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Stereoselective synthesis of glycerol-based lipids
Fodran, Peter
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Chapter 1 An Introduction to Phospholipids
Abstract: Phospholipids are compounds with enormous significance for Life. For a
long time, they were considered as passive building blocks of the membranes.
However with the discovery of the phospholipid signalling, understanding of their
roles changed. In the first part, this chapter introduces the reader to the
nomenclature of phospholipids. The second part of this chapter briefly summarizes
the biosynthetic pathways of various phospholipid classes and presents some of their
functions in living organisms. The last part of this chapter presents an outline of this
thesis.
1
Chapter 1
Introduction
1
“Lipids” is a loosely defined term for substances of biological origin, soluble
in non-polar solvents.1 Chemically, lipids can be divided into non-saponifiable and
saponifiable lipids. Steroids, prostaglandins and fat soluble vitamins comprise the
class of non-saponifiable lipids. Glycerolipids, phospholipids, sphingolipids and
waxes constitute the class of saponifiable lipids. An intriguing difference between
these classes is that while non-saponifiable lipids act mostly as single molecules,
saponifiable lipids mainly act as a collective. This can be illustrated by the following
examples. Retinal (vitamin A) is a non-saponifiable lipid. Its molecular properties
allow light-induced cis/trans isomerization which is essential for vision (Figure 1-I).
Figure 1. ( I ) Cis/trans isomerization as a principle of vision; ( II ) organization of a lipid
raft in a liquid ordered membrane; ( III ) examples of a saponifiable lipids which act as single
molecules.
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An Introduction to Phospholipids
A mixture of saturated phospholipids, cholesterol and sphingolipids is a collective
(Figure 1-II) in the liquid ordered phase. In the membrane this collective forms an
organized lipid raft2 which is essential for signal transduction.3 As this classification
to saponifiable and non-saponifiable lipids is historical, it is easy to find exceptions.
For example, lipid 1 (Figure 1-III) is a typical membrane lipid surrounded by billions
of similar lipids (slightly) differing in the length of the fatty acids and the number of
the double bonds. However, in the entire collective of the membrane lipids, 1 is also
the lipid involved in inflammation processes.4 An example of a non-saponifiable lipid
fulfilling the role of a saponifiable lipid is the archaeal membrane lipid 2. The ether
bonds make 2 resistant to saponification, but the function which 2 fulfils is typical
for saponifiable lipids.
The main challenge in the studies of saponifiable lipids is their variability.
Terms like glycero-, phospho- and spingolipids frequently account for 10s to 1000s
related, but different molecular species. This variability is determined by the modular
structure of these lipids, described in Figure 2. In Nature, 40 common fatty acids
occur which differ in their chain length and the degree of unsaturation (Figure 2-I).
Triacylglycerols (Figure 2-II) are esters of glycerol and fatty acids. Given that the 3
hydroxyl groups can be esterified with any of the 40 fatty acids, the estimated number
of possible triacylglycerols approaches 64 000 (403). In the case of glycerophospholipids (Figure 2-II), one position of the glycerol is already occupied by any
of the 6 common phosphorus headgroups. The remaining 2 positions can again be
esterified by any of the 40 fatty acids resulting in up to 9 600 (6 x 402) different
species. Spingolipids can display even greater variability (Figure 2-III). The primary
hydroxyl group can carry either a phosphorous headgroup or a glycan core resulting
in more than 100 000 different species. The current knowledge of lipids is far away
from understanding the biological significance of this variability, but it has been
established that subtle deviations in the fatty acid composition of lipids can be linked
to heart5 and neurodegenerative diseases6 or metabolic syndrome.7
This chapter briefly introduces 3 topics that are important for this thesis. In
the first part, the reader is introduced to the nomenclature of the lipids. The second
part offers a brief overview of the biosynthesis of fatty acids, triacylglycerols and
phospholipids together with some of their biological properties. The last part of the
chapter presents the outline of this thesis.
3
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1
Figure 2. Variability of saponifiable lipids. ( I ) 40 common fatty acids; ( II ) variability in
glycerol based lipids; ( III ) variability in sphingolipids.
Nomenclature
Lipid research covers multiple fields of chemistry, biology and medicine.
Therefore it is not a surprise that a unified and universally applied nomenclature is
lacking. Despite the nomenclature for organic compounds is rigorously defined by
IUPAC8, this is happily ignored in lipid research. The following table (Table 1)
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An Introduction to Phospholipids
summarizes all the fatty acids that are mentioned in this thesis in all the common
nomenclatures.
Table 1. Names and symbols for fatty acids in this thesis.
Numerical
symbol
4:0
6:0
8:0
10:0
12:0
14:0
16:0
18:0
18:1(11)
18:2(9,12)
Structure
Systematic name
Trivial name
H3C-(hydrocarbon)-CO2H
-(CH2)2-(CH2)4-(CH2)6-(CH2)8-(CH2)10-(CH2)12-(CH2)14-(CH2)16-(CH2)7-CH=CH-(CH2)9-(CH2)5-(CH2CH=CH)2-(CH2)7-
(acid)
butanoic
hexanoic
octanoic
decanoic
dodecanoic
tetradecanoic
hexadecanoic
octadecanoic
Z-9-octadecenoic
Z,Z-octadeca-9,12dienoic
Z,Z,Z,Z-eicosa5,8,11,14-tetraenoic
(acid)
butyric
caproic
caprylic
capric
lauric
myristic
palmitic
stearic
oleic
linoleic
20:4(5,8,11,14) -(CH2)4-(CH2CH=CH)4-(CH2)3
arachidonic
The description of the stereochemistry of the glycerol-based lipids might be
confusing. Given that glycerol is a prochiral compound, its substitution can lead to
a pair of enantiomers. Chemically, these are easily described using the Cahn-IngoldPrelog system (CIP). Although unambiguous, this nomenclature can obscure
biosynthetic relationships, for example in the case of triacylglycerols. Triacylglycerols
are biosynthesized by acylation of a diacylglycerol (Figure 3). An example below
(Figure 3-I) shows that depending on the length of the introduced fatty acid, the
corresponding triacylglycerols might have opposite configurational prefixes in CIP
system. In order to clearly present biological relationships, Hirschmann9 introduced
a stereospecific numbering (sn) system. This is based on the Fischer projection of the
substituted glycerol, placed in such a way that the secondary hydroxyl group points
to the left. The carbon on top is then designated as the sn-1 position and carbon on
the bottom sn-3. The advantage of the Hirschmann system is that a formal inversion
of the configuration is not possible. For comparison, the acylation of diacylglycerol
that was confusing in CIP (Figure 3-I) is now defined as an acylation on the sn-3
position (Figure 3-II).
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Chapter 1
1
Figure 3. Comparison of 2 different systems for the stereochemical description of
glycerol-based lipids. ( I ) the CIP system commonly used in organic chemistry; ( II )
Hirschmanns system used in biology and biochemistry.
Biosynthesis of fatty acids, sphingolipids, triacylglycerols, and
glycerophospholipids
Biosynthesis of fatty acids
Fatty acids are the building blocks of lipids. Their de novo synthesis is one of
the key metabolic pathways in living organisms. Chemically, this process is a
decarboxylative malonic ester synthesis of acyl coenzyme A with malonyl coenzyme
A (6) (Figure 4) followed by a deoxygenation. The synthesis of fatty acids starts with
a covalent attachment of acetyl coenzyme A 3 to the acyl carrying protein (ACP).
Malonyl coenzyme A (6) enters the cycle after covalent attachment to the acyl carrier
protein (ACP). The condensation of 4 and 6 results in thioaceto acetate 7 and
liberation of CO2.
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An Introduction to Phospholipids
1
Figure 4. De novo biosynthesis of fatty acids.
The ß-keto group is first reduced to alcohol 8 by NADPH/H+ (Figure 4), which is
subsequently dehydrated to α,ß-unsaturated 9. The conjugated double bond of 9 is
reduced by NADPH/H+ and the resulting 10 can enter the second cycle.
Alternatively, 10 (or its higher homologue) can either be hydrolysed to the
corresponding fatty acid 11 or transthioesterified to acyl coenzyme A 12. All steps in
the fatty acid synthesis are catalyzed by a fatty acid synthase (FAS). In Nature, there
are 2 types of FAS. FAS type 1 is present in animals and fungi and FAS type 2 is
found in bacteria and plants. The difference between the 2 types is that FAS type 1
is a single enzyme with 7 distinct domains and FAS type 2 is an assembly of 7
separable enzymes. A notable exception is the CMN group of bacterial species
(Corynebacterium, Mycobacterium, and Nocardia), which possesses both types of FAS.10
Desaturation of fatty acids
The fatty acid synthases tightly cooperate with desaturases that introduce
double bonds in the fatty acid chain. The most common desaturation is the
conversion of stearic acid to oleic acid by abstraction of 9-pro-R and 10-pro-R
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1
hydrogens. In human metabolism, this is catalyzed by 3 membrane-bound proteins
(Figure 5). The necessary electrons come from the electron transport chain, which
begins by reduction of reductase bound FAD (E-FAD) by NADH.
Figure 5. Δ9 desaturation of fatty acids.
The electrons are further transferred to cytochrome b5 and finally to the non-heme
Fe of the desaturase. Iron in its Fe2+ state can interact with O2 and oxidize 13 to 14.
The resulting oleoyl coenzyme A (14) can be further elongated or desaturated.11,12
Once the fatty acid has the desired length and unsaturation(s), it can enter
other metabolic pathways. This can be, for example, further modification of the fatty
acid (i.e. methylation as in Mycobacterium tuberculosis, see Chapter 2) or conversion into
sphingolipids, triacylglycerols and glycerophospholipids.
Biosynthesis of sphingolipids
The biosynthesis of fatty acids is tightly connected to the biosynthesis of
sphingolipids (derivatives of sphingosine (21)) via palmitoyl coenzyme A (15). The
biosynthesis of 21 (Figure 6) starts with a decarboxylative condensation of 15 and
serine (16).
8
An Introduction to Phospholipids
1
Figure 6. Biosynthesis of sphingosine.
The resulting 17 is reduced to aminoalcohol 18. The nitrogen reacts with a fatty acid
coenzyme A and 19 is desaturated resulting in ceramide 20, which after hydrolysis of
the amide affords 21. Sphingosine (21) can be further modified (Figure 7) to
sphinholipids like cerebrosides 22, sphingomyelines 23 or gangliosides 24.
Figure 7. Examples of sphingolipids.
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1
Sphingolipids are responsible for diverse physiological functions. As the
membrane building blocks they are located at the outer leaflet of the phospholipid
bilayer.13 As signalling molecules14 sphingolipids are an important link between
overproduction of lipids and obesity.15
Biosynthesis of triacylglycerols and glycerophospholipids
The biosynthesis of triacylglycerols and glycerophospholipids is closely
related. Both pathways start with (R)-glycerol-1-phosphate (sn-glycerol-3-phosphate)
and share the same intermediates until the phosphatidic acid stage where the
pathways divide. First the biosynthesis of triacylglycerols is discussed.
Biosynthesis of triacylglycerols
The dominant route producing more than 90%16,17,18 of the triacylglycerols is
called the Kennedy pathway.19 In the endoplasmic reticulum, (R)-glycerol-1phosphate (sn-glycerol-3-phosphate) 25 (Figure 8) is esterified with a fatty acid
coenzyme A to form lysophosphatidic acid 26. In the next step, 27 is esterified with
a second fatty acid coenzyme A.
Figure 8. The Kennedy pathway.
The phosphate in the phosphatidic acid 27 is hydrolysed and the resulting
diacylglycerol 28 is esterified with a third fatty acid coenzyme A to afford the
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An Introduction to Phospholipids
triacylglycerol 29. Subsequently, triacylglycerols can be stored in a specialized
organelle (a lipid droplet20) where they serve as energy reserve and precursors of
other lipid products.
Figure 9. ( I ) accumulation of triacylglycerols and fatty acids between the membrane
leaflets; ( II ) budding of a lipid droplet; ( III ) mature lipid droplet.
The mechanism of formation of the lipid droplets is poorly understood, but
a generally accepted theory states that these are formed by budding of the
endoplasmic reticulum (Figure 9)21 as a response to an elevated triacylglycerol
synthesis.22 Initially, the synthetized triacylglycerols concentrate between the leaflets
of the membrane (Figure 9-I). With the increasing amount of triacylglycerols, the
bud grows collecting more and more triacylglycerols (Figure 9-II). Finally, the lipid
droplet forms (Figure 9-III) as an independent organelle that can move into the
cytosol and interact with other organelles. Alternative mechanisms for the formation
of lipid droplets have been proposed by Ploegh23 and Walter and Farase.24
The content of the lipid droplets can be utilized when needed. The main
mechanism of utilization of the stored triacylglycerols and sterol esters is lipolysis.
Adipose triglyceride lipase and hormone sensitive lipase are moved to the surface of
the lipid droplet. The first enzyme hydrolyses at the sn-2 position of the
triacylglycerol. Hormone sensitive lipase further hydrolyses the 1,3-diacylglycerol to
a monoacylglycerol. The hydrolysis of the final fatty acid occurs in the cytosol and is
catalyzed by a monoacylglycerol lipase.25 The products of the hydrolysis of
triacylglycerols from the lipid droplets might be utilized for example in the
biosynthesis of phospholipids.
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1
As it was already mentioned, the biosynthesis of phospholipids is closely
related to the biosynthesis of triacylglycerols. The phosphatidic acid can be converted
to any of the 6 common phospholipids by 2 mechanisms. The first mechanism
involves cytidine triphosphate (CTP) activation of the phosphatidic acid leading to
phosphatidylinositols (PI), phosphatidylglycerols (PG) and cardiolipins. The second
mechanism utilizes CTP activation of the headgroup precursors leading to
phosphatidylcholines
(PC),
phosphatidylethanolamines
(PE)
and
phosphatidylserines (PS). The biosyntheses are presented in this order.
The activation of phosphatidic acid 27 (Figure 10) by CTP results in the cytidine
diphosphate (CDP) activated diacylglycerol 30 and liberation of diphosphate (PPi)
CDP activated 30 can react with inositol (31) resulting in phosphatidylinositol 32 and
cytidine monophosphate (CMP).
Figure 10. Biosynthesis of phospholipids via CTP activation of 27.
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An Introduction to Phospholipids
Alternatively, the CDP activated 30 (Figure 10) can react with 25, which after
hydrolysis of phosphate results in phosphatidylglycerol 34 type lipid. 34 can react
with an additional molecule of CDP-diacylglycerol, affording cardiolipin 35.26
The phosphatidyl inositol 32, phosphatidyl glycerol 34 and cardiolipin 35
families of lipids fulfil various important functions in the entire cellular life. For
example the PI lipids anchor membrane proteins to the outer leaflet of the
membrane (via protein lipidation, see chapter 6). Another important role of the PI
lipids is in signal transduction in the plant and the animal kingdom via the action of
a specific phospholipase C.27 By this mechanism, the PI lipids influence the activity
of dozens of enzymes belonging to the protein kinase C family, thus controlling key
cellular functions like differentiation, proliferation, metabolism and apoptosis. The
PG lipids serve as precursors for the cardiolipins. Cardiolipins are mainly found in
the mitochondrial membrane, where they bind and regulate the activity of various
proteins.28 Abnormalities in the cardiolipin metabolism can be linked to a variety of
diseases, including Barth syndrome29, Parkinson, Alzheimer30 and Tengier disease.31
The mentioned functions of the families of lipids (PI, PG and cardiolipins) form
only a fraction of what has been reported.
The phosphatidic acid 27 can be transformed into PC, PE and PS
phospholipids via the second mechanism involving activation of the headgroup
precursor by CTP. This pathway starts with hydrolysis of 27 to diacylglycerol 28
(Figure 11-I). The CDP-phosphorylating agents 38 and 39 are synthetized in the
cytosol by the same mechanism (Figure 11-II). The corresponding alcohols 36 are
phosphorylated with ATP resulting in phosphates 37. These react with CTP leading
to the phosphorylating agents 38 and 39, which are further transported to the
endoplasmic reticulum, where they phosphorylate diacylglycerol 28. Phosphorylation
of 28 with CDP-ethanolamine 38 results in phosphatidylethanolamine type lipid 40
and phosphorylation of 27 with 39 results in phosphatidylcholine lipid type 41. Both
40 and 41 can be further converted to phosphatidylserine 42 type lipids. And finally,
42 can be converted back to 40 by decarboxylation.
PC, PE and PS lipids are the main building blocks of biological membranes.
PC is the most common lipid in animals and plants where it constitutes up to 50%
of all phospholipids. In bacteria, PC lipids are scarcer. Due to their molecular shape,
PC, PE and PS lipids have their preferred location in the membranes. PC lipids are
mainly located in the outer leaflet while PE and PS are located in the inner leaflet.
Distribution of the lipids between the leaflets is tightly regulated by enzymes –
flippases. However, in some events the distribution of the membrane lipids is altered.
13
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1
For example during apoptosis, PS lipids are moved to the outer leaflet, where they
are recognized by macrophages. By this mechanism the apoptic cell is removed
without triggering an inflamation.32
Figure 11. ( I ) Biosynthesis of phospholipids via CTP activation of the headgroup
precursors; ( II ) biosynthesis of the CDP activated headgroup precursors 38 and 39.
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An Introduction to Phospholipids
Biosynthesis of non-archaeal ether based lipids
1
Plasmologens are ether analogues of the PE and PC lipids. Despite being
structurally related, their biosynthesis requires a specific pathway (Figure 12-I).
Figure 12. ( I ) Biosynthesis of plasmalogens; ( II ) mechanism of the substitution of acyl
for a long chain alcohol as the key step in the biosynthesis of plasmalogens.
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Chapter 1
1
The biosynthesis starts in the peroxisome, by acylation of dihydroxyacetone
phosphate (43). In the second step the carboxylate is substituted by a long-chain
alcohol resulting in 45. The mechanism of this step was elucidated by Brown and
Snyder (Figure 12-II)33. In the active site of the alkylglycerone phosphate synthase,
44 tautomerizes to 46, which after protonation leads to 47. The resulting carbocation
is attacked by a nucleophilic centre Nu of the protein (probably an amino group in
the active site) resulting in departure of the carboxylate. In a subsequent step 49
reacts with a long-chain alcohol. 50 undergoes an E1 type elimination leading to 51
which finally tautomerizes to ketone 45. Reduction of 45 (Figure 12-I) results in 53
which is acylated in the endoplasmic reticulum. From 57 on, the biosynthesis is
similar to the synthesis of PC or PE lipids. First the phosphate is hydrolyzed and
resulting 55 is phosphorylated by CDP activated choline or ethanolamine. In case of
the choline headgroup, the biosynthesis stops at this point. The lipids with
ethanolamine headgroup can be further desaturated to 58.
The biological functions of plasmalogens are still not fully understood.
Structurally, they help to maintain physical properties of the membranes.34 Broniec
et al.35 reported that the analogues of 56 act as scavengers of reactive oxygen
suggesting that they play a role in oxidative stress. An important plasmalogen is the
platelet activating factor (Figure 12-I), which is an extremely potent signalling
molecule triggering the platelet aggregation and immunological responses at pM
concentrations (10-11 M).36 An efficient synthesis of PAF is described in Chapter 3.
Outline of this thesis
Lipids play vital roles in many processes essential for life. This is illustrated
by a lipid membrane, which is a complex mixture of (phospho)lipids with various
chain lengths and degree of unsaturation. In this complex mixture, every single
component has an irreplaceable role. Of course, lipids are in principle accessible from
their natural sources, but their isolation and purification (from other lipids) is tedious
and often virtually impossible. A convincing example in this connection starts with
the impressive contribution of R. J. Anderson in 1927,37 who was the first to isolate
and describe tuberculostearic acid 59. For his studies, he needed 2 200 culture flasks
with a volume of 200 cm3. Only in 2010, 83 years later, it was established beyond
reasonable doubt that 59 is part of phospholipid 60 in M. tuberculosis.38 From 1 g of a
total lipid extract of M. tuberculosis, the authors isolated 50 μg of pure lipid 60, and
determined its structure by independent synthesis. For further illustration, 1 g of the
total lipid extract corresponds roughly to 20 g of bacteria.
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An Introduction to Phospholipids
Biology has a lot to gain from the availability of pure, well-defined, natural
and unnatural lipids in sufficient amounts, and organic chemistry can fulfil this need.
This is realized and illustrated in this thesis. In 7 chapters, novel, efficient, and
stereoselective approaches are described for the synthesis of ester-based and etherbased phospholipids and triacylglycerols.
Chapter 2 describes the catalytic asymmetric synthesis of methyl-branched
fatty acids (59 in Figure 13). The approach is based on conjugate addition of
methylmagnesium bromide to α,ß-unsaturated thioesters and subsequent chain
elongation to the desired length by Wittig reaction with a functionalized ylide. This
modular approach is applied in the synthesis of the fatty acid chain of caspofungin,
which allowed a study in the group of Prof. R. M. J. Liskamp (Molecular Medicinal
Chemistry, University of Utrecht) on the influence of the stereochemistry of this
fatty acid on its antifungal properties.
Figure 13. Examples of a fatty acid and lipid isolated from natural sources.
The theme of Chapter 3 is the transformation of fatty acids into
phospholipids. Here, the Jacobsen Co(II) salen complexes play an important role,
granting the regiospecific opening of protected glycidol with fatty acids. The chapter
further describes a migration-free deprotection of the resulting silylated
diacylglycerols, solving a long-standing problem in this field. It allows the synthesis
of various glycerophospholipids. A small modification of the catalyst opens a
convenient access to mixed ether/ester lipids represented by platelet activating
factor.
Chapter 4 is an extension of this methodology to the synthesis of enantiopure
triacylglycerols in just 3 synthetic steps. This allows the preparation of a small (>15)
17
1
Chapter 1
1
library of triacylglycerols, as a prelude to the determination of the composition of
(cow) milk fat, a piece de resistance in diary research.
Chapter 5 describes the influence of phospholipids on the function of
mechanosensitive channels of large conductance (MscL). In particular, the role of
methyl-branched lipid 60 on the MscL from the same species is studied and related
to their non-branched analogues.
Chapter 6 describes the synthesis of a fatty acid equipped with a strained
cyclooctyne. This “clickable fatty acid” is a promising tool for further studies in
chemical biology.
Chapter 7, composed of 2 parts, is dedicated to the synthesis of ether-based
Archaea lipids. In this chapter, the introduction is dedicated to the metabolism of
the unique Archaea lipids. Part one describes the synthesis of an intermediate in
Archaea lipid biosynthesis. This lipid has been used in the department of Molecular
Microbiology (GBB, Prof. A. J. M. Driessen) for the identification of CDP-archaeol
synthase, the missing link in this biosynthesis. The second part describes the
application of the aforementioned Co(II) salen complexes in a total synthesis of
cyclo-archaeol.
References and footnotes
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An Introduction to Phospholipids
(17)
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(20)
the alternative terms describing same organelle are: lipid bodies, oil bodies and
adiposomes
(21)
Martin, S.; Parton, R. G. Nat. Rev. Mol. Cell Biol. 2006, 7, 373.
(22)
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Guo, Y.; Cordes, K. R.; Farese, R. V.; Walther, T. C. J. Cell Sci. 2009, 122, 749.
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the biosynthesis of cardiolipins differs in prokaryotic and eucaryotic cells. The
depicted sequence corresponds to the prokaryotic cells.
(27)
Irvine, R. F. Curr. Opin. Cell Biol. 1992, 4, 212.
(28)
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Brown, A. J.; Snyder, F. J. Biol. Chem. 1983, 258, 4184.
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Farooqui, A. A.; Horrocks, L. A.; Farooqui, T. Chem. Phys. Lipids 2000, 106, 1.
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