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AMINO COMPOUND-CONTAINING LIPIDS

Amino acid-containing lipids

Acyl carnitines

Dopamine-containing lipids

5-HT containing lipids

Aminoalcohol-containing lipids

Urea-containing lipids

 


A – AMINO ACID-CONTAINING LIPIDS (Simple Lipoamino acids and lipopeptides)

Some bacteria species are known to contain in their inner and outer membranes amphipatic lipids based on one or two amino acids linked to a fatty acid through an amide bond and sometimes another through an ester bond. Thus, they have a structural similarity to ceramides or lipopolysaccharides.
Some of these conjugates of lipids and amino acids were also found in plants and in mammalian tissues.

New forms of these compounds are frequently described in marine organisms. Among them, unusual structures formed of fatty acids and amino acid derivatives (bromotyrosine) are isolated from sponges, they were named mololipids.

Surface-active molecules containing several amino acids and one or two fatty acids are produced by bacteria, but also in mammals, and are known as lipopeptides

Several types of lipoamino acids have been identified :

1 – Lipids containing serine

The best known is serratamic acid or hydroxydecanoyl serine.

hydroxydecanoyl serine

This compound was detected in Serratia species of bacteria (Cartwright NJ, Biochem J 1957, 67, 663).
It was suggested that this compound may contribute to the virulence of the bacteria (inhibition of phagocytosis, hemolytic activity). A hydroxydodecanoyl derivative is also known.

Another form was described in an opportunistic pathogen Flavobacterium (Kawai Y et al., Eur J Biochem 1988, 171, 73). In this compound (named "flavolipin"), serine is amide-linked to 3-hydroxyisoheptadecanoic acid which is esterified to isopentadecanoic acid. It has high hemaglutinating activity.

N-arachidonoyl serine was isolated from bovine brain (Milman G et al., PNAS 2006, 103, 2428). This compound binds very weakly to cannabinoid and vanilloid receptors but it was identified as an endocannabinoid-like constituent with vasodilatory properties.

Arachidonoyl serine


A N-acyl homoserine lactone (with an oxohexanoyl acyl group) was first described in Photobacterium fischeri and identified as an autoinducer of luciferase synthesis when excreted into the medium (Eberhard A et al., Biochemistry 1981, 20, 2444). Since these early observations, it has become evident that this lipo-amino acid is only one member of a growing family of acyl homoserine lactones which are produced by a wide spectrum of bacteria and are responsible for the regulation of diverse physiological processes in the corresponding producer organisms.
That family differs in either the presence or absence of an acyl chain C-3 substituent (oxo or hydroxy) or the length of the N-acyl side chain. One of the best studied among these molecules is N-(3-oxododecanoyl) homoserine lactone produced by Pseudomonas aeruginosa (Pearson JP et al., Proc Natl Acad Sci USA 1994, 91, 197) :  

This molecule was shown to activate several virulence genes and to be a component of the "quorum-sensing" system involved in nearly all gram-negative bacteria for controlling gene expression in response to population density. The term "quorum sensing" was coined by WC Fuqua in 1994 to describe the environmental sensing system that allows bacteria to monitor their own population density (WC Fuqua et al., J Bacteriol 1994, 176, 269). Later, quorum signaling molecules were shown to be implicated in the regulation of an array of important bacterial phenotypes including cell division, production of virulence factors, motility, sporulation, nodulation, plasmid transfer, antibiotic production, bioluminescence, and biofilm formation. It was also shown that some could be an important immune modulator (Telford G et al., Infect Immun 1998, 66, 36 and Chhabra SR et al., J Med Chem 2003, 46, 97). It has been demonstrated that N-(3-oxododecanoyl) homoserine lactone can promote the upreglation of proinflammatory cytokines and chemokines through the inhibition of PPARg receptors (Jahoor A et al., J Bacteriol 2008, 190, 4408). These results suggest that PPARg agonists could e employed as anti-inflammatory therapeutics for Pseudomonas aeruginosa infections. 
On another hand, there is now a considerable interest in the ability of specific enzymes to inactivate these molecules, thus decreasing the virulence of a number of pathogenic bacteria (Roche DM et al., Microbiology 2004, 150, 2023). Bacterial quorum sensing molecules are also recognized by eukaryotes. In this case, the cross-kingdom interaction can lead to specific adjustment and physiological adaptations in the colonized eukaryote (Hartmann A et al., J Chem Ecol 2012, 38, 704). 
It was shown that acylhomoserine lactones could be produced by bacteria associated with cultivated mushrooms (Prashanth SN et al., J Agric Food Chem 2011, 59, 11461).
The role played by acylhomeserine lactones in the rhizosphere signaling has been reviewed (Venturi V et al., Trends Plant Sci 2016, 21, 187).

Another type of homoserine lactone but with a coumaroyl group instead of an acyl group has been described in a photosynthetic bacterium Rhodopseudomonas palustris (Schaefer AL et al., Nature 2008, 454, 595). That compound (p-coumaroyl-homoserine lactone), synthesized from environmental p-coumaric acid, is used by the bacteria as quorum-sensing signal, which function with a receptor to control the expression of specific genes. It was also synthesized by other bacteria such as Bradyrhizobium and Silicibacter.

Coumaroyl-homoserine lactone
p-Coumaroyl-homoserine lactone



2 – Lipids containing ornithine

The most common structure of lipoamino acids shown below has a 3-hydroxy amide-linked acid which is itself esterified by a second fatty acid, generating an acyloxyacyl function. That structure is reminiscent of that found in lipid A of Gram-negative bacteria. They are found among others in several species of Bordetella, Pseudomonas, Flavobacterium and Achromobacter.

 

pict128.GIF (5373 octets)

This ornithine-containing lipid was recently found to be a strong stimulant for macrophages and, taking in account its biological activities, is expected to be used as a potent and nontoxic adjuvant in immunology studies (Kawai Y et al., FEMS Immunol Med Microbiol 1999, 23, 67). Similar molecules have been shown to protect animals from lethal endotoxemia (Kawai Y et al., Infect Immun 1991, 59, 2560).

Other forms were found in various Flavobacterium, opportunistic pathogens which cause infantile meningits (Kawai Y et al., Eur J Biochem 1988, 171, 73-80). In these compounds, ornithine is amide-linked to a hydroxylated fatty acid (3-hydroxyisoheptadecanoic acid) which is itself esterified to isopentadecanoic acid or 2-hydroxyisopentadecanoic acid. They were shown to exhibit high hemagglutinating activity.

Another form of ornithine-containing lipid is found in photosynthetic bacteria and contains amide and ester linkages between the amino acid and the fatty acids (one being normal, the other being hydrolylated).

One form synthesized by several bacteria species (Bordetella, Pseudomonas, Achromobavter) was found to be a strong stimulant for macrophages (Kawai Y et al., FEMS Immunol Med Microbiol 1999, 23, 67).

More complex forms containing ornithine linked to a fatty acid and a long-chain fatty alcohol were also described.
An interesting feature of these molecules appears to be in the membranes functionally interchangeable with phosphatidylethanolamine. Thus, in a culture of  Pseudomonas, phosphorus deficiency increases the acylornithine production to the exclusion of phospholipids (Minnikin DE et al., FEBS Lett 1974, 43, 257).

The bacterial Cerilipin described in Gluconobacter cerinus has an ornithine-containing lipid core but with an additional amide-linked taurine (Tahara Y. et al., Agric Biol Chem 1976, 40, 243). It was shown to exhibit excellent biosurfactant activity.

cerilipin


3 – Lipids containing tyrosine

A new series of lipophilic bromotyrosine derivatives was isolated as a white waxy extract from a Verongid sponge from Hawaii. Named mololipids, the extract contained a group of molecules consisting of bis-amides between a bromotyrosine derivative (formerly known as moloka’iamine) and long chain fatty acids ranging in size from C14  to C20 (Ross SA et al. J Nat Prod 2000, 63, 501). These compounds were shown to display anti-HIV activity.

Pure samples of mololipids with defined fatty acid composition have been prepared by total synthesis for pharmacological investigations (Schoenfeld RC et al., Bioorg Med Chem Lett 2000, 10, 2679).

4 – Lipids containing glycine

A glycine-containing lipoamino acid was described for the first time in a gliding bacteria, Cytophaga johnsonae

Its structure showed an iso-3-hydroxy heptadecanoic acid, amide linked to glycine and esterified to isopentadecanoic acid, it formed about 6% of the total bacteria lipids (Kawazoe R et al., J Bacteriol 1991, 173, 5470).

 Another glycine-containing lipoamino acid, a conjugate of arachidonic acid and glycine (N-arachidonoylglycine), was shown to be active against pain (Burstein SH et al., Prostaglandins Other Lipid Mediat 1999, 61, 29). It was later shown to be present in bovine and rat brain as well as in other tissues, Its biosynthesis and degradation being further observed to occur in the rat brain (Huang SM et al., J Biol Chem 2001, 276, 42639). Consistent with its high levels in skin and neural tissues, N-arachidonoylglycine is capable of suppressing pain via a peripheral action, suggesting that it may serve endogenously to regulate pain.

Arachidonylglycine

This lipoamino acid was first synthesized (Sheskin T et al., J Med Chem 1997, 40, 659) as a structural analog of the endogenous cannabinoid anandamide and later was shown to cause hot plate analgesia in mice (Burstein SH et al., Prost Lipid Mediat 1999, 61, 29). Thus, one possible physiological function of N-arachidonoylglycine is pain suppression (Huang SM et al., J Biol Chem 2001, 276, 42639)
It was reported that cyclooxygenase-2 selectively metabolized
N-arachidonoylglycine to PGH(2) glycine and hydroxyeicosatetraenoic glycine (Prusakiewicz JJ et al., Biochem Biophys Res Com 2002, 296, 612). These results suggest a possible role for cyclooxygenase-2 in the regulation of N-arachidonoylglycine levels and the formation of a novel class of eicosanoids.

Two other arachidonyl amino acids were shown to be natural constituents in mammalian brain: N-arachidonyl g-aminobutyric acid and N-arachidonoylalanine (Huang SM et al., J Biol Chem 2001, 276, 42639).

5 – Lipids containing Leucine

Lipstatin, a new and very potent inhibitor of pancreatic lipase (the key enzyme of intestinal fat digestion) was isolated from Streptomyces toxytricini  (Weibel EK et al., J Antibiot 1987, 1081). Lipstatin contains a beta-lactone ring, probably accounting for the irreversible lipase inhibition, which carries two aliphatic residues with chain lengths of 6 and 13 carbon atoms. One of the side chains contains two isolated double bonds and a hydroxy group esterified to N-formyl-leucine.

Several research were focused on the biosynthesis of that potent molecule (Eisenreich W et al., J Biol Chem 1997, 272, 867 and J Med Chem 2003, 46, 4209). Data indicate that the lipstatin molecule can be assembled by Claisen condensation of octanoyl-CoA with 3-hydroxy-tetradecanoyl-CoA formed from linoleic acid.
The tetrahydro derivative of lipstatin, Orlistat (Xenical), is used for the treatment of severe obesity in forming a covalent adduct with a serine moiety of human pancreatic lipase by transesterification.

6 – Lipids containing proline

In search of surfactants, it was shown that among several lipoaminoacids synthesized by coupling stearic acid with the a-amino group of an amino acid, N-stearoyl proline had the most efficient surface-active properties and is highly biodegradable. It has antimicrobial activity against several Gram-positive (Staphylococcus aureus, Micrococcus luteus, and Bacillus cerceus), and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, and against the yeast Candida albicans. Thus, it has a potential utility as biostatic additive in commercial products (Sivasamy A et al., JAOCS 2001, 78, 897). 

7 – Lipids containing glutamine

Volicitin, N-(17-hydroxylinolenoyl)-1-glutamine, has been identified in the oral secretions of caterpillars (Spodoptera exigua) shewing on corn (Alborn HT et al., Science 1997, 276, 945). That compound causes the plant to emit other volatile compounds which attract parasitoids or predators (wasps) of caterpillars. It has been determined that the plant provides linolenic acid which is conjugated onto glutamine molecule by the caterpillar (Pare PW et al., PNAS 1998, 95, 13971). Volicitin exhibited the widest range of phytohormone and volatile inducing activity, which spanned maize (Zea mays), soybean (Glycine max), and eggplant (Solanum melongena)


Volicitin

 

8 – Lipids containing taurine

A new structural class of fatty acid amides, N-acyl taurines, has been described in the central nervous system of mice (Saghatelian A et al., Biochemistry 2006, 45, 9007). 

arachidonoyl ttaurine

The fatty acids have a carbon chain of up to 20 carbon atoms. In peripheral tissues, N-acyl taurines are also present but have a polyunsaturated acyl chain (e.g., C20:4, C22:6). Their concentration rose more than 10-fold following inactivation of the catabolic enzyme fatty acid amide hydrolase. That dramatic elevation in endogenous levels of N-acyl taurines suggests the existence of a second major lipid signaling system regulated by the fatty acid amide hydrolase in vivo. N-acyl taurines were found to activate multiple members of the transient receptor potential (TRP) family of calcium channels in kidney, including TRPV1 and TRPV4. 
It was shown that N-acyl taurines may be a substrate for cyclooxygenases and lipoxygenases resulting in oxidative metabolites of N-arachidonoyl taurine which may have their own biological function (Turman MV et al., Biochemistry 2008, 47, 3917). Metabolism of arachidonoyl taurine by murine macrophages was analyzed, that compound being converted primarily to 12-HETE-taurine. Oxidative metabolism of polyunsaturated N-acyltaurines may thus represent a pathway for the generation or termination of novel signaling molecules.
N-Arachidonoyl taurine and N-oleoyl taurine have been shown to induce a significant reduction in proliferation of PC-3 cells, a human prostate adenocarcinoma cell line (Chatzakos V et al., Lipids 2012, 47, 355).

9 – Lipopeptides

A large number of cyclic lipopeptides including decapeptide antibiotics (gramicidins) and lipopeptide antibiotics (polymyxins), produced by Bacillus brevis (Marahiel M et al., Eur J Biochem 1977, 99, 49), respectively, possess remarkable surface-active properties.
As an example, the cyclic lipopeptide surfactin, produced by B. subtilis, is one of the most powerful biosurfactant known today. It lowers the surface tension from 72 to 27.9 mN/m at concentrations as low as 0.005% (Arima K et al., Biochem Biophys Res Commun 1968, 31, 488). Surfactin is composed of a seven-amino-acid ring structure coupled to one molecule of 3-hydroxy-13-methyl-tetradecanoic acid.

surfactin

A similar biosurfactant is produced by Bacillus licheniformis, with a lipophilic fatty acid moiety (4 different chain lengths) joined via a lactone linkage to a hydrophilic peptide ring structure (Jenny K et al., J Appl Microbiol Biotechnol 1991, 36, 5).

Cyclic lipopeptides are generally composed of seven amino acid units and a 3-hydroxy or 3-amino fatty acid. They have received considerable attention as key