Miscellaneous Lipid Sulfates and Sulfonates
Sulfation is a common reaction in lipid biochemistry for many reasons. For example, it can enable solubilization of a lipid or it can convert a complex lipid to a highly anionic form for specific purposes in membranes. 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. Sphingolipid sulfates are vital for the function of the brain and kidney, amongst other tissues, and they have their own web page on this site. Similarly, seminolipid, cholesterol sulfate and lipo-chitooligosaccharides (Nod factors) are important sulfur-containing lipids, which are discussed on other web pages on this website for reasons of their relevance to other topics. 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. Because of its biosynthetic and functional relationship to the mono- and digalactosyldiacylglycerols, it is also discussed in a separate web page. However, there remain many other interesting lipid sulfates and sulfonates, which are of crucial importance to the organisms that produce them.
The phytoflagellate Ochromonas danica (a chrysophyte alga) contains a number of linear alkanes (C22 and C24) substituted with sulfate groups and with both sulfate groups and chlorine, 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 examples are illustrated. Of these 'danicalipin A' (the last illustrated) is the major component, and the stereochemistry of the substituents has been determined.
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 two 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. O. danica is unable to remove the sulfate groups, so 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, which 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. Haines has postulated that an as yet unidentified molecule, possibly a divalent metal ion or protein bearing charged residues, offsets the negative charge of the sulfate group at the physiological pH. 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, and 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. For example, 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.
2. Taurine-containing Lipids (Taurolipids)
A number of 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. It is very rare in plants but is plentiful in animal tissues, especially the brain.
N-acyltaurines: These lipids 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 animals that have signalling functions in tissues. 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 acyltransferase, acyl-CoA amino acid N-acyltransferase-1. 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).
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 have been shown to induce a significant inhibition of a cancer cell line in vitro, but the 20:0 and 24:0 fatty acyl analogues are produced endogenously in vivo and regulate the healing of skin wounds in mice. Arachidonoyltaurine has been shown to be an excellent substrate for lipoxygenases, but the functions of the resulting hydroxyeicosatetraenoyltaurines have yet to be determined. Docosahexaenoyl-taurine 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 similarly acylated. 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.
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 fatty acids, which are conjugated in turn to polyunsaturated fatty acids, were shown to be 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 defense response. An unusual N-acyltaurine, linked to a dihydroxy acid, has been found in a sea urchin. Cerilipin is a bacterial analogue of the ornithine lipids and is discussed in that context.
A tauroglycolipid, 1,2-diacyl-3-glucuronopyranosyl-sn-glycerol taurineamide, was isolated from a seawater bacterium Hyphomonas jannaschiana, which has the further unusual feature of an absence of phospholipids. The main fatty acyl chains are saturated and monoenoic (C16 to C20).
An unusual ganglioside, taurine-conjugated GM2, has been isolated from brain samples from patients with Tay-Sachs disease, a well-known glycosphingolipid (GSL) storage disease. In this distinctive lipid, the carboxyl group of N-acetylneuraminic acid is amidated by taurine. 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. The marine roseobacter species Ruegeria pomeroyi contains an analogue of the ornithine lipids in which the amine component appears to be aminopropane sulfonic acid, a homologue of taurine.
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. They are believed to elicit the release of volatile organic compounds as a defence response when the insects graze upon plants. Sulfate esters of oleate, linoleate and linolenate have now been found in some fungal species, where they may have antifungal activity. 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.
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 acids that are characteristic of Mycobacteria (phthioceranic acids). 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).
Biosynthesis is initiated by a sulfotransferase that converts trehalose into trehalose-2-sulfate. As trehalose sulfates increase the virulence of M. tuberculosis in human cells in vitro, but apparently not in other animal models, inhibition of their biosynthesis is an important pharmacological target. 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. This has 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.
As discussed in our web page on Archaeal lipids, these extremophiles and especially those that tolerate high salinity can contain mono- and bis-sulfated diglycosyl diphytanylglyceroldiethers and phosphatidylglycerosulfate.
4. Sulfono-analogues of Sphingolipids
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 derivative of ceramide, N-fatty acyl capnine, is recognized as a major lipid component of gliding bacteria of the genera Cytophaga, Capnocytophaga, Sporocytophaga, and Flexibacter. These are organisms that are able to 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 N-acylated derivatives, though up to 20% of other homologues can occur, depending on species. Though 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 and 3.
The experimental evidence suggests that biosynthesis of capnine occurs by the condensation of 13-methylmyristoyl-coenzyme A with cysteic acid (R-2-amino-3-sulfopropanoic acid) in a manner analogous to the condensation of palmitoyl-coenzyme A with serine during the biosynthesis of sphingoid bases. The function of capnoids is obscure, but there are suggestions that they may have a role in the motility of the organisms.
Essentially the same lipids but termed sulfobacins A and B, 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. Similar lipids termed flavocristamides A and B were isolated from a marine bacterium Flavobacterium sp., and in the Gram-negative sea-water bacterium Cyclobacterium marinus. Subsequently, a new sulfonolipid with some structural affinity to the capnoids was isolated from the halophilic bacteria Salinibacter ruber and Salisaeta longa. It has the structure 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 relatives of animals and are normally unicellular, 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 also produces an inhibitor of rosette formation termed 'Inhibitor of Rosettes (IOR-1)' in the form of a further sulfonolipid, which is related structurally to the capnoid bases but with a hydroxyl group replacing the amine group to give the rare syn-diol configuration, i.e. 2S, 3R stereochemistry. It has been determined that there is an absolute requirement for the observed stereochemistry for all of these metabolites to exert their functions.
- Baronio, M., Lattanzio, V.M.T., Vaisman, N., Oren, A. and Corcelli, A. The acylhalocapnines of halophilic bacteria: structural details of unusual sulfonate sphingoids. J. Lipid Res., 51, 1878-1885 (2010); DOI.
- Bedke, D.K. and Vanderwal, C.D. Chlorosulfolipids: Structure, synthesis, and biological relevance. Nat. Prod. Rep., 28, 15-25 (2011); DOI.
- Bisseret, P., Ito, S., Tremblay, P.A., Volcani, B.E., Dessort, D. and Kates, M. Occurrence of phosphatidylsulfocholine, the sulfonium analog of phosphatidylcholine in some diatoms and algae. Biochim. Biophys. Acta, 796, 320-327 (1984); DOI.
- Corcelli, A., Lattanzio, V.M.T., Mascolo, G., Babudri, F., Oren, A. and Kates, M. Novel sulfonolipid in the extremely halophilic bacterium Salinibacter ruber. Appl. Env. Microbiol., 70, 6678-6685 (2004); DOI.
- Grevengoed, T.J. and 12 others. N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis. Proc. Natl. Acad. Sci. USA, 116, 24770-24778 (2019); DOI.
- Haines, T.H. Anionic lipid headgroups as a proton-conducting pathway along the surface of membranes: A hypothesis. Proc. Natl Acad. Sci. USA, 80, 160-164 (1983); DOI.
- Kaya, K. Chemistry and biochemistry of taurolipids. Prog. Lipid Res., 31, 87-108 (1992); DOI.
- Li, Y.T., Maskos, K., Chou, C.W., Cole, R.B. and Li, S.C. Presence of an unusual GM2 derivative, taurine-conjugated GM2, in Tay-Sachs brain. J. Biol. Chem., 278, 35286-35291 (2003); DOI.
- Rhoades, E.R., Streeter, C., Turk, J. and Hsu, F.F. Characterization of sulfolipids of Mycobacterium tuberculosis H37Rv by multiple-stage linear ion-trap high-resolution mass spectrometry with electrospray ionization reveals that the family of sulfolipid II predominates. Biochemistry, 50, 9135-9147 (2011); DOI.
- Woznica, A., Cantley, A.M., Beemelmanns, C., Freinkman, E., Clardy, J. and King, N. Bacterial lipids activate, synergize, and inhibit a developmental switch in choanoflagellates. PNAS, 28, 7894-7899 (2016); DOI.
|Credits/disclaimer||Updated: August 18th, 2021||Author: William W. Christie|