Entrance
Phospholipase A (PLA) comprises a supergroup of esterase enzymes present in all human cells that play a key role in mediating the production of free fatty acids and lysophospholipids from glycerophospholipids. These enzymes are essential for homeostasis regulation and disease pathogenesis in any organ system based on their activation and involvement in mediating inflammation. To date, more than 30 PLA isoforms have been identified that vary widely in function, cofactor requirements, and size. The isoforms fall into six major groups, including cytosolic PLA, calcium-independent PLA, secretory PLA, lysosomal PLA, fat-specific PLA, and platelet-activating factor acetyl hydrolase. Within each of these groups, studies have identified several subtypes. This article will focus on summarizing the critical roles of each of the six investigated PLA subtypes.[1]
The basic
PLA plays several important physiological roles, including the production of inflammatory eicosanoid compounds from arachidonic acid. These compounds are involved in the pathogenesis of various inflammatory conditions, including rheumatoid arthritis, atherosclerosis, many forms of cancer, cardiovascular diseases and other inflammatory diseases. The emergence of pharmacological compounds that act as PLA inhibitors has an exciting role in our future approach to the treatment of various inflammatory conditions.[1][2]
molecular level
secretory PLA
The molecular structure of secretory PLA consists of six to eight disulfide bonds and uses the calcium cofactor histidine/aspartate to catalyze the active site. Activation of secreted PLA increases in response to substrate aggregation, as opposed to interaction with monomers. This phenomenon is known as interfacial aggregation and relies on the interplay of electrostatic and hydrophobic interactions to facilitate binding between secreted PLA and phospholipid membranes. The binding capacity depends on the functional capacity of various aromatic amino acids, the most prominent of which is tryptophan. Within this group, the research identified ten basic subtypes.
PLA cytosol
The cytosolic PLA supergroup consists of 6 members, each containing 749 amino acids and having other structural similarities. The activity of most forms of cytosolic PLA depends on intracellular calcium binding, which facilitates the action of the enzyme on the phospholipid membrane. Especially the enzyme workssn-2position of arachidonic acid. Cytosolic PLA also acts on micelle substrates. Unlike the action on phospholipid membranes, the action on micelles does not require calcium activation.
As an independent PLA
Ca-independent PLA is named to distinguish it from secretory and cytosolic PLA, each of which requires the activation of calcium to facilitate its essential function. The enzyme consists of a sequence of 752 amino acids, which is probably regulated by various mechanisms, including ATP binding, cleavage by caspase enzymes and interaction with calmodulin.
lizosomski PLA
Lysosomal PLA gets its name from the studied location in lysosomes in cells. It contains a recognizable catalytic triad of amino acids consisting of aspartic acid, serine and histidine, which allows it to function as a phospholipase with acyltransferase activity and specificity for the substrates phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in lysosomes. The enzyme can act independently without direct interaction with calcium. However, its activity can be altered by the presence of calcium, which interacts with other upstream or downstream compounds that regulate its activity.
PLA specific for adipose tissue
Like lysosomal PLA, fat-specific PLA exhibits calcium-independent activity on PE and PC. However, it does not show acyltransferase activity. Increased activity of adipose tissue-specific PLA causes release of arachidonic acid as a precursor to prostaglandin E, resulting in a decrease in intracellular cAMP and a decrease in lipolysis. The net effect of increased enzyme activity is increased obesity by regulating intracellular cAMP.
Platelet activating factorAcetylhydrolase
This group of enzymes is calcium-independent and includes the catalytic amino acid triad of aspartic acid, serine, and histidine, and the coupling motif of lipases and serine esterases. These molecular structures enable the enzyme to interact with plasma lipoproteins and act on their substrate, platelet activating factor (PAF). PAF is a potent inflammatory mediator that plays a significant role in many inflammatory disease processes.[1][3][4]
Work
secretory PLA
Secretory PLA has been studied and shown to have many different functions in the body. The enzyme has strong antibacterial and antiviral activity against many gram-positive and gram-negative bacteria. The mechanism of this action involves penetration into the cell wall of peptidoglycan by breaking down membrane phospholipids. The antiviral mechanism of PLA secretion is the inhibition of chemokine receptors, which ultimately prevents viruses from entering host cells. Another important function of secretory PLA is the initiation of inflammatory mediation by prostanoids and leukotrienes. This mediation occurs through the breakdown of arachidonic acid and subsequent conversion to bioavailable eicosanoid compounds. Research into PLA has also focused on its role in allergic and anaphylactic reactions via mast cell activation and subsequent histamine release.
PLA cytosol
The primary functions of cytosolic PLA under investigation depend on an increase in intracellular calcium that facilitates translocation of the enzyme to intracellular phospholipid membranes surrounding the nucleus. The binding of intracellular calcium to the enzyme enables this by neutralizing anionic molecules within the enzyme and by promoting hydrophobic interactions with membrane substrates. After binding to the phospholipid membrane, many other enzymes help regulate cytosolic PLA activity through phosphorylation. An important primary function of cytosolic PLA is to hydrolyze arachidonic acid to promote substrate metabolism in cyclooxygenase (COX) or lipoxygenase (LOX) pathways. The obtained compounds are biologically active eicosanoids that play an important role in intracellular immunity. Cytosolic PLA also plays a role in stimulating a powerful immune enzyme known as NADPH oxidase, which produces superoxide compounds to eliminate pathogens. Other important functions of cytosolic PLA include the regulation of the progression of the G1 phase of the cell cycle.
As an independent PLA
The researchers investigated the calcium-independent functions of PLA, which play a key role in normal cellular homeostasis. There have been implications regarding its role in promoting cell cycle progression and, paradoxically, cell apoptosis depending on the target cell. Other functions of the studied enzyme include normal bone formation, glucose-dependent insulin secretion, sperm maturation, normal skeletal and smooth muscle function, and neuroaxon regeneration in response to injury.
lizosomski PLA
Lysosomal PLA plays an essential role in the degradation of phospholipids in lysosomes. First of all, its function and high level of expression in alveolar macrophages enable it to degrade surfactant phospholipids. This process prevents the accumulation of phospholipids in the cells. Failure of normal enzyme function leads to phospholipidosis with significant phenotypic features in knockout mice, including splenomegaly and increased foam cell formation. Lysosomal PLA also plays an important immunological role by processing lipid antigens and then being used by CD1 proteins for presentation to leukocytes. This role has been investigated in relation to lung infectionsMycobacterium tuberculosis. The results show that lysosomal PLA plays a key role in the development of Th1 T-cell adaptive immunity totuberculosis.
PLA specific for adipose tissue
Specifically for adipose tissue, PLA is a tumor suppressor in the body. Enzyme function in adipocytes is important for the regulation of lipolysis and prostaglandin production. Increased enzyme activity results in the formation of prostaglandin E, which causes a decrease in intracellular cAMP and an increase in obesity.
Platelet acetylhydrolase activating factor
Macrophages in the body mainly synthesize the platelet-activating factor acetylhydrolase. Enzyme protein synthesis is increased in the process of differentiation of monocytes into macrophages. The enzyme is more catalytically active in LDL particles than in HDL particles, suggesting that their role in interacting with HDL may involve a reservoir function when more enzyme is needed to interact with LDL. The evidence for the proper function of platelet-activating factor acetylhydrolase has changed considerably over time. It was originally thought to play a key role in preventing the development of atherosclerosis; however, recent evidence suggests that its function is atherogenic. Therefore, this enzyme is now considered an independent risk factor for the development of atherosclerosis and coronary heart disease.[1][5][3][6]
Pathophysiology
secretory PLA
Secretory PLA plays an important role in the pathogenesis of many inflammatory conditions, including rheumatoid arthritis, atherosclerosis, asthma, acute respiratory distress syndrome (ARDS), Crohn's disease, ulcerative colitis, and tumor cell growth.
The pathophysiology of ARDS and asthma involves two mechanisms related to normal respiratory physiology. Normal expression of secreted PLA results in an increase in leukotrienes that serve as potent chemokines, causing leukocyte attraction and subsequent release of pro-inflammatory cytokines. This role has been established in the pathogenesis of asthma. Another mechanism that contributes more to the pathophysiology of ARDS involves the secretory breakdown of PLA lung surfactants phosphatidylcholine and phosphatidylglycerol, leading to further airway inflammation and alveolar collapse.
The pathogenesis of atherosclerosis is also correlated with increased expression of secretory PLA. The proposed mechanism involves hydrolysis of phospholipids in LDL particles, resulting in macrophage uptake and subsequent lipid accumulation in the intima. Studies have shown a positive correlation between the level of secretory PLA in the blood and coronary artery disease due to coronary atherosclerosis due to oxidative damage.
PLA cytosol
Disruption of the normal function of cytosolic PLA prevents the onset of an inflammatory response that results in immunity to various inflammatory pathologies, including anaphylaxis, rheumatoid arthritis, fatty liver, and acute respiratory distress syndrome. Studies have shown that cytosolic PLA plays a significant role in the pathogenesis of many types of cancer, including estrogen-dependent breast cancer, lung adenocarcinoma, and glioblastoma multiforme. The effect of enzyme hyperactivity on many disease processes makes it a viable research target for disease interventions. An adverse effect observed in knockout mice lacking enzyme activity included decreased renal concentration function.
As an independent PLA
One of the most studied roles of Ca-independent PLA is its involvement in inducing beta-cell apoptosis, resulting in the pathogenesis of diabetes. This situation occurs through the production of superoxide compounds by neutrophils, which ultimately leads to cell death. In contrast, the lack of function of the enzyme under normal physiological conditions is associated with earlier onset of neuroaxonal dystrophy disease.
lizosomski PLA
Although not as well studied as other phospholipases, evidence suggests that lack of lysosomal PLA function plays a role in atherosclerosis and the formation of phospholipidosis. From an immunological point of view, reduced enzyme function results in a lack of activation of lung T cells. That role was at the center of studies of pulmonary tuberculosis infection, where enzyme-deficient mice showed increased numbers of mycobacteria and a reduced inflammatory response to infection.
PLA specific for adipose tissue
Although referred to as fat-specific PLA, this enzyme is expressed in many tissues, with the highest level of expression found in adipocytes. The role of the enzyme in the regulation of lipolysis and fatty acid oxidation is currently under investigation, making it a viable target for further obesity research.
Platelet acetylhydrolase activating factor
As previously mentioned, researchers have investigated the role of platelet-activating factor acetylhydrolase, which plays a role in vascular atherogenesis. This process showed increased enzyme expression in combination with oxidized LDL and inflammation, promoting the formation of atherosclerotic plaque. This investigated function of the enzyme makes it a potential pharmaceutical target to prevent the progression of atherosclerotic disease.
Another studied pathophysiological mechanism involving platelet-activating factor acetylhydrolase is neonatal necrotizing enterocolitis (NEC). This disease causes intestinal necrosis in premature babies. Low enzyme levels together with accumulation of platelet-activating factor in newborns correlate with the pathogenesis of the disease. These results suggest that administration of exogenous forms of the enzyme may improve outcomes in NEC.[1][6][7][8][9]
Clinical significance
secretory PLA
Because of the known importance of secretory PLA in the pathogenesis of many different inflammatory disease processes, attempts have been made for a long time to synthesize inhibitors of this enzyme for the treatment of asthma and atherosclerosis associated with cardiovascular diseases. Broad-spectrum enzyme inhibitors such as warespladib have been shown to significantly reduce the size of atherosclerotic lesions and increase HDL in mice. These results indicate that the enzyme remains a viable target for the prevention and treatment of atherosclerosis, and further research is needed to assess its safety and efficacy in humans. Other enzyme-related research targets can be moved to enzymes upstream or downstream of the same pathway to achieve similar results, such as peroxisome proliferator-activated receptors (PPARs).
PLA cytosol
Cytosolic PLA has received much attention as a target for pharmaceutical drugs, being the most potent PLA enzyme studied as playing a key role in the pathogenesis of inflammatory diseases. A wide variety of cytosolic PLA inhibitors have been developed and tested for their efficacy in the treatment of inflammatory diseases such as rheumatoid arthritis and inflammation-induced hyperalgesia. Clinical trials are needed to confirm the safety and effectiveness of these experimental drugs in humans. Future studies are needed to evaluate pharmacological targeting of this enzyme on cell cycle progression in the treatment of various cancers and proliferative glomerulopathies.
As an independent PLA
Research into the clinical role of Ca-independent PLA inhibitors is much more limited than for some other, better studied forms of the enzyme. As further research elucidates the clinical significance of the enzyme, the development of pharmaceutical targets in the enzyme will become more apparent. It is worth noting that a recent study showing the effectiveness of 2 calcium-independent PLA inhibitors in combination with traditional chemotherapeutic agents showed that they were effective in inhibiting the development of some types of ovarian cancer.
lizosomski PLA
One of the important functions of lysosomal PLA under investigation involves the activation of pulmonary T cells in response to Mycobacterium tuberculosis infection. This role requires further research into the pharmacological treatment of tuberculosis. Further studies are needed to evaluate the role of enzymatic manipulation of lysosomal PLA in various other disease processes.
PLA specific for adipose tissue
Knockout mice lacking fat-specific PLA show a high rate of lipolysis and an increase in fatty acid oxidation in adipocytes. These findings suggest that pharmacological inhibition of normal enzyme function may be beneficial in the treatment of obesity.
Platelet acetylhydrolase activating factor
Because of its well-studied role in the pathogenesis of atherosclerosis, researchers have investigated platelet-activating factor acetylhydrolase inhibitors for their effectiveness in reducing the risk of cardiovascular events. A notable inhibitor being tested in clinical trials is darapladib, which has shown promising results in the prevention and mitigation of coronary artery disease.[1][2][7][5][6]
Review the questions
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