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Plasmalogens are a class of glycerophospholipid with a plasmenyl group linked to a lipid at the sn-1 position of the glycerol backbone. Plasmalogens are found in multiple domains of life, including Mammal, Invertebrate, protozoa, and anaerobic bacteria. They are commonly found in cell membranes in the nervous system, immune system, and cardiovascular systems. 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.
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. In addition, they have been implicated as being signaling molecules and modulators of membrane dynamics.
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. 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. 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). 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.
Deficits in plasmalogen levels contribute to pathology in Zellweger syndrome.
Plasmalogen-knockout mouse show similar alterations like arrest of spermatogenesis, development of cataract and defects in central nervous system myelination.
Plasmalogen alkyl chains have been shown to promote or inhibit the cell death from ferroptosis, depending on their degree of saturation.
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. A study with mice concluded that plasmalogens can eliminate aging-associated synaptic defects.
More recently, population studies have also associated lower circulating plasmalogen levels with cardiometabolic disease. Animal studies have also demonstrated lower cardiac plasmalogen levels under settings of dilated cardiomyopathy and myocardial infarction.
Plasmalogens form a major component in the cell membranes of deep-sea animals like the Ctenophora, enhancing molecular resistance to high pressure.
During inflammation
During inflammation, neutrophil-derived myeloperoxidase produces hypochlorous acid, which causes oxidative chlorination of plasmalogens at the sn-1 chain by reacting with the enol ether bond. Several researchers are currently investigating the impact of chlorinated lipids on pathology.
Possible disease links
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. 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. One study showed that plasmalogen levels are reduced in people with COPD who smoked compared with non-smokers.
Evolution
In bacteria
Plasmalogens are found in bacteria, but there are two separate biosynthetic pathways. One is the aerobic oxidation pathway of Myxobacteria based on the plasmanylethanolamine desaturase (CarF), which is homologous to the animal (and thus human) pathway. The other is the anaerobic reduction pathway of Clostridia, Megasphaera, and Veillonella, which instead generates plasmalogen directly from an ester. The fact that there are two different pathways suggest that plasmalogens have evolved twice in the history of life.
Among eukaryotes
Eukaryotes inherited an aerobic oxidation pathway from bacteria. In addition to mammals, plasmalogens are also found in invertebrates and single cell organisms loosely grouped as protozoans.
Among primates
In 2011 it was reported that the red blood cells of and (, and ) have differences in their plasmalogen composition. Total RBC plasmalogen levels were found to be lower in humans than in , or , but higher than in . 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.
See also
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