Plasmalogen

Plasmalogens are found in numerous human tissues, with particular enrichment in the nervous, immune, and cardiovascular systems.[8][9][10] In human heart tissue, nearly 30–40% of choline glycerophospholipids 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 of reactive oxygen species.[8][9][10] 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.[8] They treated these tissue sections with acid or mercuric chloride as part of a method to stain the nucleus. This resulted in the breakage of the plasmalogen vinyl-ether bond to yield aldehydes. In turn, the latter reacted with a fuchsine-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.[8]

Pathway of plasmalogen synthesis

Biosynthesis of plasmalogens begins with association of peroxisomal matrix enzymes GNPAT (glycerone phosphate acyl transferase) and AGPS (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 acylates dihydroxyacetone 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 phosphate reductase located in both peroxisomal and endoplasmatic reticulum membranes.[16] All other modifications occur in the endoplasmatic reticulum. There an acyl group is placed at the sn-2 position by an alkyl/acyl GPA acyltransferase and the phosphate group is removed by a phosphatidic acid phosphatase to form 1-O-alkyl-2-acyl-sn-glycerol.

Using CDP-ethanolamine a phosphotransferase forms 1-O-alkyl-2-acyl-sn-GPEtn. After dehydrogenation at the 1- and 2-positions of the alkyl group by an electron transport system and plasmanylethanolamine 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 by choline phosphotransferase. As there is no plasmenylcholine desaturase choline plasmalogens can be formed only after hydrolysis of ethanolamine 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 the GNPAT or AGPS genes can result in plasmalogen deficiencies, which lead to the development of rhizomelic chondrodysplasia punctata (RCDP) type 2 or 3, respectively.[21] In such cases, both copies of the GNPAT or AGPS 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]

Deficits in plasmalogen levels contribute to pathology in Zellweger syndrome.[20]

Plasmalogen-knockout mice show similar alterations like arrest of spermatogenesis, development of cataract and defects in central nervous system myelination.[9][23]

Plasmalogen alkyl chains have been shown to promote or inhibit the cell death from ferroptosis, depending on their degree of saturation.[24][25]

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 of bronchopulmonary dysplasia, which is an important complication of premature birth.[20] And one study shows that plasmalogen levels are reduced in people with COPD who smoked compared with non-smokers. There is some evidence from humans and animals that there are reduced levels of plasmalogens in the brain in neurodegenerative disorders including Alzheimer disease, Parkinson's disease, Niemann–Pick disease, type C, Down syndrome, and multiple sclerosis, it is not clear if this is causal or correlative.[20] A study with mice concluded that plasmalogens can eliminate aging-associated synaptic defects.[27]

In addition to mammals, plasmalogens are also found in invertebrates and single cell organisms protozoans. Among bacteria they have been found in many anaerobic species including Clostridia, Megasphaera, and Veillonella. 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.[28]

Recently, it has been demonstrated that the red blood cells of humans and great apes (chimpanzees, gorillas and orangutans) have differences in their plasmalogen composition.[10] Total RBC plasmalogen levels were found to be lower in humans than in chimpanzees, or gorillas, but higher than in orangutans. Gene expression data from all these species caused the authors to speculate that other human and great ape 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.

• Ether lipid

• Plasmalogens at the U.S. National Library of Medicine Medical Subject Headings (MeSH)