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phospholipase A2
Phospholipase Cleavage Sites. Note that an enzyme that displays both PLA1 and PLA2 activities is called a Phospholipase B
EC number
CAS number 9001-84-7
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures
Gene Ontology AmiGO / EGO
Phospholipase A2
ee venom phospholipase A2 sPLA2. Middle plane of the lipid bilayer - black dots. Boundary of the hydrocarbon core region - red dots (extracellular side). Layer of lipid phosphates - yellow dots.
Symbol Phospholip_A2_1
Pfam PF00068
InterPro IPR001211
SCOP 1bbc
OPM family 90
OPM protein 1g4i

Phospholipases A2 (PLA2s) EC are enzymes that release fatty acids 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 cyclooxygenases, arachidonic acid is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes which are categorized as inflammatory mediators.[1]

PLA2 are commonly found in mammalian tissues as well as insect and snake venom.[2] 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.[3] There are also prokaryotic A2 phospholipases.

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



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, 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).

Phospholipases A2 can be classified based on sequence homology.[5]

Lipoprotein-associated PLA2s (lp-PLA2)

Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to atherosclerosis[6].


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 histidine 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. [7]

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.[8]
Mechanism of hydrolysis catalyzed by PLA2

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.[7]


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. [9]

Phosphorylation of PLA2 may be a result of ligand binding to receptors, including:

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.[11]

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. 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.[12]


Human phospholipase A2 isozymes include:

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


  1. ^ Dennis EA (May 1994). "Diversity of group types, regulation, and function of phospholipase A2". J. Biol. Chem. 269 (18): 13057–60. PMID 8175726.  
  2. ^ Nicolas JP, Lin Y, Lambeau G, Ghomashchi F, Lazdunski M, Gelb MH (March 1997). "Localization of structural elements of bee venom phospholipase A2 involved in N-type receptor binding and neurotoxicity". J. Biol. Chem. 272 (11): 7173–81. doi:10.1074/jbc.272.11.7173. PMID 9054413.  
  3. ^ Argiolas A, Pisano JJ (November 1983). "Facilitation of phospholipase A2 activity by mastoparans, a new class of mast cell degranulating peptides from wasp venom". J. Biol. Chem. 258 (22): 13697–702. PMID 6643447.  
  4. ^ Cox, Michael; Nelson, David R.; Lehninger, Albert L (2005). Lehninger principles of biochemistry (4th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-4339-6.  
  5. ^ Six DA, Dennis EA (2000). "The expanding superfamily of phospholipase A(2) enzymes: classification and characterization". Biochim. Biophys. Acta 1488 (1-2): 1–19. PMID 11080672.  
  6. ^ Wilensky RL, Shi Y, Mohler ER, et al. (October 2008). "Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development". Nat. Med. 14 (10): 1059–66. doi:10.1038/nm.187010.1038/nm.1870 (inactive 2009-11-08). PMID 18806801.  
  7. ^ a b Berg OG, Gelb MH, Tsai MD, Jain MK (September 2001). "Interfacial enzymology: the secreted phospholipase A(2)-paradigm". Chem. Rev. 101 (9): 2613–54. doi:10.1021/cr990139w. PMID 11749391. "See page 2640".  
  8. ^ PDB 1FXF; Pan YH, Epstein TM, Jain MK, Bahnson BJ (January 2001). "Five coplanar anion binding sites on one face of phospholipase A2: relationship to interface binding". Biochemistry 40 (3): 609–17. doi:10.1021/bi002514g. PMID 11170377.  
  9. ^ Leslie CC (July 1997). "Properties and regulation of cytosolic phospholipase A2". J. Biol. Chem. 272 (27): 16709–12. doi:10.1074/jbc.272.27.16709. PMID 9201969.  
  10. ^ a b c d e Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 103. ISBN 1-4160-2328-3.  
  11. ^ Farooqui AA, Ong WY, Horrocks LA (September 2006). "Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders". Pharmacol. Rev. 58 (3): 591–620. doi:10.1124/pr.58.3.7. PMID 16968951.  
  12. ^ Bell JG, MacKinlay EE, Dick JR, MacDonald DJ, Boyle RM, Glen AC (October 2004). "Essential fatty acids and phospholipase A2 in autistic spectrum disorders". Prostaglandins Leukot. Essent. Fatty Acids 71 (4): 201–4. doi:10.1016/j.plefa.2004.03.008. PMID 15301788.  

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