Plasmalogen

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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 Plasmalogen.png
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

Glycerophospholipids of biochemical relevance are divided into three subclasses based on the substitution present at the sn-1 position of the glycerol backbone: acyl, alkyl and alkenyl. [1] Of these, the alkyl and alkenyl moiety in each case form an ether bond, which makes for two types of ether phospholipids, plasmanyl (alkyl moiety at sn-1), and plasmenyl (alkenyl moiety with vinyl ether linkage at sn-1). Plasmalogens are plasmenyls with an ester (acyl group) linked lipid at the sn-2 position of the glycerol backbone, [2] [3] chemically designated 1-0(1Z-alkenyl)-2-acyl-glycerophospholipids. [4] The lipid attached to the vinyl ether at sn-1 can be C16:0, C18:0, or C18:1 (saturated and monounsaturated), [4] [2] 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). [5] Plasmalogens are classified according to their head group, mainly as PC plasmalogens (plasmenylcholines) and PE plasmalogens (plasmenylethalomines) [6] [7] Plasmalogens should not be confused with plasmanyls.

Contents

Plasmalogens are commonly found in cell membranes in the nervous, immune, and cardiovascular systems. [8] [9] [10]

Functions

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.

History

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]

Biosynthesis

Pathway of plasmalogen synthesis Plasmalogen-synthesis-pathway.png
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]

Pathology

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]

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 vinyl 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 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]

Evolution

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.

See also

Related Research Articles

<span class="mw-page-title-main">Lipid</span> Substance of biological origin that is soluble in nonpolar solvents

Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries, and in nanotechnology.

<span class="mw-page-title-main">Peroxisome</span> Type of organelle

A peroxisome (IPA:[pɛɜˈɹɒksɪˌsoʊm]) is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen peroxide (H2O2) is then formed. Peroxisomes owe their name to hydrogen peroxide generating and scavenging activities. They perform key roles in lipid metabolism and the reduction of reactive oxygen species.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

<span class="mw-page-title-main">Glycerophospholipid</span> Class of lipids

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.

Cardiolipin is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most bacteria. The name "cardiolipin" is derived from the fact that it was first found in animal hearts. It was first isolated from the beef heart in the early 1940s by Mary C. Pangborn. In mammalian cells, but also in plant cells, cardiolipin (CL) is found almost exclusively in the inner mitochondrial membrane, where it is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism.

<span class="mw-page-title-main">Ether lipid</span>

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. This is in contrast to the more common ester linkage found in conventional glycerophospholipids and triglycerides. Structural types include:

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered as the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

sn-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of two stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of bacterial and eukaryotic glycerophospholipids. From a historical reason, it is also known as L-glycerol 3-phosphate, D-glycerol 1-phosphate, L-α-glycerophosphoric acid.

<span class="mw-page-title-main">Glycerol-3-phosphate dehydrogenase</span> Class of enzymes

Glycerol-3-phosphate dehydrogenase (GPDH) is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate to sn-glycerol 3-phosphate.

<span class="mw-page-title-main">Phosphatidylglycerol</span> Lipid

Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant and in the plasma membrane where it directly activates lipid-gated ion channels.

In enzymology, an acylglycerone-phosphate reductase (EC 1.1.1.101) is an enzyme that catalyzes the chemical reaction

In enzymology, a plasmanylethanolamine desaturase (EC 1.14.99.19) is an enzyme that catalyzes the chemical reaction

In enzymology, an alkenylglycerophosphocholine hydrolase (EC 3.3.2.2) is an enzyme that catalyzes the chemical reaction

In enzymology, a 1-acylglycerol-3-phosphate O-acyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a 1-alkyl-2-acetylglycerol O-acyltransferase is an enzyme that catalyzes the chemical reaction

In the field of enzymology, a glycerophospholipid arachidonoyl-transferase (CoA-independent) is an enzyme that catalyzes the chemical reaction:

In enzymology, a 1-alkenyl-2-acylglycerol choline phosphotransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Diacylglycerol cholinephosphotransferase</span>

In enzymology, a diacylglycerol cholinephosphotransferase is an enzyme that catalyzes the chemical reaction

Archaeol is composed of two phytanyl chains linked to the sn-2 and sn-3 positions of glycerol. As its phosphate ester, it is a common component of the membranes of archaea.

<span class="mw-page-title-main">Glycerol 1-phosphate</span> Chemical compound

sn-Glycerol 1-phosphate is the conjugate base of a phosphoric ester of glycerol. It is a component of ether lipids, which are common for archaea.

References

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  22. ↑ Braverman NE, Steinberg SJ, Fallatah W, et al. (2020). Adam MP, Ardinger HH, Pagon RA, et al. (eds.). "Rhizomelic Chondrodysplasia Punctata Type 1". GeneReviews® [Internet]. University of Washington. PMID   20301447. NBK1270.
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  24. ↑ Zou, Yilong; Henry, Whitney S.; Ricq, Emily L.; Graham, Emily T.; Phadnis, Vaishnavi V.; Maretich, Pema; Paradkar, Sateja; Boehnke, Natalie; Deik, Amy A.; Reinhardt, Ferenc; Eaton, John K. (September 2020). "Plasticity of ether lipids promotes ferroptosis susceptibility and evasion". Nature. 585 (7826): 603–8. Bibcode:2020Natur.585..603Z. doi:10.1038/s41586-020-2732-8. PMC   8051864 . PMID   32939090.
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