Phospholipase A2
Encyclopedia
Phospholipases A2 are enzymes that release fatty acid
s from the second carbon group of glycerol
. This particular phospholipase
specifically recognizes the sn-2 acyl
bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid
and lysophospholipids. Upon downstream modification by cyclooxygenase
s, arachidonic acid
is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes, which are categorized as inflammatory mediators.
PLA2 are commonly found in mammalian tissues as well as insect and snake venom. Venom from both snakes and insects is largely composed of melittin
, which is a stimulant of PLA2. Due to the increased presence and activity of PLA2 resulting from a snake or insect bite, arachidonic acid
is released from the phospholipid membrane disproportionately. As a result, inflammation and pain occur at the site. There are also prokaryotic A2 phospholipases
.
Additional types of phospholipases include phospholipase A1
, phospholipase B
, phospholipase C
, and phospholipase D
.
with common enzymatic activity. Two most notable families are secreted and cytosolic phospholipases A2. Other families include Ca2+ independent PLA2 (iPLA2) and lipoprotein-associated PLA2s (lp-PLA2), also known as platelet activating factor acetylhydrolase (PAF-AH).
forms of phospholipases A2 have been isolated from different venom
s (snake
, bee
, and wasp
), from virtually every studied mammal
ian tissue
(including pancreas
and kidney
) as well as from bacteria
. They require Ca
2+ for activity.
Pancreatic sPLA2 serve for the initial digestion
of phospholipid compounds in dietary fat
. Venom phospholipases help to immobilize prey by promoting cell lysis
.
In mice, group III sPLA2 are involved in sperm maturation, and group X are thought to be involved in sperm capacitation
.
sPLA2 has been shown to promote inflammation
in mammals by catalyzing the first step of the arachidonic acid pathway by breaking down phospholipids, resulting in the formation of fatty acids including arachidonic acid
. This arachidonic acid is then metabolized to form several inflammatory and thrombogenic
molecules. Excess levels of sPLA2 is thought to contribute to several inflammatory diseases, and has been shown to promote vascular inflammation correlating with coronary events in coronary artery disease and acute coronary syndrome
, and possibly leading to acute respiratory distress syndrome
in children. In mice, excess levels of sPLA2 have been associated with inflammation thought to exacerbate asthma
and ocular surface inflammation (dry eye).
Increased sPLA2 activity is observed in the cerebrospinal fluid
of humans with Alzheimer’s disease and Multiple Sclerosis
, and may serve as a marker of increases in permeability of the blood-cerebrospinal fluid barrier.
PLA2 are also Ca-dependent, but they have completely different 3D structure
and significantly larger than secreted PLA2 (more than 700 residues). They include C2 domain
and large catalytic domain.
These phospholipases are involved in cell signaling
processes, such as inflammatory response
. The produced arachidonic acid
is both a signaling molecule
and the precursor for other signalling molecules termed eicosanoid
s. These include leukotriene
s and prostaglandin
s. Some eicosanoids are synthesized from diacylglycerol
, released from the lipid bilayer
by phospholipase C (see below).
Phospholipases A2 can be classified based on sequence homology.
.
and the ester
. The basicity of His-48 is thought to be enhanced through hydrogen bonding with Asp-99. An asparagine
substitution for His-48 maintains wild-type activity, as the amide
functional group on asparagine
can also function to lower the pKa, or acid dissociation constant
, of the bridging water molecule. The rate limiting state is characterized as the degradation of the tetrahedral intermediate composed of a calcium coordinated oxyanion
. The role of calcium can also be duplicated by other relatively small cations like cobalt and nickel.
PLA2 can also be characterized as having a channel featuring a hydrophobic wall in which hydrophobic amino acid residues such as Phe
, Leu
, and Tyr serve to bind the substrate. Another component of PLA2 is the seven disulfide bridges that are influential in regulation and stable protein folding.
and calcium concentrations. PLA2 is phosphorylated by a MAPK at Ser
ine-505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and can translocate to the membrane to begin catalysis
.
Phosphorylation of PLA2 may be a result of ligand binding to receptors, including:
conversion into proinflammatory mediators and arachidonic acid
reincorporation into the membrane. In the absence of strict regulation of PLA2 activity, a disproportionate amount of proinflammatory mediators are produced. The resulting induced oxidative stress
and neuroinflammation is analogous to neurological diseases such as Alzheimer’s disease, epilepsy
, multiple sclerosis
, ischemia
. Lysophospholipids are another class of molecules released from the membrane that are upstream predecessors of platelet activating factors (PAF). Abnormal levels of potent PAF are also associated with neurological damage. An optimal enzyme inhibitor
would specifically target PLA2 activity on neural cell membranes already under oxidative stress
and potent inflammation
. Thus, specific inhibitors of brain PLA2 could be a pharmaceutical approach to treatment of several disorders associated with neural trauma.
Increase in phospholipase A2 activity is an acute-phase reaction that rises during inflammation, which is also seen to be exponentially higher in low back disc herniation
s compared to rheumatoid arthritis
. It is a mixture of inflammation and substance P
that are responsible for pain.
Increased phospholipase A2 has also been associated with neuropsychiatric disorders such as schizophrenia
and pervasive developmental disorders (such as autism
), though the mechanisms involved are not known.
s include:
In addition, the following human proteins contain the phospholipase A2 domain
:
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s from the second carbon group of glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
. This particular phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
specifically recognizes the sn-2 acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
and lysophospholipids. Upon downstream modification by cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
s, arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes, which are categorized as inflammatory mediators.
PLA2 are commonly found in mammalian tissues as well as insect and snake venom. Venom from both snakes and insects is largely composed of melittin
Melittin
Melittin is the principal active component of apitoxin and is a powerful stimulator of phospholipase A2. Melittin is a peptide consisting of 26 amino acids with the sequence GIGAVLKVLTTGLPALISWIKRKRQQ.-Biological effects:...
, which is a stimulant of PLA2. Due to the increased presence and activity of PLA2 resulting from a snake or insect bite, arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
is released from the phospholipid membrane disproportionately. As a result, inflammation and pain occur at the site. There are also prokaryotic A2 phospholipases
Prokaryotic phospholipase A2
The prokaryotic phospholipase A2 domain is found in bacterial and fungal phospholipases. It enables the liberation of fatty acids and lysophospholipid by hydrolysing the 2-ester bond of 1,2-diacyl-3-sn-phosphoglycerides. The domain adopts an alpha-helical secondary structure, consisting of five...
.
Additional types of phospholipases include phospholipase A1
Phospholipase A1
Phospholipase A1 is a phospholipase enzyme which removes the 1-acyl. Phospholipase A1 is a component of snake venom, but it also serves in normal metabolism to produce fatty acids from phospholipids. In melanocytic cells the Phospholipase A1 gene may be regulated by MITF.-External links:*...
, phospholipase B
Phospholipase B
Phospholipase B is an enzyme with a combination of both PLA1 and PLA2 activities; that is, it can cleave acyl chains from both the sn-1 and sn-2 positions of a phospholipid. In general, it acts on lysolecithin ....
, phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
, and phospholipase D
Phospholipase D
Phospholipase D is an enzyme which is located in the plasma membrane and catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid , releasing the soluble choline headgroup into the cytosol...
.
Families
Phospholipases A2 include several unrelated protein familiesProtein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
with common enzymatic activity. Two most notable families are secreted and cytosolic phospholipases A2. Other families include Ca2+ independent PLA2 (iPLA2) and lipoprotein-associated PLA2s (lp-PLA2), also known as platelet activating factor acetylhydrolase (PAF-AH).
Secreted phospholipases A2 (sPLA2)
The extracellularExtracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
forms of phospholipases A2 have been isolated from different venom
Venom
Venom is the general term referring to any variety of toxins used by certain types of animals that inject it into their victims by the means of a bite or a sting...
s (snake
Snake venom
Snake venom is highly modified saliva that is produced by special glands of certain species of snakes. The glands which secrete the zootoxin are a modification of the parotid salivary gland of other vertebrates, and are usually situated on each side of the head below and behind the eye,...
, bee
Apitoxin
Apitoxin, or honey bee venom, is a bitter colorless liquid. The active portion of the venom is a complex mixture of proteins, which causes local inflammation and acts as an anticoagulant. The venom is produced in the abdomen of worker bees from a mixture of acidic and basic secretions. Apitoxin...
, and wasp
Wasp
The term wasp is typically defined as any insect of the order Hymenoptera and suborder Apocrita that is neither a bee nor an ant. Almost every pest insect species has at least one wasp species that preys upon it or parasitizes it, making wasps critically important in natural control of their...
), from virtually every studied mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
(including pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
) as well as from bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. They require Ca
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
2+ for activity.
Pancreatic sPLA2 serve for the initial digestion
Digestion
Digestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....
of phospholipid compounds in dietary fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
. Venom phospholipases help to immobilize prey by promoting cell lysis
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
.
In mice, group III sPLA2 are involved in sperm maturation, and group X are thought to be involved in sperm capacitation
Capacitation
Capacitation is the penultimate step in the maturation of mammalian spermatozoa and is required to render them competent to fertilize an oocyte.This step is a biochemical event; the sperm move normally and look mature prior to capacitation....
.
sPLA2 has been shown to promote inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
in mammals by catalyzing the first step of the arachidonic acid pathway by breaking down phospholipids, resulting in the formation of fatty acids including arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
. This arachidonic acid is then metabolized to form several inflammatory and thrombogenic
Thrombogenicity
Thrombogenicity refers to the tendency of a material in contact with the blood to produce a thrombus, or clot. It not only refers to fixed thrombi but also to emboli, thrombi which have become detached and travel through the bloodstream. Thrombogenicity can also encompass events such as the...
molecules. Excess levels of sPLA2 is thought to contribute to several inflammatory diseases, and has been shown to promote vascular inflammation correlating with coronary events in coronary artery disease and acute coronary syndrome
Acute coronary syndrome
Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....
, and possibly leading to acute respiratory distress syndrome
Acute respiratory distress syndrome
Acute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
in children. In mice, excess levels of sPLA2 have been associated with inflammation thought to exacerbate asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
and ocular surface inflammation (dry eye).
Increased sPLA2 activity is observed in the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
of humans with Alzheimer’s disease and Multiple Sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, and may serve as a marker of increases in permeability of the blood-cerebrospinal fluid barrier.
Cytosolic phospholipases A2 (cPLA2)
The intracellularIntracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
PLA2 are also Ca-dependent, but they have completely different 3D structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
and significantly larger than secreted PLA2 (more than 700 residues). They include C2 domain
C2 domain
A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. It is a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by the first and final loops of the domain, on the membrane binding face.-Coupling...
and large catalytic domain.
These phospholipases are involved in cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
processes, such as inflammatory response
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. The produced arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
is both a signaling molecule
Signaling molecule
A signaling molecule is a chemical involved in transmitting information between cells. Such molecules are released from the cell sending the signal, cross over the gap between cells by diffusion, and interact with specific receptors in another cell, triggering a response in that cell by activating...
and the precursor for other signalling molecules termed eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
s. These include leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
s and prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s. Some eicosanoids are synthesized from diacylglycerol
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
, released from the lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
by phospholipase C (see below).
Phospholipases A2 can be classified based on sequence homology.
Lipoprotein-associated PLA2s (lp-PLA2)
Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to atherosclerosisAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
.
Mechanism
The suggested catalytic mechanism of pancreatic sPLA2 is initiated by a His-48/Asp-99/calcium complex within the active site. The calcium ion polarizes the sn-2 carbonyl oxygen while also coordinating with a catalytic water molecule, w5. His-48 improves the nucleophilicity of the catalytic water via a bridging second water molecule, w6. It has been suggested that two water molecules are necessary to traverse the distance between the catalytic histidineHistidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
and the ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
. The basicity of His-48 is thought to be enhanced through hydrogen bonding with Asp-99. An asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
substitution for His-48 maintains wild-type activity, as the amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
functional group on asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
can also function to lower the pKa, or acid dissociation constant
Acid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...
, of the bridging water molecule. The rate limiting state is characterized as the degradation of the tetrahedral intermediate composed of a calcium coordinated oxyanion
Oxyanion
An oxyanion or oxoanion is a chemical compound with the generic formula AxOyz− . Oxoanions are formed by a large majority of the chemical elements. The formulae of simple oxoanions are determined by the octet rule...
. The role of calcium can also be duplicated by other relatively small cations like cobalt and nickel.
 |
 |
PLA2 can also be characterized as having a channel featuring a hydrophobic wall in which hydrophobic amino acid residues such as Phe
PHE
PHE may refer to:* Population Health and Environment , an approach to development that integrates health or family planning with conservation efforts* Paramount Home Entertainment* BitTorrent protocol encryption...
, Leu
Leu
Leu may refer to:* Leu, a commune in Dolj County, Romania* Leucine, amino acid abbreviated Leu* LEU, Low-Enriched Uranium* Moldovan leu, the standard of currency in Moldova* Romanian leu, the standard of currency in Romania...
, and Tyr serve to bind the substrate. Another component of PLA2 is the seven disulfide bridges that are influential in regulation and stable protein folding.
Regulation
Due to the importance of PLA2 in inflammatory responses, regulation of the enzyme is essential. PLA2 is regulated by phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and calcium concentrations. PLA2 is phosphorylated by a MAPK at Ser
Ser
Ser is a gender-neutral form of Sir that has been used in the Dragon Age video game series by BioWare, in Greg Bear's The Way novels, and in A Song of Ice and Fire by George R R Martin...
ine-505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and can translocate to the membrane to begin catalysis
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
.
Phosphorylation of PLA2 may be a result of ligand binding to receptors, including:
- 5-HT2 receptor5-HT2 receptorThe 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT2 subfamily consists of three G protein-coupled receptors which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C...
s - mGLUR1Metabotropic glutamate receptor 1The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 protein.-Function:...
- bFGFBasic fibroblast growth factorBasic fibroblast growth factor, also known as bFGF, FGF2 or FGF-β, is a member of the fibroblast growth factor family.- Function :...
receptor - IFN-α receptor
- IFN-γ receptorInterferon-gamma receptorThe interferon-gamma receptor is a receptor which binds interferon-γ, the sole member of interferon type II.- Structure and function :...
Relevance in Neurological Disorders
In normal brain cells, PLA2 regulation accounts for a balance between arachidonic acidArachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
conversion into proinflammatory mediators and arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
reincorporation into the membrane. In the absence of strict regulation of PLA2 activity, a disproportionate amount of proinflammatory mediators are produced. The resulting induced oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
and neuroinflammation is analogous to neurological diseases such as Alzheimer’s disease, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
. Lysophospholipids are another class of molecules released from the membrane that are upstream predecessors of platelet activating factors (PAF). Abnormal levels of potent PAF are also associated with neurological damage. An optimal enzyme inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
would specifically target PLA2 activity on neural cell membranes already under oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
and potent inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. Thus, specific inhibitors of brain PLA2 could be a pharmaceutical approach to treatment of several disorders associated with neural trauma.
Increase in phospholipase A2 activity is an acute-phase reaction that rises during inflammation, which is also seen to be exponentially higher in low back disc herniation
Spinal disc herniation
A spinal disc herniation , informally and misleadingly called a "slipped disc", is a medical condition affecting the spine due to trauma, lifting injuries, or idiopathic, in which a tear in the outer, fibrous ring of an intervertebral disc allows the soft, central portion A spinal disc herniation...
s compared to rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. It is a mixture of inflammation and substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
that are responsible for pain.
Increased phospholipase A2 has also been associated with neuropsychiatric disorders such as schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and pervasive developmental disorders (such as autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
), though the mechanisms involved are not known.
Isozymes
Human phospholipase A2 isozymeIsozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
s include:
- Group I: PLA2G1BPLA2G1BPhospholipase A2 is an enzyme that in humans is encoded by the PLA2G1B gene.- Function :Phospholipase A2 catalyzes the release of fatty acids from glycero-3-phosphocholines. The best known varieties are the digestive enzymes secreted as zymogens by the pancreas of mammals as well as fish...
- Group II: PLA2G2APLA2G2APhospholipase A2, membrane associated is an enzyme that in humans is encoded by the PLA2G2A gene.-Further reading:...
, , PLA2G2DPLA2G2DGroup IID secretory phospholipase A2 is an enzyme that in humans is encoded by the PLA2G2D gene.-Further reading:...
, , - Group III:
- Group IV: PLA2G4APLA2G4ACytosolic phospholipase A2 is an enzyme that in humans is encoded by the PLA2G4A gene.-Further reading:...
, PLA2G4BPLA2G4BPhospholipase A2, group IVB , also known as PLA2G4B, is a human gene.-Further reading:...
, PLA2G4CPLA2G4CCytosolic phospholipase A2 gamma is an enzyme that in humans is encoded by the PLA2G4C gene.-Further reading:...
, , , - Group V: PLA2G5PLA2G5Calcium-dependent phospholipase A2 is an enzyme that in humans is encoded by the PLA2G5 gene.-Further reading:...
- Group VI: PLA2G6PLA2G685 kDa calcium-independent phospholipase A2 is an enzyme that in humans is encoded by the PLA2G6 gene.-Further reading:...
- Group VII: PLA2G7Lipoprotein-associated phospholipase A2Lipoprotein-associated phospholipase A2 also known as platelet-activating factor acetylhydrolase is a phospholipase A2 enzyme that in humans is encoded by the PLA2G7 gene. Lp-PLA2 is a 45-kDa protein of 441 amino acids.- Function :In the blood it travels mainly with low-density lipoprotein...
- Group X: PLA2G10PLA2G10Group 10 secretory phospholipase A2 is an enzyme that in humans is encoded by the PLA2G10 gene.-Further reading:...
- Group XII: PLA2G12APLA2G12AGroup XIIA secretory phospholipase A2 is an enzyme that in humans is encoded by the PLA2G12A gene.-Further reading:...
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In addition, the following human proteins contain the phospholipase A2 domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
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