Phospholipase A2

Phospholipases A2 (PLA2s) EC number|3.1.1.4 are upstream regulators of many inflammatory processes. 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 cyclooxygenases, arachidonic acid is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes which are categorized as inflammatory mediators. [Dennis, et al. "Diversity of Group Types, Regulation, and Function of Phospholipase A2." The Journal of Biological Chemistry. VOl. 269. No 18. 13057-13060.]

PLA2 are commonly found in mammalian tissues as well as insect and snake venom. [ Nicholas, et al. "Localization of Structural Elements of Bee Venom Phospholipase A2 Involved in N-type Receptor Binding and Neurotoxicity." Journal of Biological Chemistry. Vol. 227. No. 11. 7173-7181.] 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. [Argiolas, Pianso. "Facilitation of Phospholipase A2 Activity by Mastoparans, a New Class of Mast Cell Degranulating Peptides from Wasp Venom." Journal of Biological Chemistry. Vol. 285. Issue 122. 13697-13702] There are also prokaryotic A2 phospholipases.

Additional types of phospholipases include phospholipase A1, phospholipase B, phospholipase C, and phospholipase D. [Lehninger. "Principles of Biochemistry". 2004. W H Freeman and Company. Fourth Edition.]

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).

ecreted phospholipases A2 (sPLA2)

The extracellular forms of phospholipases A2 have been isolated from different venoms (snake, bee, and wasp), from virtually every studied mammalian tissue (including pancreas and kidney) as well as from bacteria. They require Ca²⁺ for activity.

Pancreatic PLA2 serve for the initial digestion of phospholipid compounds in dietary fat. Venom phospholipases help to immobilize prey by promoting cell lysis.

Cytosolic phospholipases A2 (cPLA2)

The intracellular 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 eicosanoids. These include leukotrienes and prostaglandins. Some eicosanoids are synthesized from diacylglycerol, released from the lipid bilayer by phospholipase C (see below).

Lipoprotein-associated PLA2s (lp-PLA2)

Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to atherosclerosis [http://www.nature.com/nm/journal/v14/n10/abs/nm.1870.html] .

Mechanism

. The role of calcium can also be duplicated by other relatively small cations like colbalt and nickel. [Berg et al. “Interfacial Enzymology: The Secreted Phospholipase A2-Paradigm” Chemical Review, 2001. Vol. 101. No. 9 2638-2640.]

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 which are influential in regulation and stable protein folding. [Berg et al. “Interfacial Enzymology: The Secreted Phospholipase A2-Paradigm” Chemical Review, 2001. Vol. 101. No. 9 2638-2640.]

Regulation

Due to the importance of PLA2 in inflammatory responses, regulation of the enzyme is essential. PLA2 is regulated by phosphorylation and calcium concentrations. PLA2 is phosphorylated by a MAPK at Serine-505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and can translocate to the membrane to begin catalysis. [Leslie et al. “Properties and Regulation of Cytosolic Phospholipase A2”. 1997. The Journal of Biochemistry. Vol. 272. No. 27. 16709-16712.]

Relevance in Neurological Disorders

In normal brain cells, PLA2 regulation accounts for a balance between arachidonic acid 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. [Farooqui et al. “Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders” 2006. Pharmacological Reviews. Vol. 58. 591-620.]

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. [Bell, JG et al.. Essential fatty acids and phospholipase A2 in autistic spectrum disorders. 2004. Prostaglandins, Leukotrienes and Essential Fatty Acids. Vol. 71. 201-204]

Human proteins containing phospholipase A2 domain

OC90; PLA2G10; PLA2G1B; PLA2G2A; PLA2G2D; PLA2G2E; PLA2G2F; PLA2G3; PLA2G5;

References

Genes

External links

* [http://www.expasy.org/cgi-bin/nicedoc.pl?PDOC00109 Phospholipase A2 active sites] in PROSITE
* - Secreted phospholipases A2 in the lipid bilayer
* - Cytosolic phospholipase A2 and patatin
*

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