Lipids are a broad group of naturally-occurring
molecules which includes
fats,
waxes,
sterols, fat-soluble
vitamins (such as vitamins A, D, E and K),
monoglycerides,
diglycerides,
phospholipids, and others. The main biological functions of lipids include energy storage, as structural components of
cell membranes, and as important
signaling molecules.
Lipids may be broadly defined as
hydrophobic or
amphiphilic small molecules; the amphiphilic nature of some lipids allows them to form structures such as
vesicles,
liposomes, or membranes in an aqueous environment. Biological lipids originate entirely or in part from two distinct types of biochemical subunits or "building blocks":
ketoacyl and
isoprene groups. Using this approach, lipids may be divided into eight categories:
fatty acyls,
glycerolipids,
glycerophospholipids,
sphingolipids,
saccharolipids and
polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).
Although the term
lipid is sometimes used as a synonym for
fats, fats are a subgroup of lipids called
triglycerides. Lipids also encompass molecules such as
fatty acids and their derivatives (including
tri-,
di-, and
monoglycerides and
phospholipids), as well as other
sterol-containing
metabolites such as
cholesterol. Although humans and other mammals use various
biosynthetic pathways to both break down and synthesize lipids, some essential lipids cannot be made this way and must be obtained from the diet.
Categories of lipids
Fatty acyls
Fatty acyls, a generic term for describing
fatty acids, their conjugates and derivatives, are a diverse group of molecules synthesized by chain-elongation of an
acetyl-CoA primer with
malonyl-CoA or
methylmalonyl-CoA groups in a process called
fatty acid synthesis.
They are made of a
hydrocarbon chain that terminates with a
carboxylic acid group; this arrangement confers the molecule with a
polar,
hydrophilic end, and a nonpolar,
hydrophobic end that is
insoluble in water. The fatty acid structure is one of the most fundamental categories of biological lipids, and is commonly used as a building block of more structurally complex lipids. The carbon chain, typically between four to 24 carbons long,
may be saturated or
unsaturated, and may be attached to
functional groups containing
oxygen,
halogens,
nitrogen and
sulfur. Where a double bond exists, there is the possibility of either a
cis or
trans geometric isomerism, which significantly affects the molecule's
molecular configuration.
Cis-double bonds cause the fatty acid chain to bend, an effect that is more pronounced the more double bonds there are in a chain. This in turn plays an important role in the structure and function of cell membranes. Most naturally occurring fatty acids are of the
cis configuration, although the
trans form does exist in some natural and partially hydrogenated fats and oils.
Examples of biologically important fatty acids are the
eicosanoids, derived primarily from
arachidonic acid and
eicosapentaenoic acid, which include
prostaglandins,
leukotrienes, and
thromboxanes. Other major lipid classes in the fatty acid category are the fatty esters and fatty amides. Fatty esters include important biochemical intermediates such as
wax esters, fatty acid thioester
coenzyme A derivatives, fatty acid thioester
ACP derivatives and fatty acid carnitines. The fatty amides include
N-acyl ethanolamines, such as the
cannabinoid neurotransmitter
anandamide.
Glycerolipids (triglycerides)
Glycerolipids are composed mainly of mono-, di- and tri-substituted
glycerols, the most well-known being the fatty acid esters of glycerol (triacylglycerols), also known as
triglycerides. In these compounds, the three hydroxyl groups of glycerol are each esterified, usually by different fatty acids. Because they function as a food store, these lipids comprise the bulk of storage fat in animal tissues. The hydrolysis of the
ester bonds of triacylglycerols and the release of glycerol and fatty acids from
adipose tissue is called fat mobilization.
Additional subclasses of glycerolipids are represented by glycosylglycerols, which are characterized by the presence of one or more
sugar residues attached to glycerol via a
glycosidic linkage. Examples of structures in this category are the digalactosyldiacylglycerols found in plant membranes
and seminolipid from mammalian
sperm cells.
Glycerophospholipids
Glycerophospholipids, also referred to as
phospholipids, are ubiquitous in nature and are key components of the
lipid bilayer of cells, as well as being involved in
metabolism and
cell signaling. Neural tissue (including the brain) contains relatively high amounts of glycerophospholipids, and alterations in their composition has been implicated in various neurological disorders.
Glycerophospholipids may be subdivided into distinct classes, based on the nature of the polar headgroup at the
sn-3 position of the glycerol backbone in
eukaryotes and eubacteria, or the
sn-1 position in the case of
archaebacteria.
PhosphatidylethanolamineExamples of glycerophospholipids found in
biological membranes are
phosphatidylcholine (also known as PC, GPCho or
lecithin),
phosphatidylethanolamine (PE or GPEtn) and
phosphatidylserine (PS or GPSer). In addition to serving as a primary component of cellular membranes and binding sites for intra- and intercellular proteins, some glycerophospholipids in eukaryotic cells, such as
phosphatidylinositols and
phosphatidic acids are either precursors of, or are themselves, membrane-derived
second messengers. Typically, one or both of these hydroxyl groups are acylated with long-chain fatty acids, but there are also alkyl-linked and 1Z-alkenyl-linked (
plasmalogen) glycerophospholipids, as well as dialkylether variants in archaebacteria.
Sphingolipids
Sphingolipids are a complex family of compounds
[Merrill AH, Sandhoff K. (2002). "Sphingolipids: metabolism and cell signaling",in New Comprehensive Biochemistry: Biochemistry of Lipids, Lipoproteins,and Membranes, Vance, D.E. and Vance, J.E., eds. Elsevier Science, NY. Ch. 14.] that share a common structural feature, a
sphingoid base backbone that is synthesized
de novo from the amino acid
serine and a long-chain fatty acyl CoA, then converted into
ceramides, phosphosphingolipids, glycosphingolipids and other compounds. The major sphingoid base of mammals is commonly referred to as
sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of sphingoid base derivatives with an
amide-linked fatty acid. The fatty acids are typically saturated or mono-unsaturated with chain lengths from 16 to 26 carbon atoms.
Sphingomyelin[Stryer et al., p. 330.]The major phosphosphingolipids of mammals are
sphingomyelins (ceramide phosphocholines), whereas insects contain mainly ceramide phosphoethanolamines
and fungi have phytoceramide phosphoinositols and
mannose-containing headgroups.
The glycosphingolipids are a diverse family of molecules composed of one or more sugar residues linked via a
glycosidic bond to the sphingoid base. Examples of these are the simple and complex glycosphingolipids such as
cerebrosides and
gangliosides.
Sterol lipids
Sterol lipids, such as
cholesterol and its derivatives, are an important component of membrane lipids, along with the glycerophospholipids and sphingomyelins. The
steroids, all derived from the same fused four-ring core structure, have different biological roles as
hormones and
signaling molecules. The eighteen-carbon (C18) steroids include the
estrogen family whereas the C19 steroids comprise the
androgens such as
testosterone and
androsterone. The C21 subclass includes the
progestogens as well as the
glucocorticoids and
mineralocorticoids. The
secosteroids, comprising various forms of
vitamin D, are characterized by cleavage of the B ring of the core structure.
Other examples of
sterols are the
bile acids and their conjugates, which in mammals are oxidized derivatives of cholesterol and are synthesized in the liver. The plant equivalents are the
phytosterols, such as
β-sitosterol,
stigmasterol, and
brassicasterol; the latter compound is also used as a
biomarker for
algal growth. The predominant sterol in
fungal cell membranes is
ergosterol.
Prenol lipids
Prenol lipids are synthesized from the 5-carbon precursors
isopentenyl diphosphate and
dimethylallyl diphosphate that are produced mainly via the
mevalonic acid (MVA) pathway. The simple isoprenoids (linear alcohols, diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to number of these
terpene units. Structures containing greater than 40 carbons are known as polyterpenes.
Carotenoids are important simple isoprenoids that function as
antioxidants and as precursors of
vitamin A.
Another biologically important class of molecules is exemplified by the
quinones and
hydroquinones, which contain an isoprenoid tail attached to a quinonoid core of non-isoprenoid origin.
and
vitamin K, as well as the
ubiquinones, are examples of this class. Prokaryotes synthesize polyprenols (called
bactoprenols) in which the terminal isoprenoid unit attached to oxygen remains unsaturated, whereas in animal polyprenols (
dolichols) the terminal isoprenoid is reduced.
Saccharolipids
Structure of the saccharolipid Kdo
2-Lipid A.
[ Glucosamine residues in blue, Kdo residues in red, acyl chains in black and phosphate groups in green.]Saccharolipids describe compounds in which fatty acids are linked directly to a sugar backbone, forming structures that are compatible with membrane bilayers. In the saccharolipids, a
monosaccharide substitutes for the glycerol backbone present in glycerolipids and glycerophospholipids. The most familiar saccharolipids are the acylated
glucosamine precursors of the
Lipid A component of the
lipopolysaccharides in
Gram-negative bacteria. Typical lipid A molecules are
disaccharides of glucosamine, which are derivatized with as many as seven fatty-acyl chains. The minimal lipopolysaccharide required for growth in
E. coli is Kdo
2-Lipid A, a hexa-acylated disaccharide of glucosamine that is glycosylated with two 3-deoxy-D-manno-octulosonic acid (Kdo) residues.
Polyketides
Polyketides are synthesized by polymerization of
acetyl and
propionyl subunits by classic enzymes as well as iterative and multimodular enzymes that share mechanistic features with the
fatty acid synthases. They comprise a large number of
secondary metabolites and
natural products from animal, plant, bacterial, fungal and marine sources, and have great structural diversity.
Many
polyketides are cyclic molecules whose backbones are often further modified by
glycosylation,
methylation,
hydroxylation,
oxidation, and/or other processes. Many commonly used
anti-microbial,
anti-parasitic, and
anti-cancer agents are polyketides or polyketide derivatives, such as
erythromycins,
tetracyclines,
avermectins, and antitumor
epothilones.
Biological functions
Membranes
Eukaryotic cells are compartmentalized into membrane-bound
organelles which carry out different biological functions. The
glycerophospholipids are the main structural component of
biological membranes, such as the cellular
plasma membrane and the intracellular membranes of
organelles; in animal cells the plasma membrane physically separates the
intracellular components from the
extracellular environment. The glycerophospholipids are
amphipathic molecules (containing both
hydrophobic and
hydrophilic regions) that contain a glycerol core linked to two fatty acid-derived "tails" by
ester linkages and to one "head" group by a
phosphate ester linkage. While glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such as
sphingomyelin and
sterols (mainly
cholesterol in animal cell membranes) are also found in biological membranes. In plants and algae, the galactosyldiacylglycerols,
[Heinz E.(1996). Plant glycolipids: structure, isolation and analysis. in Advances in Lipid Methodology - 3, pp. 211–332 (ed. W.W. Christie, Oily Press, Dundee) ] and sulfoquinovosyldiacylglycerol,
which lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are the most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.
Bilayers have been found to exhibit high levels of
birefringence which can be used to probe the degree of order (or disruption) within the bilayer using techniques such as
dual polarisation interferometryA biological membrane is a form of lipid bilayer. The formation of lipid bilayers is an energetically-preferred process when the
glycerophospholipids described above are in an aqueous environment. In an aqueous system, the polar heads of lipids align towards the polar, aqueous environment, while the hydrophobic tails minimize their contact with water and tend to cluster together, forming a
vesicle; depending on the
concentration of the lipid, this biophysical interaction may result in the formation of
micelles,
liposomes, or
lipid bilayers. Other aggregations are also observed and form part of the polymorphism of
amphiphile (lipid) behavior.
Phase behavior is an area of study within
biophysics and is the subject of current academic research.
Micelles and bilayers form in the polar medium by a process known as the
hydrophobic effect. When dissolving a lipophilic or amphiphilic substance in a polar environment, the polar molecules (i.e., water in an aqueous solution) become more ordered around the dissolved lipophilic substance, since the polar molecules cannot form
hydrogen bonds to the lipophilic areas of the
amphiphile. So in an aqueous environment, the water molecules form an ordered "
clathrate" cage around the dissolved lipophilic molecule.
Energy storage
Triacylglycerols, stored in adipose tissue, are a major form of energy storage in animals. The adipocyte, or fat cell, is designed for continuous synthesis and breakdown of triacylglycerols, with breakdown controlled mainly by the activation of hormone-sensitive enzyme
lipase. The complete oxidation of fatty acids provides high caloric content, about 9
kcal/g, compared with 4 kcal/g for the breakdown of
carbohydrates and
proteins. Migratory birds that must fly long distances without eating use stored energy of triacylglycerols to fuel their flights.
Signaling
In recent years, evidence has emerged showing that
lipid signaling is a vital part of the
cell signaling. Lipid signaling may occur via activation of
G protein-coupled or
nuclear receptors, and members of several different lipid categories have been identified as signaling molecules and
cellular messengers. These include
sphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in regulating calcium mobilization,
cell growth, and apoptosis;
(DAG) and the
phosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation of
protein kinase C;
the
prostaglandins, which are one type of fatty-acid derived eicosanoid involved in
inflammation and
immunity;
the steroid hormones such as
estrogen,
testosterone and
cortisol, which modulate a host of functions such as reproduction, metabolism and blood pressure; and the
oxysterols such as 25-hydroxy-cholesterol that are
liver X receptor agonists.
Other functions
The "fat-soluble" vitamins (
A,
D,
E and
K) – which are isoprene-based lipids – are essential nutrients stored in the liver and fatty tissues, with a diverse range of functions.
Acyl-carnitines are involved in the transport and metabolism of fatty acids in and out of mitochondria, where they undergo
beta oxidation. Polyprenols and their phosphorylated derivatives also play important transport roles, in this case the transport of
oligosaccharides across membranes. Polyprenol phosphate sugars and polyprenol diphosphate sugars function in extra-cytoplasmic glycosylation reactions, in extracellular polysaccharide biosynthesis (for instance,
peptidoglycan polymerization in bacteria), and in eukaryotic protein N-
glycosylation.
Cardiolipins are a subclass of glycerophospholipids containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial membrane.
They are believed to activate enzymes involved with
oxidative phosphorylation.
Metabolism
The major dietary lipids for humans and other animals are animal and plant triglycerides, sterols, and membrane phospholipids. The process of lipid metabolism synthesizes and degrades the lipid stores and produces the structural and functional lipids characteristic of individual tissues.
Biosynthesis
In animals, when there is an oversupply of dietary carbohydrate, the excess carbohydrate is converted to triacylglycerol. This involves the synthesis of fatty acids from acetyl-CoA and the esterification of fatty acids in the production of triacylglycerol, a process called
lipogenesis. Fatty acids are made by
fatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the acetyl group, reduce it to an alcohol,
dehydrate it to an
alkene group and then reduce it again to an
alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional protein, while in plant
plastids and bacteria separate enzymes perform each step in the pathway. The fatty acids may be subsequently converted to triacylglycerols that are packaged in
lipoproteins and secreted from the liver.
The synthesis of
unsaturated fatty acids involves a
desaturation reaction, whereby a double bond is introduced into the fatty acyl chain. For example, in humans, the desaturation of
stearic acid by
stearoyl-CoA desaturase-1 produces
oleic acid. The doubly-unsaturated fatty acid
linoleic acid as well as the triply-unsaturated
linolenic acid cannot be synthesized in mammalian tissues, and are therefore
essential fatty acids and must be obtained from the diet.
Triacylglycerol synthesis takes place in the
endoplasmic reticulum by metabolic pathways in which acyl groups in fatty acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol.
Terpenes and
isoprenoids, including the
carotenoids, are made by the assembly and modification of
isoprene units donated from the reactive precursors
isopentenyl pyrophosphate and
dimethylallyl pyrophosphate.
These precursors can be made in different ways. In animals and
archaea, the
mevalonate pathway produces these compounds from acetyl-CoA, while in plants and bacteria the
non-mevalonate pathway uses pyruvate and
glyceraldehyde 3-phosphate as substrates.
[ One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.]Degradation
Beta oxidation is the metabolic process by which fatty acids are broken down in the mitochondria and/or in peroxisomes to generate acetyl-CoA. For the most part, fatty acids are oxidized by a mechanism that is similar to, but not identical with, a reversal of the process of fatty acid synthesis. That is, two-carbon fragments are removed sequentially from the carboxyl end of the acid after steps of dehydrogenation, hydration, and oxidation to form a beta-keto acid, which is split by thiolysis. The acetyl-CoA is then ultimately converted into ATP, CO2, and H2O using the citric acid cycle and the electron transport chain. The energy yield of the complete oxidation of the fatty acid palmitate is 106 ATP. Unsaturated and odd-chain fatty acids require additional enzymatic steps for degradation.Nutrition and health
Most of the lipid found in food is in the form of triacylglycerols, cholesterol and phospholipids. A minimum amount of dietary fat is necessary to facilitate absorption of fat-soluble vitamins (A, D, E and K) and carotenoids. Humans and other mammals have a dietary requirement for certain essential fatty acids, such as linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) because they cannot be synthesized from simple precursors in the diet. Both of these fatty acids are 18-carbon polyunsaturated fatty acids differing in the number and position of the double bonds. Most vegetable oils are rich in linoleic acid (safflower, sunflower, and corn oils). Alpha-linolenic acid is found in the green leaves of plants, and in selected seeds, nuts and legumes (particularly flax, rapeseed, walnut and soy).
A few studies have suggested that total diary fat intake is linked to an increased risk of obesitySee also
