Phospholipase A2

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phospholipase A2
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Phospholipase A2
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The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyses the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:

phosphatidylcholine + H2O = 1-acylglycerophosphocholine + a carboxylate

This particular

lysophosphatidyl choline, a precursor of lysophosphatidic acid. Upon downstream modification by cyclooxygenases or lipoxygenases, arachidonic acid is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes, which are categorized as anti-inflammatory and inflammatory mediators.[1]

PLA2 enzymes are commonly found in mammalian tissues as well as arachnid, insect, and snake venom.

phospholipid membrane disproportionately. As a result, inflammation and pain occur at the site.[3] There are also prokaryotic A2 phospholipases
.

Additional types of

phospholipases include phospholipase A1, phospholipase B, phospholipase C, and phospholipase D.[4]

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 forms of phospholipases A2 have been isolated from different venoms (snake,[5] bee, and wasp), from virtually every studied mammalian 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[citation needed].

In mice, group III sPLA2 are involved in sperm maturation,[6] and group X are thought to be involved in sperm capacitation.[7]

sPLA2 has been shown to promote

inflammatory diseases, and has been shown to promote vascular inflammation correlating with coronary events in coronary artery disease and acute coronary syndrome,[8] and possibly leading to acute respiratory distress syndrome[9] and progression of tonsillitis.[10]

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

dry eye).[12]

Increased sPLA2 activity is observed in the

blood-cerebrospinal fluid barrier.[13]

There are atypical members of the phospholipase A2 family, such as PLA2G12B, that have no phospholipase activity with typical phospholipase substrate.[14] 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[15][16]

Cytosolic phospholipases A2 (cPLA2)

The

intracellular, 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
and a large catalytic domain.

These phospholipases are involved in

signaling molecule and the precursor for the synthesis of other signaling molecules termed eicosanoids. These include leukotrienes and prostaglandins. 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.[17]

Lipoprotein-associated PLA2s (lp-PLA2)

Main article: Lipoprotein-associated phospholipase A2

Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to atherosclerosis.[18] 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.[19]

Mechanism

The suggested

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.[20]
Before becoming active in digestion, the proform of PLA2 is activated by Trypsin.

Close-up rendering of PLA2 active site with phosphate enzyme inhibitor. Calcium ion (pink) coordinates with phosphate (light blue). Phosphate mimics tetrahedral intermediate blocking substrate access to active site. His-48, Asp-99, and 2 water molecules are also shown.[21]
Mechanism of hydrolysis catalyzed by PLA2

PLA2 can also be characterized as having a channel featuring a

disulfide bridges that are influential in regulation and stable protein folding.[20]

Biological Effects

PLA2 action can release histamine from rat peritoneal mast cells.[22] It also causes histamine release in human basophils.[23]

Regulation

Due to the importance of PLA2 in

MAPK at Serine-505. When phosphorylation is coupled with an influx of calcium ions, cPLA2 becomes stimulated and can translocate to the membrane to begin catalysis.[24]

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

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

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.[26]

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.[citation needed] It is a mixture of inflammation and substance P that are responsible for pain.[citation needed
]

Increased phospholipase A2 has also been associated with neuropsychiatric disorders such as

autism), though the mechanisms involved are not known.[27]
[28]

Isozymes

Human phospholipase A2 isozymes include:

In addition, the following human proteins contain the phospholipase A2 domain:

See also

References

  1. PMID 8175726
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  2. PMID 9054413
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  3. PMID 6643447
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  4. ISBN 0-7167-4339-6
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  17. S2CID 23717374
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  20. ^
    PMID 11749391
    . See page 2640
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  26. S2CID 6137443
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  27. PMID 15301788
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  28. PMID 16585943
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External links
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