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Fatty Acids: Straight-Chain Saturated



1. Structure, Nomenclature and Occurrence

Straight- or normal-chain, saturated components (even-numbered) make up 10 to 40% of the total fatty acids in most natural lipids. The most abundant saturated fatty acids 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 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. However, 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
 

Long-chain saturated fatty acids (12:0 upwards) have relatively high melting points. Animal fats and seed oils such as palm oil in which these components are especially abundant tend to be solids at room temperature. Such saturated fatty acids in esterified form also increase the rigidity of membranes.

Not everyone would consider formic or methanoic acid (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. It has also been found esterified to aliphatic alcohols in acarid mites.

Formula of acetic acidAcetic or ethanoic acid (2:0) is of great importance in living tissues, as the biosynthetic precursor of fatty acids and innumerable other lipids. However, it 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; 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 also the most common fatty acid linked to platelet-activating factor. In seed oils, acetic acid occurs in position sn-3 of triacylglycerols of Euonymus verrucosus, and related species, while in Polygala virgata it is in position sn-2. In other vegetable oils, 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, 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 in 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. Indeed, acetate is a common constituent of complex sphingolipids, usually in amide linkage to glucosamine, galactosamine, neuraminic acid or even sphingosine.

Propanoic acid (3:0) is important as the biosynthetic precursor of some amino acids. 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 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. It is found in milk fats of other ruminants, but not in the lipids of other tissues of these species.

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. It is also found as a minor component of certain seed oils rich in medium-chain saturated fatty acids (see below).

Formula of lipoic acid.Medium-chain fatty acids, such as octanoic (8:0), decanoic (10:0) and dodecanoic (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 important exceptions. Thus, they are major components of such seed oils as coconut oil, palm kernel oil and Cuphea species. Octanoic acid is esterified to a serine residue in the active form of the peptide hormone ghrelin, as discussed in our web page on proteolipids. It is also the biosynthetic precursor of lipoic acid, which is required by many enzymes involved in aerobic metabolism.

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, presumably having been taken up as part of the food chain. In particular, 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. However, it is more abundant in cow's milk fat, some fish oils and in 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 found very specifically in 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 comprises 20 to 30% of the lipids in most animal tissues and lipid classes, and it is present in amounts that vary from 10 to 40% in seed oils. 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 has a vital function in cells in specific proteolipids, where it is linked to internal cysteine residues via thioester bonds. However, many negative effects on health have been reported also.

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 to produce oleic acid in animal tissues

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 normal and important constituents of animal and plant sphingolipids. 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 also found in some animal waxes such as wool and meibum wax.


2. Biosynthesis and Metabolism of Saturated Fatty Acids

Animals obtain fatty acids both from the diet and from synthesis de novo, and some parasitic organisms acquire them from their hosts, but most 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 the acetate is derived from glucose metabolism via pyruvate. In some plants, it may be formed similarly 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.

Acetyl-CoA carboxylase: Malonyl-CoA is formed from acetyl CoA by the activity of the enzyme acetyl-CoA carboxylase in which biotin is the prosthetic group (and thus can be inhibited by avidin). Four different components are required for activity: biotin carboxylase, biotin carboxyl carrier protein, and α- and β-carboxyltransferases. In the first step in the ATP-dependent reaction, a carboxyl group derived from bicarbonate (HCO3-) is transferred to biotin, which serves as a temporary carrier of CO2 before transferring it to acetyl-CoA in a second step to yield malonyl-CoA.

Reaction of acetyl-CoA carboxylase to produce malonyl-CoA

In prokaryotes and primitive plants, the enzyme complex comprises four dissociable proteins, i.e. it is heteromeric, but in higher plants and animals, the enzyme is a single multifunctional or homomeric complex that exists in two main isoforms (ACC1 and ACC2). ACC1 is expressed most actively in the cytosol of lipogenic tissues, such as adipose tissue and lactating mammary gland, and the malonyl-CoA produced is used for fatty acid synthesis. Malonyl-CoA produced mainly in heart and muscle but also in liver is involved in the regulation of fatty acid oxidation by inhibiting carnitine palmitoyl-CoA transferase-1. The two pools are highly segregated and do not mix. As acetyl-CoA carboxylase is the first committed step in lipid biosynthesis, its acute regulation is especially important. Among a number of factors, including transcription and phosphorylation, it 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.

Successive molecules of malonyl-CoA are then added to the single primer molecule of acetyl-CoA in a sequence of reactions catalysed by a multifunctional enzyme complex, the fatty acid synthase, which can be of three types.

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. 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. Mycobacteria contain both FAS 1 and FAS II (see below) systems.

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 sample each of the enzymatic domains during fatty acid biosynthesis. This enables the sequence of reactions in which the chain is extended and butanoate is formed, as illustrated. First, 3-oxobutanoate is produced by a reaction catalysed by β-ketoacyl-ACP synthetase, this is reduced to 3-hydroxy-butanoate by β-ketoacyl-ACP reductase, which is in turn dehydrated to trans-2-butenoate by β-hydroxyacyl-ACP hydratase before it is reduced to butanoate by enoyl-ACP reductase. The process then continues with the addition of a further six units of malonyl-ACP by successive cycles of these reactions until palmityl-ACP is formed. At this point, a thioesterase removes the fatty acyl product as the free acid (with the mammalian enzyme), and it must be converted to the CoA-ester before it can enter into the various biosynthetic pathways for the production of specific lipids. 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

In the production 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 produced as by-products of oxidative processes. 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 addition, shorter chain fatty acids can be produced in some tissues, such as the mammary gland, by a separate chain-termination enzyme, thioesterase II, which is able to modify the specificity of the fatty acids synthase. Type I fatty acid synthases are generally considered to be more efficient than type II, because all the enzymatic activities are linked in a single polypeptide template from which the intermediates cannot easily diffuse.

It has long been known that for activity the mammalian fatty acid synthases exists 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 key chain-elongation step. This amazing dodecameric enzyme complex contains 48 active centres held together by linkage units in a single barrel shaped structure. Although the structure of the fungal FAD I is very different, it appears that the β-ketoacyl synthase domain is again the dominant factor controlling polymerization. Of course, this account presents the basic details of the biosynthetic process only.

Type II fatty acid synthases (FAS II): These consist of separate proteins encoded by different genes that each catalyse a separate step analogous to those by FAS I enzymes; they can be dissociated and purified, although they normally operate in concert. They have been characterized in bacteria (e.g. E. coli - considered the model system), parasites, algae, higher plants and perhaps surprisingly mitochondria in animals. In general, prokaryotes utilize acyltransferases to terminate the reaction (not thioesterases) and esterify new fatty acids directly to a lipid. The E. coli FAS II is not in fact typical of bacterial enzymes in that it is also capable of producing unsaturated fatty acids (see our web page on monoenoic fatty acids). It has only recently been recognized that the Archaea have a non-typical fatty acid synthase.

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. In addition, ACP-intermediates from the process, which are diffusible discrete proteins that must deliver intermediates to independent catalytic partners, can be used for production of other important cellular constituents.

Mitochondria in animals including humans and in 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 a variant has been described in 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. 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 has this function in synthesis, an arrangement that separates the two metabolical pathways and prevents futile cycling. An important product of mitochondrial fatty acid synthesis is octanoyl-ACP for lipoic acid biosynthesis. Links between mitochondrial type II fatty acid synthases and RNA processing have also been uncovered in vertebrates and yeast, and this pathway may be involved in the coordination of intermediary metabolism in eukaryotic cells.

Type III fatty acid synthases - elongases: the latter term is more often used for enzymes on the cytosolic side of the endoplasmic reticulum that catalyse the addition of C2 units to preformed fatty acids. For example, 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) and are believed to perform the condensation reaction in the elongation cycle. Three of these (ELOVL 1, 3 and 6) are involved in the production of saturated and monoenoic fatty acids, while the remainder are elongases of polyunsaturated fatty acids, especially those of the essential n-6 and n-3 families. Of these, ELOVL1 is expressed ubiquitously in tissues and has been linked to the production of C24 fatty acids for sphingolipid biosynthesis; in the epidermis, it is regulated by ceramide synthases to produce C26 fatty acids, which can be further elongated by ELOV4 up to C36; ELOV4 is also involved in docosahexaenoic acid metabolism in the retina. ELOV3 is expressed in sebaceous glands and brown adipose tissue. ELOVL6 appears to be the only enzyme capable of elongating palmitate to a significant extent (in addition to 12:0 and 14:0). A separate enzyme system that uses acetate as chain extender is present in mitochondria.

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. 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 reduced by a β-ketoacyl-CoA reductase, requiring NADPH as the source of reducing equivalents, to produce 3-hydroxyacyl-CoA. 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 produce a fatty acid two methylene groups longer than the starting molecule. Depending on the requirement of the organism at any particular time, the product can be incorporated into lipids or undergo additional cycles of elongation.

Chain elongation of fatty acids

In higher plants such as Arabidopsis thaliana, the four components of the elongation system have been identified, but share little homology with the animal and yeast equivalents; it is not known whether they are organized in a single complex. 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. For example, Trypanosoma brucei, the human parasite that causes sleeping sickness, uses three elongases. The first converts C4 to C10, the second extends C10 to C14, and the third elongates C14 to C18. There are three fatty acid elongases in yeast also, all of which produce very-long-chain fatty acids.


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 addition to the formation of 9-16:1, palmitic acid can also be desaturated by a Δ6-desaturase in human sebaceous glands to produce sapienic acid (6-16:1), which may have antimicrobial activity.


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 on carnitines.


3. Saturated Fatty Acids in Health and Disease

In addition to being a source of energy in tissues, saturated fatty acids provide desirable properties to lipids in membranes by conferring rigidity where this is required, and in controlling the activities of membrane proteins through covalent bonding. They are essential especially for the function of sphingolipids, which are able to alter the thickness of the plasma membrane locally by varying the lengths of the fatty acid chains, This is a key factor also 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, while saturated fatty acids are also indispensable components of proteolipids (S-palmitoylation and N-myristoylation). Of course, they are also a source of monounsaturated fatty acids via the action of desaturases.

There is evidence that saturated fatty acids activate certain transcription factors that target lipogenic target genes, while in the unesterified (free) form they activate G protein-coupled receptors now termed Free Fatty Acid Receptors (FFAR). This can lead to negative health effects. For example, palmitic acid can activate inflammatory pathways directly by increasing signalling by toll-like receptor 4, and by stimulating such signalling molecules such protein kinase R. Excessive levels are believed to be contributory factors in the development of obesity, type 2 diabetes mellitus, cardiovascular diseases and cancer. While deregulation of fatty acid biosynthesis de novo can lead to innumerable metabolic problems, I will let others debate this topic.

The vital functions of saturated fatty acids are often forgotten when their nutritional properties are debated. On the other hand, there is little doubt that there are many potential deleterious effects. Most nutritionists recommend keeping dietary intakes of saturated fatty acids as low as possible, but again I prefer to leave discussion of this complex topic to others who may be better qualified.


Recommended Reading

I can also 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).



Lipid listings Credits/disclaimer Updated: May 3rd, 2017 Author: William W. Christie LipidWeb icon