Ether lipid explained

In biochemistry, an ether lipid refers to any lipid in which the lipid "tail" group is attached to the glycerol backbone via an ether bond at any position. In contrast, conventional glycerophospholipids and triglycerides are triesters.^[1] Structural types include:

• Ether phospholipids: phospholipids are known to have ether-linked "tails" instead of the usual ester linkage.^[1]
  • Ether on sn-1, ester on sn-2: "ether lipids" in the context of bacteria and eukaryotes refer to this class of lipids. Compared to the usual 1,2-diacyl-sn-glycerol (DAG), the sn-1 linkage is replaced with an ester bond.^{[1] [2] [3]}

Based on whether the sn-1 lipid is unsaturated next to the ether linkage, they can be further divided into alkenyl-acylphospholipids ("plasmenylphospholipid", 1-0-alk-1’-enyl-2-acyl-sn-glycerol) and alkyl-acylphospholipids ("plasmanylphospholipid"). This class of lipids have important roles in human cell signaling and structure.^[4]

• • Ether on sn-2 and sn-3: this class with flipped chirality on the phosphate connection is called an "archaeal ether lipid". With few (if any) exceptions, it is only found among archaea. The part excluding the phoshphate group is known as archaeol.^{[5] [6]}
• Ether analogues of triglycerides: 1-alkyldiacyl-sn-glycerols (alkyldiacylglycerols) are found in significant proportions in marine animals.^[5]
• Other ether lipids: a number of other lipids not belonging to any of the classes above contain the ether linkage. For example, seminolipid, a vital part of the testes and sperm cells, has a ether linkage.^[1]

The term "plasmalogen" can refer to any ether lipid with a vinyl ether linkage, i.e. ones with a carbon-carbon double bond next to the ether linkage. Without specification it generally refers to alkenyl-acylphospholipids, but "neutral plasmalogens" (alkenyldiacylglycerols) and "diplasmalogens" (dialkenylphospholipids) also exist.^[1] The prototypical plasmalogen is platelet-activating factor.^[7]

In eukaryotes

Biosynthesis

The formation of the ether bond in mammals requires two enzymes, dihydroxyacetonephosphate acyltransferase (DHAPAT) and alkyldihydroxyacetonephosphate synthase (ADAPS), that reside in the peroxisome.^[8] Accordingly, peroxisomal defects often lead to impairment of ether-lipid production.

Monoalkylglycerol ethers (MAGEs) are also generated from 2-acetyl MAGEs (precursors of PAF) by KIAA1363.

Functions

Structural

Plasmalogens as well as some 1-O-alkyl lipids are ubiquitous and sometimes major parts of the cell membranes in mammals.^[9] The glycosylphosphatidylinositol anchor of mammalian proteins generally consist of an 1-O-alkyl lipid.^[1]

Second messenger

Differences between the catabolism of ether glycerophospholipids by specific phospholipases enzymes might be involved in the generation of lipid second messenger systems such as prostaglandins and arachidonic acid that are important in signal transduction.^[10] Ether lipids can also act directly in cell signaling, as the platelet-activating factor is an ether lipid signaling molecule that is involved in leukocyte function in the mammalian immune system.^[11]

Antioxidant

Another possible function of the plasmalogen ether lipids is as antioxidants, as protective effects against oxidative stress have been demonstrated in cell culture and these lipids might therefore play a role in serum lipoprotein metabolism.^[12] This antioxidant activity comes from the enol ether double bond being targeted by a variety of reactive oxygen species.^[13]

Synthetic ether lipid analogs

Synthetic ether lipid analogs have cytostatic and cytotoxic properties, probably by disrupting membrane structure and acting as inhibitors of enzymes within signal transmission pathways, such as protein kinase C and phospholipase C.

A toxic ether lipid analogue miltefosine has recently been introduced as an oral treatment for the tropical disease leishmaniasis, which is caused by leishmania, a protozoal parasite with a particularly high ether lipid content in its membranes.^[14]

In archaea

The cell membrane of archaea consist mostly of ether phospholipids. These lipids have a flipped chirality compared to bacterial and eukaryotic membranes, a conundrum known as the "lipid divide". The "tail" groups are also not simply n-alkyl groups, but highly methylated chains made up of saturated isoprenoid units (e.g. phytanyl).^[15]

Among different groups of archaea, diverse modifications on the basic archaeol backbone have emerged.

• The two tails can be linked together, forming a macrocyclic lipid.^[15]
• Bipolar macrocyclic tetraether lipids (caldarchaeol), with two glycerol units connected by two C₄₀ "tail" chains, form covalently linked 'bilayers'.^{[16] [15]}
  • Some such covelant bilayers feature crosslinks between the two chains, giving an H-shaped molecule.^[15]
  • Crenarchaeol is a tetraether backbone with cyclopentane and cyclohexane rings on the cross-linked "tail"s.^[15]
• Some lipids replace the glycerol backbone with four-carbon polyols (tetriols).^[15]

In bacteria

Ether phospholipids are major parts of the cell membrane in anaerobic bacteria.^[1] These lipids can be variously 1-O-alkyl, 2-O-alkyl, or 1,2-O-dialkyl. Some groups have, like archaea, evolved tetraether lipids.^[17]

In prokaryotes

Some ether lipids found in marine animals are S-batyl alcohol, S-chimyl alcohol, and S-selachyl alcohol.

See also

• Membrane lipid
• Glycerol dialkyl glycerol tetraether

Notes and References

1. Web site: Ether lipids - glyceryl ethers, plasmalogens, aldehydes, structure, biochemistry, composition and analysis . William . Christie . vanc . www.lipidmaps.org.
2. Dean JM, Lodhi IJ . Structural and functional roles of ether lipids . Protein & Cell . 9 . 2 . 196–206 . February 2018 . 28523433 . 5818364 . 10.1007/s13238-017-0423-5 .
3. Ford DA, Gross RW . 1042240 . Differential metabolism of diradyl glycerol molecular subclasses and molecular species by rabbit brain diglyceride kinase . The Journal of Biological Chemistry . 265 . 21 . 12280–6 . July 1990 . 10.1016/S0021-9258(19)38342-5 . 2165056 . free .
4. Dean . JM . Lodhi . IJ . Structural and functional roles of ether lipids. . Protein & Cell . February 2018 . 9 . 2 . 196–206 . 10.1007/s13238-017-0423-5 . 28523433. 5818364 .
5. Villanueva . Laura . von Meijenfeldt . F. A. Bastiaan . Westbye . Alexander B. . Yadav . Subhash . Hopmans . Ellen C. . Dutilh . Bas E. . Damsté . Jaap S. Sinninghe . Bridging the membrane lipid divide: bacteria of the FCB group superphylum have the potential to synthesize archaeal ether lipids . The ISME Journal . January 2021 . 15 . 1 . 168–182 . 10.1038/s41396-020-00772-2. 32929208 . 7852524 . 2021ISMEJ..15..168V .
6. Web site: Di- and Tetra-Alkyl Ether Lipids of the Archaea . lipidmaps.org.
7. Book: Ronald Ross . Watson . Fabien . De Meester . vanc . Omega 3 fatty acids in brain and neurological health . 2014 . Elsevier Academic Press . 978-0-12-410527-0 . 10.1016/C2012-0-06006-1 .
8. Hajra AK . Glycerolipid biosynthesis in peroxisomes (microbodies) . Progress in Lipid Research . 34 . 4 . 343–64 . 1995 . 8685243 . 10.1016/0163-7827(95)00013-5 .
9. Paltauf F . Ether lipids in biomembranes . Chemistry and Physics of Lipids . 74 . 2 . 101–39 . December 1994 . 7859340 . 10.1016/0009-3084(94)90054-X .
10. Spector AA, Yorek MA . Membrane lipid composition and cellular function . Journal of Lipid Research . 26 . 9 . 1015–35 . September 1985 . 10.1016/S0022-2275(20)34276-0 . 3906008 . 2007-03-08 . 2008-10-10 . https://web.archive.org/web/20081010231534/http://www.jlr.org/cgi/reprint/26/9/1015 . dead . free .
11. Demopoulos CA, Pinckard RN, Hanahan DJ . Platelet-activating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators) . The Journal of Biological Chemistry . 254 . 19 . 9355–8 . October 1979 . 10.1016/S0021-9258(19)83523-8 . 489536 . free .
12. Brosche T, Platt D . The biological significance of plasmalogens in defense against oxidative damage . Experimental Gerontology . 33 . 5 . 363–9 . August 1998 . 9762517 . 10.1016/S0531-5565(98)00014-X . 20977817 .
13. Engelmann B . Plasmalogens: targets for oxidants and major lipophilic antioxidants . Biochemical Society Transactions . 32 . Pt 1 . 147–50 . February 2004 . 14748736 . 10.1042/BST0320147 .
14. Lux H, Heise N, Klenner T, Hart D, Opperdoes FR . Ether--lipid (alkyl-phospholipid) metabolism and the mechanism of action of ether--lipid analogues in Leishmania . Molecular and Biochemical Parasitology . 111 . 1 . 1–14 . November 2000 . 11087912 . 10.1016/S0166-6851(00)00278-4 .
15. 10.1016/j.bbalip.2016.12.006. Archaeal phospholipids: Structural properties and biosynthesis . 2017 . Caforio . Antonella . Driessen . Arnold J.M. . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1862 . 11 . 1325–1339 . 28007654 . 27154462 .
16. Koga Y, Morii H . Recent advances in structural research on ether lipids from archaea including comparative and physiological aspects . Bioscience, Biotechnology, and Biochemistry . 69 . 11 . 2019–34 . November 2005 . 16306681 . 10.1271/bbb.69.2019 . free .
17. Grossi . V . Mollex . D . Vinçon-Laugier . A . Hakil . F . Pacton . M . Cravo-Laureau . C . Mono- and dialkyl glycerol ether lipids in anaerobic bacteria: biosynthetic insights from the mesophilic sulfate reducer Desulfatibacillum alkenivorans PF2803T. . Applied and Environmental Microbiology . 1 May 2015 . 81 . 9 . 3157–68 . 10.1128/AEM.03794-14 . 25724965. 4393425. 2015ApEnM..81.3157G .