Miscellaneous Lipid Sulfates and Sulfonates


Sulfation is a common reaction in lipid biochemistry for many reasons, but especially in that it can enable solubilization of a lipid for transport or elimination, or it can convert a complex lipid to a highly anionic form for specific functions in membranes, or it can have a defence function against predators. Sulfonolipids have the sulfur atom linked directly to a carbon atom, while in lipid sulfates the sulfur is linked to the lipid component by an oxygen atom. Many interesting lipid sulfates and sulfonates, which are vital for the organisms that produce them, are described below, Scottish thistlebut other important sulfur-containing lipids are discussed elsewhere on this website for reasons of their relevance to other topics. For example, sphingolipid sulfates are essential for the function of the brain and kidney, amongst other tissues, and they have their own web page on this site. Other such molecules include seminolipid, sterol sulfates, phosphatidylsulfocholine, lipo-chitooligosaccharides (Nod factors) and some Archaeal lipids (extremophiles such as those that tolerate high salinity can contain mono- and bis-sulfated diglycosyl diphytanylglyceroldiethers and phosphatidylglycerosulfate).

The best known and most abundant of the sulfonolipids in nature is sulfoquinovosyldiacylglycerol or 1,2-di-O-acyl-3-O-(6'-deoxy-6'-sulfo-α-D-glucopyranosyl)-sn-glycerol, a key component of the photosynthetic mechanism of higher plants and other photosynthetic organisms, and because of its biosynthetic and functional relationship to the mono- and digalactosyldiacylglycerols, it is discussed in a separate web page.


1.   Chlorosulfolipids

The phytoflagellate Ochromonas danica (a chrysophyte alga) contains linear alkanes (C22 and C24) substituted with sulfate groups and with both sulfate groups and chlorine atoms, i.e., chlorosulfolipids, the discovery and exploration of which are largely associated with Thomas H. Haines. Generally, there are two sulfate groups in the 1 and 14 positions of the C22 alkyl chain (positions 1 and 15 of the C24 compounds), and there can be one to six chlorine atoms in various positions. They constitute approximately 15% of the total lipids, but 90% of the polar lipids of the flagella. Eight chlorosulfolipids have now been characterized from this organism, and some representative structures are illustrated. Of these, 'danicalipin A' (the last formula in the figure) is the major component, and the position and stereochemistry of each of the substituents has been determined.

Structures of some chlorosulfolipids of Ochromonas danica

Many aspects of the biosynthesis of these unusual lipids remain to be confirmed, but it is believed that docosanoic acid is hydroxylated at C14, before reduction to the 1,14-diol and sulfation. Chlorine atoms are presumed to be inserted into the saturated alkyl chain of the 1,14-diol sulfate in a stepwise fashion by a free radical process involving chlorinases, which have yet to be characterized. The end points of the biosynthetic process are 2,2,11,13,15,16-hexachloro-1,14-docosanediol disulfate and 2,2,12,14,16,17-hexachloro-1,15-tetracosanediol disulfate. As O. danica is unable to remove the sulfate groups, the lipids are remarkably inert metabolically. When this organism is grown with excess bromide ions, bromosulfolipids are produced with the same positional and stereochemical selectivity as in danicalipin A.

Such a high proportion of chlorosulfolipids (and an absence of phospholipids) in the flagella of O. danica implies that they must be the major constituents of the membranes of this organelle and must be differentiated in some manner from the contiguous exterior surface membranes. At first glance, it is not easy to understand how such lipids, which are highly soluble in water and carry a polar substituent in the centre of the hydrocarbon chain, can form a membrane bilayer. This can only be possible if there are some positively charged ions buried deep in the hydrocarbon layer that shield the negative sulfate groups, and Haines has postulated that an unidentified molecule, possibly a divalent metal ion or protein bearing charged residues, offsets the negative charge of the sulfate group at the physiological pH. Physical chemical studies suggest that danicalipin A inserts into lipid bilayers in the headgroup region to thins the bilayer and fluidizes it, permitting even saturated lipids to form fluid bilayers. The anionic lipid head groups may serve as a proton-conducting pathway along the surface of membranes.

Since the initial studies, a range of further chloro- and bromosulfolipids have been found in algae and other organisms, some as toxins affecting shellfish. Many of the chlorosulfolipids found in fresh-water algae are the same as those of O. danica, but others have some distinctive features, including a chlorovinylsulfate group. Complex multi-chloro-sulfolipids isolated from the digestive glands of toxic mussels are causative agents of diarrhetic shellfish poisonings, which tend to be associated with marine algal blooms, and mytilipin B isolated from the culinary mussel Mytilus galloprovincialis contains an ester-linked fatty acid in addition to eleven chlorine atoms and a sulfate moiety; the stereochemistry of this molecule is obviously highly complex.

Formula of mytilipin B


2.   Taurine-containing Lipids (Taurolipids)

Several lipids have been found that are conjugated to taurine (ethanolaminesulfonic acid), of which the best known are certain bile acids, which are discussed elsewhere on this site. Taurine itself is synthesised from cysteine via oxidation and decarboxylation reactions and is plentiful in animal tissues, especially the brain, but is very rare in plants.

N-acyltaurines: These lipids are endogenous bioactive acyl-amino acids and were first encountered in marine invertebrates, but there is increasing interest in a range of fatty N‑acyltaurines isolated from both the central nervous system and peripheral tissues of mice and the islets of Langherans and in plasma of humans that have signalling functions. In brain, the fatty acyl groups are largely long-chain saturated, but in liver and kidney, arachidonoyl and docosahexaenoyl species predominate, while N-oleoyltaurine is the most abundant form in plasma. They are believed to be produced through enzyme-dependent conjugation of fatty acyl-CoA esters with taurine via the action of the peroxisomal bile acid-CoA:amino acid N-acyltransferase in the liver of mice and humans. Like the other biologically active amides in animals, the levels of these metabolites are controlled by the activity of the fatty acid amide hydrolase (FAAH).

Formula of N-acyltaurines

N-Acyltaurines, and specifically N-oleoyltaurine, improve insulin sensitivity and augment the secretion of the anti-diabetic hormone GLP‑1, insulin and glucagon through activation of GPR119, an abundant receptor in pancreatic and intestinal endocrine cells. In kidney, N‑acyltaurines have been shown to activate receptors that control calcium channels. N‑Arachidonoyl- and N‑oleoyltaurine induce a significant inhibition of a cancer cell line in vitro, while the 20:0 and 24:0 fatty acyl analogues are produced endogenously in vivo and regulate the healing of skin wounds in mice. Arachidonoyltaurine is an excellent substrate for lipoxygenases, but the functions of the resulting hydroxyeicosatetraenoyltaurines have yet to be determined. Docosahexaenoyl-taurine in bile limits excess intestinal lipid absorption and averts hepatic lipid accumulation.

Other taurolipids: Aside from the bile acids, the first taurolipids to be recognized were novel C18 hydroxy acids (3, 4 or 5 hydroxyl groups) with an amide link to taurine, which were isolated from the ciliated protozoan Tetrahymena. The hydroxyl on carbon 3 is acylated with normal fatty acids (approx. 30% 16:0), i.e., it is an estolide, and in one variant, carbon 7 is acylated in the same way. The deacylated backbone has been termed ‘lipotaurine’. Biosynthesis is believed to involve conjugation of stearic acid with taurine, with subsequent sequential insertion of hydroxyl groups.

Formula of a taurolipid
Taurolipid R1 R2 R3 R4
 
Taurolipid A OH OH H H
7-Acyltaurolipid A CH3(CH2)14COO OH H H
Taurolipid B OH OH OH H
Taurolipid C OH OH OH OH

Marine invertebrates are a rich source of unusual lipids, including some containing taurine. For example, a biologically active taurine-containing lipid, termed 'irciniasulfonic acid B', was isolated from a marine sponge, Ircinia sp., and comprised 3-methyl-8-hydroxy-dec-2-enoic acid conjugated to taurine with various unusual fatty acids linked to the hydroxyl group; carteriosulfonic acids and taurospongin A are related lipids found in sponges. In addition, compounds termed copepodamides and consisting of taurine connected by an amide linkage to isoprenoid hydroxy fatty acids, to which polyunsaturated fatty acids are linked as estolides, are produced by marine copepods (zooplankton). At minute concentrations, these act as a signal to bloom-forming dinoflagellates (phytoplankton) and induce production of paralytic shellfish toxins, presumably as a defence response. An unusual N-acyltaurine, linked to a dihydroxy acid, has been found in a sea urchin.

Formulae of miscellaneous taurolipids

A tauroglycolipid, 1,2-diacyl-3-glucuronopyranosyl-sn-glycerol taurineamide, was isolated from a seawater bacterium Hyphomonas jannaschiana, which has another unusual feature in that it lacks phospholipids. The main fatty acyl chains are saturated and monoenoic (C16 to C20).

Formula of 1,2-diacyl-3-glucuronopyranosyl-sn-glycerol taurineamide

Formula of cysteinolide AA novel ganglioside with the carboxyl group of N-acetylneuraminic acid amidated by taurine has been isolated from brain samples from patients with Tay-Sachs disease, a well-known glycosphingolipid (GSL) storage disease. As this lipid is not present in normal brains, it seems probable that it is associated with the pathogenesis of the disease, possibly as a means of removing the excess of ganglioside GM2 from the tissue.

One class of lipids have a substituted taurine component, i.e., an N,O-acylated cysteinolic acid-containing head group carrying various different (α‑hydroxy)carboxylic acids, and now termed cysteinolides, are produced by marine Roseobacter species, and were once erroneously identified as homotaurine analogues. Other unusal sulfolipids from these organisms are described below.


3.   Other Lipid Sulfates

The first sulfated fatty acids to be identified were the 'caeliferins', which were found in the oral secretions of a species of grasshopper and are believed to elicit the release of volatile organic compounds as a defence response when the insects graze upon plants. Synthetic caeliferin A (16:0) was found to induce significant production of jasmonic acid and ethylene in Arabidopsis at concentrations equivalent to those found in grasshopper saliva. Sulfamisterin produced by the fungus Pycnidiella sp., an analogue of the sphingoid bases, has antibiotic properties and it is a specific inhibitor of serine palmitoyltransferase, the key enzyme in the biosynthesis of such bases, while sulfate esters of oleate, linoleate and linolenate have now been found in some fungal species, where they may have antifungal activity. The lipid designated IOR-1A is produced by bacteria to inhibit rosette development in choanoflagellates. When under attack by predators, nematodes can emit fatty acid sulfates, iso-methyl-tetradecanoic acid with sulfate moieties at positions 9 or 10, for defence purposes.

Structures of caeliferin A, sulfamisterin and IOR-1A

The outer membranes of the cell walls of virulent strains of Mycobacterium tuberculosis contain a number of trehalose-containing glycolipids. Some of these are sulfated and consist of a sulfated trehalose moiety to which up to four fatty acids are linked, including palmitate or stearate and two or three of the very-long-chain multi-branched phthioceranic acids that are characteristic of Mycobacteria. There are two main forms; sulfolipid-I comprises a family of homologous 2‑palmitoyl(stearoyl)-3-phthioceranoyl(C37)-6,6'-bis(hydroxyphthioceranoyl)trehalose 2'-sulfates, while sulfolipid-II constitutes a family of homologous 2‑stearoyl(palmitoyl)-3,6,6'-tris(hydroxyphthioceranoyl)(C40)trehalose 2'-sulfates (see our web page on mycolic acids, where mycobacterial cell wall constituents are discussed at greater length).

Sulfolipid from Mycobacterium tuberculosis

Biosynthesis is initiated by a sulfotransferase that converts trehalose into trehalose-2-sulfate. As trehalose sulfates and especially sulfolipid-I increase the virulence of M. tuberculosis in human cells in vitro, an action enhanced by cord factor, a means of inhibition of their biosynthesis is a pharmacological target. The immunogenicity is dependent on the sulfate moiety, although the number of methyl substituents is a relevant factor. In an infection, they are reported to hijack the host cell membrane, affecting its order, fluidity and stiffness as well as interacting with the underlying cytoskeleton with profound effects on downstream signalling and on membrane-associated immune processes in the host. These lipids do not appear to be present in other species of Mycobacteria.


4.   Sulfono-Analogues of Sphingolipids (Capnoids)

1-Deoxyceramide-1-sulfonate was first isolated from the Bryozoa Watersipora cucullata and consists of a long chain-base analogous to sphinganine but with a sulfonate moiety attached to carbon 1. The predominant fatty acid (64%) in this lipid in Nitzschia alba is trans-3-hexadecenoic acid, which is normally associated with the phosphatidylglycerol of plant chloroplasts. A sulfonic acid analogue of ceramide, N-fatty acyl capnine, is a major lipid component of gliding bacteria of the genera Cytophaga, Capnocytophaga, Sporocytophaga and Flexibacter where it may have a role in the motility of the organisms. These are organisms that can move over solid surfaces, but not through liquids, although they do not appear to have flagella or other organs of propulsion. Capnine is 2-amino-3-hydroxy-15-methylhexadecane-1-sulfonic acid and occurs in the organisms both in the free form and as the N-acylated derivatives, though up to 20% of other homologues can occur, depending on species. Although it was not the first to be discovered, the generic term 'capnoid' is widely used for such lipids. The N-acyl fatty acids are much more heterogeneous and vary from C14 to C16 in chain-length, a high proportion with iso- or anteiso-methyl branches and hydroxyl groups in positions 2 or 3.

Capnoids - formulae

Essentially the same lipids but termed sulfobacins A and B (differing in the presence of a hydroxyl group), i.e., (2R,3R)-3-hydroxy-2-[(R)-3-hydroxy-15-methylhexadecanamido]-15-methylhexadecanesulfonic and (2R,3R)-3-hydroxy-15-methyl-2-[13-methyltetradecanamido]-hexadecanesulfonic acids, respectively, were found in several bacterial species from the genera Chryseobacterium, Alistipes and Odoribacterin (all from the Bacteroidetes phylum) in the gut microbiome in mice. Indeed, capnine lipids are now known to be common in the genus Bacteroidetes, including environmental, pathogenic and human oral and intestinal microbiome bacteria, but their function is obscure. In animals, they are known to be antagonists of the von Willebrand receptor of importance in platelet aggregation and thrombosis, and they are pro-inflammatory with mice primary macrophages. Similar lipids termed flavocristamides A and B were isolated from a marine bacterium Flavobacterium sp. and the Gram-negative sea-water bacterium Cyclobacterium marinus, and these have been shown to inhibit DNA polymerase α. Subsequently, a new sulfonolipid with some structural affinity to the capnoids was isolated from the halophilic bacteria Salinibacter ruber and Salisaeta longa, i.e., it is 2‑carboxy-2-amino-3,4-hydroxy-17-methyloctadec-5-ene-1-sulfonic acid for which the trivial name halocapnine is suggested. As its 3-O-acyl derivative (and not N-acyl), it represents about 10% of the total cellular lipids of the former.

Choanoflagellates are motile microbial eukaryotes that live in aquatic environments and feed on bacteria. They are believed to be the closest living unicellular relatives of animals, but on exposure to sulfonolipids related to the capnoids produced by Algoriphagus machipongonensis, a marine bacterium that serves as its prey the choanoflagellate, Salpingoeca rosetta, forms multicellular 'rosettes' in a manner that may provide insights into how multicellularity evolved in animals. Two such lipids have been isolated and characterized and they have been termed 'Rosette-Inducing Factors' - RIF-1 (illustrated) and RIF-2. Both have capnoid bases attached to 2‑hydroxy,iso-methylbranched fatty acids, but RIF-2 differs from RIF-1 in that the former has a double bond and second hydroxyl is in a different position of the capnoid component. S. rosetta is extraordinarily sensitive to RIF-1 and is induced to form rosettes at femtomolar (10‑15M) concentrations. Lysophosphatidylethanolamines produced also by the symbiotic bacteria elicit no response on their own but act synergistically with the RIFs to maximize the activity of the latter. The same bacterial species produce sulfobacins D and F (initially termed 'Inhibitor of Rosettes (IOR-1)'), and these are inhibitors of rosette formation in a concentration-dependent manner; presumably, they compete for the same cellular target. It has been determined that there is an absolute requirement for the observed stereochemistry for all of these metabolites to exert their functions.

The first steps in the biosynthesis of capnine occur by a reaction of O-phospho-L-serine with sulfite catalysed by a cysteate synthase to form cysteic acid (R-2-amino-3-sulfopropanoic acid), which is then condensed with 13-methylmyristoyl-ACP by a cysteate acyl-acyl carrier protein (ACP) transferase (SulA, from the α-oxoamine synthase protein superfamily) with pyridoxal phosphate as a cofactor to generate 3-ketocapnine as an intermediate. A reductase presumably converts this to capnine.

Biosynthesis of capnine

The reaction can be compared to the condensation of palmitoyl-coenzyme A with serine during the biosynthesis of sphingoid bases.


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