University of Groningen

Stereoselective synthesis of glycerol-based lipidsFodran, 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.

Chapter 1

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Introduction

“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.

An Introduction to Phospholipids

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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 glycero-

phospholipids (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.

Chapter 1

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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)

An Introduction to Phospholipids

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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

Structure

H3C-(hydrocarbon)-CO2H

Systematic name

(acid)

Trivial name

(acid)

4:0 -(CH2)2- butanoic butyric

6:0 -(CH2)4- hexanoic caproic

8:0 -(CH2)6- octanoic caprylic

10:0 -(CH2)8- decanoic capric

12:0 -(CH2)10- dodecanoic lauric

14:0 -(CH2)12- tetradecanoic myristic

16:0 -(CH2)14- hexadecanoic palmitic

18:0 -(CH2)16- octadecanoic stearic

18:1(11) -(CH2)7-CH=CH-(CH2)9- Z-9-octadecenoic oleic

18:2(9,12) -(CH2)5-(CH2CH=CH)2-(CH2)7- Z,Z-octadeca-9,12-

dienoic

linoleic

20:4(5,8,11,14) -(CH2)4-(CH2CH=CH)4-(CH2)3 Z,Z,Z,Z-eicosa-

5,8,11,14-tetraenoic

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-Ingold-

Prelog 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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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.

An Introduction to Phospholipids

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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

Chapter 1

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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).

An Introduction to Phospholipids

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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.

Chapter 1

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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-1-

phosphate (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

An Introduction to Phospholipids

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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.

Chapter 1

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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.

An Introduction to Phospholipids

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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.

Chapter 1

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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.

An Introduction to Phospholipids

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Biosynthesis of non-archaeal ether based lipids

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.

Chapter 1

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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.

An Introduction to Phospholipids

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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 ether-

based 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)

Chapter 1

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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

(1) Moss, G. P.; Smith, P. A. S.; Tavernier, D. Pure Appl. Chem. 1995, 67, 1307.

(2) Pike, L. J. J. Lipid Res. 2003, 44, 655.

(3) Simons, K.; Toomre, D. Nat. Rev. Mol. Cell Biol. 2000, 1, 31.

(4) Fernandis, A. Z.; Wenk, M. R. Curr. Opin. Lipidol. 2007, 18, 121.

(5) Beilin, L. J.; Burke, V.; Puddey, I. B.; Mori, T. A.; Hodgson, J. M. Clin. Exp.

Pharmacol. Physiol. 2001, 28, 1078.

(6) Han, X. Front. Biosci. 2007, 12, 2601.

(7) Carpentier, Y. A.; Portois, L.; Malaisse, W. J. Am. J. Clin. Nutr. 2006, 83, S1499.

(8) Eur. J. Biochem. 1977, 79, 11.

(9) Hirschmann, H. J. Biol. Chem. 1960, 235, 2762.

(10) Gebhardt, H.; Meniche, X.; Tropis, M.; Krämer, R.; Daffé, M.; Morbach, S.

Microbiology 2007, 153, 1424.

(11) Nakamura, M. T.; Nara, T. Y. Annu. Rev. Nutr. 2004, 24, 345.

(12) Qiu, X. Prostaglandins Leukot. Essent. Fatty Acids 2003, 68, 181.

(13) Berridge, M. J. Nature 1993, 361, 315.

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(15) Summers, S. A. Prog. Lipid Res. 2006, 45, 42.

(16) Lehner, R.; Kuksis, A. J. Biol. Chem. 1993, 268, 8781.

An Introduction to Phospholipids

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(17) For other biosynthetic pathways see ref. 18 and 19.

(18) (a) Cagliari, A.; Margis, R.; Dos, S. M. F.; Turchetto-Zolet, A. C.; Loss, G.; Margis-

Pinheiro, M. Int. J. Plant Biol. 2011, 2, 40 (b) Coleman, R. A.; Lee, D. P. Prog. Lipid Res. 2004,

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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) Pol, A.; Martin, S.; Fernandez, M. A.; Ferguson, C.; Carozzi, A.; Luetterforst, R.;

Enrich, C.; Parton, R. G. Mol. Biol. Cell 2004, 15, 99.

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459.

(25) Guo, Y.; Cordes, K. R.; Farese, R. V.; Walther, T. C. J. Cell Sci. 2009, 122, 749.

(26) 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) Haines, T. H. Biochim. Biophys Acta - Biomembranes 2009, 1788, 1997.

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(32) Verhoven, B.; Schlegel, R. A.; Williamson, P. J. Exp. Med. 1995, 182, 1597.

(33) Brown, A. J.; Snyder, F. J. Biol. Chem. 1983, 258, 4184.

(34) Farooqui, A. A.; Horrocks, L. A.; Farooqui, T. Chem. Phys. Lipids 2000, 106, 1.

(35) Broniec, A.; Klosinski, R.; Pawlak, A.; Wrona-Krol, M.; Thompson, D.; Sarna, T.

Free Radic. Biol. Med. 2011, 50, 892.

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(37) Anderson, R. J. J. Biol. Chem. 1927, 74, 525.

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