Example of an ethanolamine plasmalogen with the characteristic vinyl ether linkage at the sn-1 position and an ester linkage at the sn-2 position
Plasmalogens are a class ofglycerophospholipid with aplasmenyl group linked to a lipid at the sn-1 position of the glycerol backbone. Plasmalogens are found in multiple domains of life, includingmammals,invertebrates,protozoa, andanaerobic bacteria. They are commonly found in cell membranes in thenervous,immune, andcardiovascular systems.[1][2][3] In humans, lower levels of plasmalogens are studied in relation to some diseases. Plasmalogens are also associated with adaptations to extreme environments in non-human organisms.
Glycerophospholipids of biochemical relevance are divided into three subclasses based on the substitution present at thesn-1 position of theglycerol backbone:acyl,alkyl andalkenyl.[4] Of these, the alkyl and alkenyl moiety in each case form anether bond, which makes for two types ofether phospholipids,plasmanyl (alkyl moiety at sn-1), andplasmenyl (alkenyl moiety with vinyl ether linkage at sn-1).Plasmalogens are plasmenyls with anester (acyl group) linked lipid at the sn-2 position of the glycerol backbone,[5][6] chemically designated 1-0(1Z-alkenyl)-2-acyl-glycerophospholipids.[7] The lipid attached to thevinylether at sn-1 can be C16:0, C18:0, or C18:1 (saturated and monounsaturated),[7][5] and the lipid attached to the acyl group at sn-2 can be C22:6 ω-3 (docosahexaenoic acid) or C20:4 ω-6 (arachidonic acid), (both are polyunsaturated acids).[8] Plasmalogens are classified according to their head group, mainly asPC plasmalogens (plasmenylcholines) andPE plasmalogens (plasmenylethalomines).[9][10] Plasmalogens should not be confused with plasmanyls.
Plasmalogens are found in numerous human tissues, with particular enrichment in the nervous, immune, and cardiovascular systems.[1][2][3] In human heart tissue, nearly 30–40% ofcholineglycerophospholipids are plasmalogens. Even more striking is the fact that 32% of the glycerophospholipids in the adult human heart and 20% in brain and up to 70% of myelin sheath ethanolamine glycerophospholipids are plasmalogens.[11]
Although the functions of plasmalogens have not yet been fully elucidated, it has been demonstrated that they can protect mammalian cells against the damaging effects ofreactive oxygen species.[1][2][3] In addition, they have been implicated as being signaling molecules and modulators of membrane dynamics.
Plasmalogens were first described by Feulgen and Voit in 1924 based on studies of tissue sections.[1] They treated these tissue sections with acid ormercuric chloride as part of a method to stain the nucleus. This resulted in the breakage of the plasmalogen vinyl-ether bond to yieldaldehydes. In turn, the latter reacted with afuchsine-sulfurous acid stain used in this nuclear staining method and gave rise to colored compounds inside the cytoplasm of the cells. Plasmalogens were named based on the fact that these colored compounds were present in the "plasmal" or inside of the cell.[1]
Biosynthesis of plasmalogens begins with association ofperoxisomal matrix enzymesGNPAT (glycerone phosphate acyl transferase) andAGPS (alkyl-glycerone phosphate synthase)on the luminal side of the peroxisomal membrane.[12]These two enzymes can interact with each other to increase efficiency. Therefore,fibroblasts without AGPS activity have a reduced GNPAT level and activity.[13][14]
The first step of the biosynthesis is catalyzed by GNPAT. This enzyme acylatesdihydroxyacetone phosphate at the sn-1 position. This is followed by the exchange of the acyl group for an alkyl group by AGPS.[15]The 1-alkyl-DHAPdihydroxyacetone phosphate is then reduced to 1-O-alkyl-2-hydroxy-sn-glycerophosphate (GPA) by an acyl/alkyl-dihydroxyacetone phosphatereductase located in both peroxisomal andendoplasmatic reticulum membranes.[16]All other modifications occur in the endoplasmatic reticulum. There anacyl group is placed at the sn-2 position by an alkyl/acyl GPAacyltransferase and the phosphate group is removed by aphosphatidic acid phosphatase to form 1-O-alkyl-2-acyl-sn-glycerol.
Using CDP-ethanolamine aphosphotransferase forms 1-O-alkyl-2-acyl-sn-GPEtn. After dehydrogenation at the 1- and 2-positions of thealkyl group by an electron transport system andplasmanylethanolamine desaturase the vinyl ether bond of plasmalogens is finally formed. The protein corresponding to plasmanylethanolamine desaturase has been identified and is called CarF in bacteria and PEDS1 (TMEM189) in humans (and animals).[17][18]Plasmenylcholine is formed from 1-O-alkyl-2-acyl-sn-glycerol bycholine phosphotransferase. As there is no plasmenylcholine desaturase choline plasmalogens can be formed only afterhydrolysis ofethanolamine plasmalogens to 1-O-(1Z-alkenyl)-2-acyl-sn-glycerol that can be modified by choline phosphotransferase and CDP choline.[19][20]
Peroxisome biogenesis disorders are autosomal recessive disorders often characterized by impaired plasmalogen biosynthesis. In these cases, the peroxisomal enzyme GNPAT, necessary for the initial steps of plasmalogen biosynthesis, is mislocalized to the cytoplasm where it is inactive. In addition, genetic mutations in theGNPAT orAGPS genes can result in plasmalogen deficiencies, which lead to the development ofrhizomelic chondrodysplasia punctata (RCDP) type 2 or 3, respectively.[21] In such cases, both copies of theGNPAT orAGPS gene must be mutated in order for disease to manifest. Unlike the peroxisome biogenesis disorders, other aspects of peroxisome assembly in RCDP2 and RCDP3 patients are normal as is their ability to metabolize very long chain fatty acids. Individuals with severe plasmalogen deficiencies frequently show abnormal neurological development, skeletal malformation, impaired respiration, and cataracts.[22]
During inflammation, neutrophil-derivedmyeloperoxidase produceshypochlorous acid, which causes oxidativechlorination of plasmalogens at the sn-1 chain by reacting with thevinyl ether bond.[26] Several researchers are currently investigating the impact of chlorinated lipids on pathology.
The lack of good methods to assay plasmalogen has created difficulties for scientists to assess how plasmalogen might be involved in human diseases other than RCDP and Zellweger spectrum, in which the involvement is certain.[20] There is some evidence in humans that low plasmalogens are involved in the pathology ofbronchopulmonary dysplasia, which is an important complication ofpremature birth.[20] One study showed that plasmalogen levels are reduced in people withCOPD who smoked compared with non-smokers.
In addition to mammals, plasmalogens are also found ininvertebrates and single cell organismsprotozoans. Amongbacteria they have been found in many anaerobic species includingClostridia,Megasphaera, andVeillonella. Among aerobic bacteria, plasmalogens occur in myxobacteria, and their plasmanylethanolamine desaturase (CarF) required to generate the vinyl ether bond, and hence plasmalogen, is conserved as TMEM189 in humans (and animals).[17] Plasmalogens have been shown to have a complex evolutionary history based on the fact that their biosynthetic pathways differ in aerobic and anaerobic organisms.[35]
Recently, it has been demonstrated that the red blood cells ofhumans andgreat apes (chimpanzees,gorillas andorangutans) have differences in their plasmalogen composition.[3] Total RBC plasmalogen levels were found to be lower in humans than inchimpanzees, orgorillas, but higher than inorangutans. Gene expression data from all these species caused the authors to speculate that other human and greatape cells and tissues differ in plasmalogen levels. Although the consequences of these potential differences are unknown, cross-species differences in tissue plasmalogens could influence organ functions and multiple biological processes.
Plasmalogens form a major component in the cell membranes of deep-sea animals like thecomb jelly, enhancing molecular resistance to high pressure.[36]
^abBraverman NE, Moser AB (September 2012). "Functions of plasmalogen lipids in health and disease".Biochim Biophys Acta.1822 (9):1442–52.doi:10.1016/j.bbadis.2012.05.008.PMID22627108.
^Brites P, Waterham HR, Wanders RJ (March 2004). "Functions and biosynthesis of plasmalogens in health and disease".Biochim Biophys Acta.1636 (2–3):219–31.doi:10.1016/j.bbalip.2003.12.010.PMID15164770.
^Hardeman D, van den Bosch H (November 1989). "Topography of ether phospholipid biosynthesis".Biochim Biophys Acta.1006 (1):1–8.doi:10.1016/0005-2760(89)90315-9.PMID2804060.
^abcdeBraverman, NE; Moser, AB (September 2012). "Functions of plasmalogen lipids in health and disease".Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.1822 (9):1442–52.doi:10.1016/j.bbadis.2012.05.008.PMID22627108.
^Meikle, Peter J.; Wong, Gerard; Tsorotes, Despina; Barlow, Christopher K.; Weir, Jacquelyn M.; Christopher, Michael J.; MacIntosh, Gemma L.; Goudey, Benjamin; Stern, Linda; Kowalczyk, Adam; Haviv, Izhak; White, Anthony J.; Dart, Anthony M.; Duffy, Stephen J.; Jennings, Garry L. (November 2011)."Plasma Lipidomic Analysis of Stable and Unstable Coronary Artery Disease".Arteriosclerosis, Thrombosis, and Vascular Biology.31 (11):2723–2732.doi:10.1161/ATVBAHA.111.234096.ISSN1079-5642.
