Glycerophospholipids
Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.
Structures
T ...
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. Of these, the alkyl and alkenyl moiety in each case form an ether bond, which makes for two types of
ether phospholipid
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
s, 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,
chemically designated 1-0(1Z-alkenyl)-2-acyl-glycerophospholipids.
The lipid attached to the vinyl ether at sn-1 can be C16:0, C18:0, or C18:1 (saturated and monounsaturated),
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). Plasmalogens are classified according to their head group, mainly as PC plasmalogens (plasmenylcholines) and PE plasmalogens (plasmenylethalomines) Plasmalogens should not be confused with plasmanyls.
Plasmalogens are commonly found in cell membranes in the
nervous,
immune
In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...
, and
cardiovascular system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
s.
Functions
Plasmalogens are found in numerous human tissues, with particular enrichment in the nervous, immune, and cardiovascular system.
In human heart tissue, nearly 30–40% of
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but re ...
glycerophospholipid
Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.
Structures
The t ...
s 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.
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 chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
.
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.
They treated these tissue sections with acid or
mercuric chloride
Mercury(II) chloride (or mercury bichloride, mercury dichloride), historically also known as sulema or corrosive sublimate, is the inorganic chemical compound of mercury and chlorine with the formula HgCl2. It is white crystalline solid and is a ...
as part of a method to stain the nucleus. This resulted in the breakage of the plasmalogen vinyl-ether bond to yield
aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
s. In turn, the latter reacted with a
fuchsine
Fuchsine (sometimes spelled fuchsin) or rosaniline hydrochloride is a magenta dye with chemical formula C20H19N3·HCl. -
sulfurous acid
Sulfurous acid (also sulfuric(IV) acid, sulphurous acid (UK), sulphuric(IV) acid (UK)) is the chemical compound with the formula . There is no evidence that sulfurous acid exists in solution, but the molecule has been detected in the gas phase. ...
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.
Biosynthesis
![Plasmalogen-synthesis-pathway](https://upload.wikimedia.org/wikipedia/commons/6/67/Plasmalogen-synthesis-pathway.png)
Biosynthesis of plasmalogens begins with association of
peroxisomal
A peroxisome () 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 per ...
matrix enzymes
GNPAT (glycerone phosphate acyl transferase) and
AGPS (alkyl-glycerone phosphate synthase)
on the luminal side of the peroxisomal membrane.
These two enzymes can interact with each other to increase efficiency. Therefore,
fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s without AGPS activity have a reduced GNPAT level and activity.
The first step of the biosynthesis is catalyzed by GNPAT. This enzyme acylates
dihydroxyacetone phosphate
Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; Co ...
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
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
membranes.
All other modifications occur in the endoplasmatic reticulum. There an
acyl
In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC n ...
group is placed at the sn-2 position by an alkyl/acyl GPA
acyltransferase and the phosphate group is removed by a
phosphatidic acid 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 ac ...
phosphatase to form 1-O-alkyl-2-acyl-sn-glycerol.
Using CDP-ethanolamine a
phosphotransferase
Phosphotransferases are a category of enzymes ( EC number 2.7) that catalyze phosphorylation reactions. The general form of the reactions they catalyze is:
:A-P + B \rightleftharpoons B-P + A
Where ''P'' is a phosphate group and A and B are the do ...
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
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of
ethanolamine
Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is an organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid wit ...
plasmalogens to 1-O-(1Z-alkenyl)-2-acyl-sn-glycerol that can be modified by choline phosphotransferase and CDP choline.
Pathology
Peroxisome biogenesis disorders
Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by ''PEX'' genes that are cri ...
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
Rhizomelic chondrodysplasia punctata is a rare developmental brain disorder characterized by systemic shortening of the proximal bones (i.e. rhizomelia), seizures, recurrent respiratory tract infections and congenital cataracts. The affected indivi ...
(RCDP) type 2 or 3, respectively.
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.
Deficits in plasmalogen levels contribute to pathology in
Zellweger syndrome
Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophie ...
.
[
Plasmalogen-]knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
show similar alterations like
arrest of spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
, development of cataract
A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...
and defects in central nervous system myelination
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
.
Plasmalogen alkyl chains have been shown to promote or inhibit the cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
form ferroptosis
Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Ferroptosis is ini ...
, depending on their degree of saturation.
During inflammation
During inflammation, neutrophil-derived myeloperoxidase
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the ''MPO'' gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry ou ...
produces Hypochlorous acid
Hypochlorous acid (HClO, HOCl, or ClHO) is a weak acid that forms when chlorine dissolves in water, and itself partially dissociates, forming hypochlorite, ClO−. HClO and ClO− are oxidizers, and the primary disinfection agents of chlorine so ...
, which causes oxidative chlorination Chlorination may refer to:
* Chlorination reaction
In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transform ...
of plasmalogens at the sn-1 chain by reacting with the vinyl 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
Bronchopulmonary dysplasia (BPD; part of the spectrum of chronic lung disease of infancy) is a chronic lung disease in which premature infants, usually those who were treated with supplemental oxygen, require long-term oxygen. The alveoli that are ...
, which is an important complication of premature birth
Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...
.[ And one study shows that plasmalogen levels are reduced in people with ]COPD
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce mu ...
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
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
including Alzheimer disease
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
, Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, Niemann–Pick disease, type C
Niemann–Pick type C (NPC) (colloquially, "Childhood Alzheimer's") is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present b ...
, Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
, and multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, it is not clear if this is causal or correlative.[ A study with mice concluded that plasmalogens can eliminate aging-associated synaptic defects.]
Evolution
In addition to mammals, plasmalogens are also found in invertebrates
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
and single cell organisms protozoans
Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...
. Among bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
they have been found in many anaerobic species including ''Clostridia
The Clostridia are a highly polyphyletic class of Bacillota, including '' Clostridium'' and other similar genera. They are distinguished from the Bacilli by lacking aerobic respiration. They are obligate anaerobes and oxygen is toxic to them. Sp ...
'', ''Megasphaera
''Megasphaera'' is a genus of Bacillota bacteria classified within the class Negativicutes.
This classification has been reexamined.Yutin N, Galperin MY (2013) A genomic update on Clostridial phylogeny: Gram-negative spore formers and other mi ...
'', and ''Veillonella
''Veillonella'' are Gram-negative bacteria (Gram stain pink) anaerobic cocci, unlike most Bacillota, which are Gram-positive bacteria. This bacterium is well known for its lactate fermenting abilities. It is a normal bacterium in the intestine ...
''. 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). Plasmalogens have been shown to have a complex evolutionary history based on the fact that their biosynthetic pathways differ in aerobic and anaerobic organisms.
Recently, it has been demonstrated that the red blood cells of human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s and great apes
The Hominidae (), whose members are known as the great apes or hominids (), are a taxonomic family of primates that includes eight extant species in four genera: '' Pongo'' (the Bornean, Sumatran and Tapanuli orangutan); ''Gorilla'' (the east ...
(chimpanzee
The chimpanzee (''Pan troglodytes''), also known as simply the chimp, is a species of great ape native to the forest and savannah of tropical Africa. It has four confirmed subspecies and a fifth proposed subspecies. When its close relative th ...
s, gorilla
Gorillas are herbivorous, predominantly ground-dwelling great apes that inhabit the tropical forests of equatorial Africa. The genus ''Gorilla'' is divided into two species: the eastern gorilla and the western gorilla, and either four or fi ...
s and orangutan
Orangutans are great apes native to the rainforests of Indonesia and Malaysia. They are now found only in parts of Borneo and Sumatra, but during the Pleistocene they ranged throughout Southeast Asia and South China. Classified in the genus ...
s) have differences in their plasmalogen composition. Total RBC plasmalogen levels were found to be lower in humans than in chimpanzee
The chimpanzee (''Pan troglodytes''), also known as simply the chimp, is a species of great ape native to the forest and savannah of tropical Africa. It has four confirmed subspecies and a fifth proposed subspecies. When its close relative th ...
s, or gorilla
Gorillas are herbivorous, predominantly ground-dwelling great apes that inhabit the tropical forests of equatorial Africa. The genus ''Gorilla'' is divided into two species: the eastern gorilla and the western gorilla, and either four or fi ...
s, but higher than in orangutan
Orangutans are great apes native to the rainforests of Indonesia and Malaysia. They are now found only in parts of Borneo and Sumatra, but during the Pleistocene they ranged throughout Southeast Asia and South China. Classified in the genus ...
s. Gene expression data from all these species caused the authors to speculate that other human and great ape
Apes (collectively Hominoidea ) are a clade of Old World simians native to sub-Saharan Africa and Southeast Asia (though they were more widespread in Africa, most of Asia, and as well as Europe in prehistory), which together with its sister g ...
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
*Ether lipid
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
References
External links
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