pathways whereby it is converted to linoleate and linolenate (see our web page on polyunsaturated fatty acids).

Catabolism: Fatty acids are broken down in animal tissues to produce energy by a multi-step process of β-oxidation. This is discussed in our web page dealing with carnitines.

5. Dicarboxylic Acids

In animals, medium and long-chain saturated fatty acids are subjected to oxidation at the terminal (ω) carbon atom by enzymes of the cytochrome P450 (CYP) family, mainly CYP4A, in the endoplasmic reticulum of kidney and liver, and the process has been extensively studies for lauric and stearic acids (the related process for eicosanoids is discussed in a separate webpage here..). The final products, dicarboxylic acids, are detected in urine after ingestion of medium-chain fatty acids especially CYP enzymes insert a hydroxyl group, which is first oxidized by an NAD+-dependent alcohol dehydrogenase to form an oxo-fatty acid and then by an NAD+-dependent aldehyde dehydrogenase to form the dicarboxylic acid. Shorter-chain homologues are synthesised in animals during peroxidation and aldehyde formation. Catabolism occurs in peroxisomes.

Biosynthesis of dicarboxylic acids
Figure 4. Biosynthesis of dicarboxylic acids in animal tissues

Saturated straight-chain dicarboxylic acids, together with some monoenes and dienes, are major components of the cutin/suberin layers of plants, and are presumed to be formed in the same way by oxidation at the terminal carbon atom of monocarboxylic acids. Bacteria and yeasts also produce the latter by related mechanisms. Many of the dicarboxylic acids tested may be of value pharmacologically as they display antioxidant, anti-inflammatory and anti-cancer properties, although they can lead to triacylglycerol accumulation in liver (steatosis) with ketogenic diets. They can accumulate in urine during peroxisomal disorders.

6. Saturated Fatty Acids in Health and Disease

The vital functions of saturated fatty acids are often forgotten when their properties are discussed in a nutritional context, and until recently there appeared to be little doubt that there are many potentially deleterious effects when they are consumed in excess, especially when this is accompanied by insufficient uptake of essential unsaturated fatty acids. Most nutritionists recommend keeping dietary intakes of saturated fatty acids as low as possible, and synthesis de novo is probably sufficient for most purposes; there is no doubt that dysregulation of fatty acid intake and biosynthesis can lead to innumerable metabolic problems, including obesity. Public health policy in most developed countries has been determined by the belief that saturated fat causes cardiovascular disease by raising serum cholesterol, but this hypothesis is increasingly being questioned as re-examination of clinical data has failed to establish a causal link. As I prefer to leave discussion of this complex and contentious topic to others who are better qualified in the subject, these brief comments are intended only to introduce the debate concerning this and other health issues; the reading list below may help. I have learned to distrust nutritional pronouncements.

Saturated fatty acids are resistant to autoxidation and enzymic oxidation in general (other than β‑oxidation), and they are major components of the wax layer that protects the external surface of plants and of some skin secretions in animals, where resistance to oxidation and chemical attack is critical. In addition to being a source of energy in tissues, long-chain saturated fatty acids provide desirable properties to lipids in membranes by conferring rigidity where this is required. They are essential components of sphingolipids, which alter the thickness of the plasma membrane locally by varying the lengths of the fatty acid chains, and this is a key factor in the formation of raft domains in membranes and in the barrier properties of the ceramides in the epidermis of the skin.

As mentioned briefly above and discussed in much greater detail elsewhere in this web site, palmitic acid is the precursor of sphingoid bases and thence of all sphingolipids. Saturated fatty acids are also indispensable components of proteolipids (S‑palmitoylation and N‑myristoylation), as they direct proteins to their functional locations in membranes. Of course, they are a source of monounsaturated fatty acids via the action of desaturases. There is evidence that long-chain saturated fatty acids activate certain transcription factors that target lipogenic target genes in animals, and synthesis of palmitic acid de novo is necessary for the development of the brain in human infants. Methyl esters of palmitic and stearic acid are produced by ganglion cells of brain and are reported to be protective against cerebral ischemia.

Fatty acid synthesis de novo is an important factor in how dietary polyunsaturated fatty acids (PUFA) are utilized in mice and humans, and combining inhibition of the fatty acid synthase with PUFA-supplementation decreases liver triacylglycerol synthesis in mice fed with a high-fat diet by increasing PUFA uptake and diacylglycerol O-acyltransferase 2 (DGAT2) activity. In cancer, fatty acid synthesis is a crucial factor as abnormally high levels of the fatty acid synthase are present in tumour tissues in patients at later stages of the disease, and this overexpression is a predictor of poor prognosis. Inhibiting the enzyme leads to the death of tumour cells while sparing normal cells, which do not depend on this enzyme for routine functions, and it restores membrane architecture enabling a better response to chemotherapies. One drug with this property has reached the stage of clinical studies in patients with solid tumours. Fatty acid elongation by ELOVL5 reportedly promotes cellular proliferation and invasion in renal cell carcinoma.

Unesterified saturated fatty acids can activate G protein-coupled receptors, including Free Fatty Acid Receptors (FFAR), sometimes leading to negative health effects. For example, palmitic acid can trigger inflammatory pathways directly by stimulating macrophages to produce cytokines via toll-like receptors 2 and 4 (TLR2 and 4) and by stimulating such signalling molecules as protein kinase R and sirtuin (SIRT2). Excessive levels are believed to be contributory factors towards lipotoxicity and thence in the development of obesity, type 2 diabetes mellitus and cardiovascular diseases. In brain, it can cause augmented susceptibility to the development of Alzheimer's and Parkinson's diseases. The neurodegenerative disease X-linked adrenoleukodystrophy is characterized by an accumulation of unesterified very-long-chain fatty acids (24:0, 26:0 and 26:1) and is caused by mutations in the ABCD1 transporter that imports these fatty acids into peroxisomes so reducing degradation. On the other hand, very-long-chain saturated and monoenoic fatty acids are crucial in brain, and reduced ELOV1 activity has been correlated with other neurological diseases.

Short- and medium chain saturated fatty acids are metabolized very differently from the those of longer chain-length; they are substrates for energy metabolism and anabolic processes in mammals, and some act in signalling. Octanoic acid (8:0 or caprylic) is a potential therapeutic agent for certain cancers, because of its ready conversion to ketone bodies during β-oxidation, and that produced in the gastrointestinal microbiome is reported to be protective towards sepsis.

Recommended Reading

I can recommend the chapter on fatty acid biosynthesis in the book - Gurr, M.I., Harwood, J.L., Frayn, K.N., Murphy, D.J. and Michell, R.H. Lipids: Biochemistry, Biotechnology and Health (6th Edition). (Wiley-Blackwell) (2016).

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