The enzyme phospholipase A₂ (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is ...

s in position 2 of

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

s, hydrolyzing the bond between the second fatty acid “tail” and the

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids know ...

molecule: :phosphatidylcholine + H₂O = 1-acylglycerophosphocholine + a carboxylate This particular

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step i ...

specifically recognizes the ''sn''₂

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 ...

bond of

s and catalytically

hydrolyzes Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

the bond, releasing

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arach ...

and

lysophosphatidic acid Lysophosphatidic acid (LPA) is a phospholipid derivative that can act as a signaling molecule. Function LPA acts as a potent mitogen due to its activation of three high-affinity G-protein-coupled receptors called LPAR1, LPAR2, and LPAR3 (als ...

. Upon downstream modification by

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as p ...

s or

lipoxygenase Lipoxygenases () are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as a ...

is modified into active compounds called eicosanoids. Eicosanoids include

prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deri ...

s and

leukotriene Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase. Leukotrien ...

s, which are categorized as anti-inflammatory and inflammatory mediators. PLA2 enzymes are commonly found in mammalian tissues as well as arachnid, insect, and snake venom. Venom from bees is largely composed of

melittin Melittin is the main component (40–60% of the dry weight) and the major pain producing substance of honeybee (''Apis mellifera'') venom. Melittin is a basic peptide consisting of 26 amino acids. Function The principal function of melittin a ...

, which is a stimulant of PLA2. Due to the increased presence and activity of PLA2 resulting from a snake or insect bite,

is released from the

phospholipid membrane The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many ...

disproportionately. As a result, inflammation and pain occur at the site. There are also prokaryotic A₂ phospholipases. Additional types of

phospholipases A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...

include phospholipase A₁,

phospholipase B Phospholipase B, also known as lysophospholipase, 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 (wh ...

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...

, and phospholipase D.

Families

Phospholipases A₂ include several unrelated protein families 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

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

forms of phospholipases A₂ have been isolated from different

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a st ...

s (

snake Snakes are elongated, limbless, carnivorous reptiles of the suborder Serpentes . Like all other squamates, snakes are ectothermic, amniote vertebrates covered in overlapping scales. Many species of snakes have skulls with several more ...

bee Bees are winged insects closely related to wasps and ants, known for their roles in pollination and, in the case of the best-known bee species, the western honey bee, for producing honey. Bees are a monophyletic lineage within the superfa ...

, and

wasp A wasp is any insect of the narrow-waisted suborder Apocrita of the order Hymenoptera which is neither a bee nor an ant; this excludes the broad-waisted sawflies (Symphyta), which look somewhat like wasps, but are in a separate suborde ...

), from virtually every studied

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fu ...

ian tissue (including

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an ...

and

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

) as well as from bacteria. They require Ca²⁺ for activity. Pancreatic sPLA2 serve for the initial

digestion Digestion is the breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorbed into the watery blood plasma. In certain organisms, these smaller substances are absorbed through the small intes ...

of phospholipid compounds in dietary fat. Venom phospholipases help to immobilize prey by promoting cell

lysis Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bi ...

. 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 Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

in mammals by catalyzing the first step of the arachidonic acid pathway by breaking down

phospholipids Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typi ...

, resulting in the formation of

fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

including

. 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 Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...

and

acute coronary syndrome Acute coronary syndrome (ACS) is a syndrome (a set of signs and symptoms) due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally lo ...

, and possibly leading to

acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin col ...

and progression of

tonsillitis Tonsillitis is inflammation of the tonsils in the upper part of the throat. It can be acute or chronic. Acute tonsillitis typically has a rapid onset. Symptoms may include sore throat, fever, enlargement of the tonsils, trouble swallowing, and ...

. In children, excess levels of sPLA2 have been associated with inflammation thought to exacerbate

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, ...

and ocular surface inflammation (

dry eye Dry or dryness most often refers to: * Lack of rainfall, which may refer to **Arid regions **Drought * Dry or dry area, relating to legal prohibition of selling, serving, or imbibing alcoholic beverages * Dry humor, deadpan * Dryness (medical) ...

). Increased sPLA2 activity is observed in the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the br ...

of humans with

Alzheimer's 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 ...

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. Thi ...

, and may serve as a marker of increases in permeability of the blood-cerebrospinal fluid barrier. There are atypical members of the phospholipase A₂ family, such as PLA2G12B, that have no phospholipase activity with typical phospholipase substrate. The lack of enzymatic activity of PLA2G12B indicates that it may have unique function distinctive from other sPLA2s. It has been shown that in PLA2G12B null mice VLDL levels were greatly reduced, suggesting it could have an effect in lipoprotein secretion

Cytosolic phospholipases A₂ (cPLA2)

The

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

, group IV PLA2 are also Ca-dependent, but they have a different 3D structure and are significantly larger than secreted PLA2 (more than 700 residues). They include a

C2 domain A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by ...

and a large catalytic domain. These phospholipases are involved in

cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

processes, such as

inflammatory response Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

. They release

from membrane phospholipids. Arachidonic acid is both a

signaling molecule In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

and the precursor for the synthesis of other signaling molecules termed eicosanoids. These include

s and

s. Some eicosanoids are synthesized from

diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...

, released from the

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many v ...

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

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no ...

. Although, the role of LP-PLA2 in atherosclerosis may depend on its carrier in plasma, and several lines of evidence suggest that HDL-associated Lp-PLA2 may substantially contribute to the HDL antiatherogenic activities.

Mechanism

The suggested

catalytic Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recy ...

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

water molecule, w5. His-48 improves the nucleophilicity of the

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

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the d ...

and the

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glyceride ...

. The

basicity In chemistry, there are three definitions in common use of the word base, known as Arrhenius bases, Brønsted bases, and Lewis bases. All definitions agree that bases are substances that react with acids, as originally proposed by G.-F. Ro ...

of His-48 is thought to be enhanced through

hydrogen bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

with Asp-99. An

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

substitution for His-48 maintains wild-type activity, as the

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

functional group on

can also function to lower the pKa, or

acid dissociation constant In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction ...

, of the bridging water molecule. The rate limiting state is characterized as the degradation of the tetrahedral intermediate composed of a calcium coordinated

oxyanion An oxyanion, or oxoanion, is an ion with the generic formula (where A represents a chemical element and O represents an oxygen atom). Oxyanions are formed by a large majority of the chemical elements. The formulae of simple oxyanions are determine ...

. The role of calcium can also be duplicated by other relatively small cations like cobalt and nickel. Before becoming active in digestion, the proform of PLA2 is activated by Trypsin. PLA2 can also be characterized as having a channel featuring a

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, t ...

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 In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

that are influential in regulation and stable protein folding.

Biological Effects

PLA2 action can release histamine from rat peritoneal mast cells. It also causes histamine release in human basophils.

Regulation

Due to the importance of PLA2 in

s, regulation of the enzyme is essential. cPLA2 is regulated by

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

and calcium concentrations. cPLA2 is phosphorylated by a

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...

Serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form ...

-505. When phosphorylation is coupled with an influx of calcium ions, cPLA2 becomes stimulated and can translocate to the membrane to begin

catalysis Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recy ...

. Phosphorylation of cPLA2 may be a result of ligand binding to receptors, including: *

5-HT2 receptor The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT2 subfamily consists of three G protein-coupled receptors (GPCRs) which are coupled to Gq/G11 and medi ...

s * mGLUR1 *

bFGF Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...

receptor * IFN-α receptor * IFN-γ receptor In the case of an inflammation, the application of glucocorticoids up-regulate (mediated at the gene level) the production of the protein lipocortin which may inhibit cPLA2 and reduce the inflammatory response.

Relevance in neurological disorders

In normal brain cells, PLA2 regulation accounts for a balance between

's conversion into proinflammatory mediators and its 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 reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...

and neuroinflammation is analogous to neurological diseases such as

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems w ...

. 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 An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a s ...

would specifically target PLA2 activity on neural cell membranes already under

and potent

. 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 herniations compared to

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

. It is a mixture of inflammation and

substance P Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its cl ...

that are responsible for pain. Increased phospholipase A₂ has also been associated with neuropsychiatric disorders such as

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social with ...

and

pervasive developmental disorders The diagnostic category pervasive developmental disorders (PDD), as opposed to specific developmental disorders (SDD), is a group of disorders characterized by delays in the development of multiple basic functions including socialization and co ...

(such as

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

), though the mechanisms involved are not known.

Isozymes

Human phospholipase A₂

isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

s include: * Group I: PLA2G1B * Group II: PLA2G2A, , PLA2G2D, , * Group III: * Group IV: PLA2G4A, PLA2G4B, PLA2G4C, , , * Group V: PLA2G5 * Group VI:

PLA2G6 85 kDa calcium-independent phospholipase A2, also known as 85/88 kDa calcium-independent phospholipase A2, Group VI phospholipase A2, Intracellular membrane-associated calcium-independent phospholipase A2 beta, or Patatin-like phospholipase domain ...

* Group VII: PLA2G7 * Group X: PLA2G10 * Group XII: PLA2G12A, In addition, the following human proteins contain the phospholipase A₂

domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function ** Domain of holomorphy of a function * ...

: *

References

External links

* Peripheral membrane proteins