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390  structures 315  species 2  interactions 1645  sequences 16  architectures

Family: Phospholip_A2_1 (PF00068)

Summary: Phospholipase A2

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Phospholipase A2 Edit Wikipedia article

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 RCSB PDB PDBe PDBsum
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 superfamily 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 anti-inflammatory and 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 sPLA2 serve for the initial digestion of phospholipid compounds in dietary fat. Venom phospholipases help to immobilize prey by promoting cell lysis.

In mice, group III sPLA2 are involved in sperm maturation,[5] and group X are thought to be involved in sperm capacitation.[6]

sPLA2 has been shown to promote inflammation in mammals by catalyzing the first step of the arachidonic acid pathway by breaking down phospholipids, resulting in the formation of fatty acids including arachidonic acid. 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 and acute coronary syndrome,[7] and possibly leading to acute respiratory distress syndrome [8] and progression of tonsillitis[9] in children. In mice, excess levels of sPLA2 have been associated with inflammation thought to exacerbate asthma[10] and ocular surface inflammation (dry eye).[11]

Increased sPLA2 activity is observed in the cerebrospinal fluid of humans with Alzheimer's disease and multiple sclerosis, and may serve as a marker of increases in permeability of the blood-cerebrospinal fluid barrier.[12]

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 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.[13]

Lipoprotein-associated PLA2s (lp-PLA2)

Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to atherosclerosis.[14]


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.[15]

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.[16]
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 that are influential in regulation and stable protein folding.[15]


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.[17]

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

In the case of an inflammation the application of glucocorticoids will stimulate the release of the protein lipocortin which will inhibit PLA2 and reduce the inflammatory response.

Relevance in Neurological Disorders

In normal brain cells, PLA2 regulation accounts for a balance between arachidonic acid'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 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.[19]

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 schizophrenia and pervasive developmental disorders (such as autism), though the mechanisms involved are not known.[20]


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. ^ Sato, H; Taketomi, Y; Isogai, Y; et al, Yoshimi; Yamamoto, Kei; Masuda, Seiko; Hosono, Tomohiko; Arata, Satoru et al. (May 2010). "Group X phospholipase A2 is released during sperm acrosome reaction and controls fertility outcome in mice". Journal of Clinical Investigation 120 (5): 1415–28. doi:10.1172/JCI40493. PMC 2860917. PMID 20424323. 
  6. ^ Escoffier, J; Jemel, I; Tanemoto, A; et al, Yoshitaka; Payre, Christine; Coatrieux, Christelle; Sato, Hiroyasu; Yamamoto, Kei et al. (May 2010). "Group X phospholipase A2 is released during sperm acrosome reaction and controls fertility outcome in mice". Journal of Clinical Investigation 120 (5): 1415–28. doi:10.1172/JCI40494. PMC 2860919. PMID 20424324. 
  7. ^ Mallat, Z.; Lambeau, G.; Tedgui, A. (November 2010). "Lipoprotein-Associated and Secreted Phospholipases A2 in Cardiovascular Disease: Roles as Biological Effectors and Biomarkers". Circulation 122 (21): 2183–2200. doi:10.1161/CIRCULATIONAHA.110.936393. PMID 21098459. 
  8. ^ De Luca, D.; Minucci, A.; Cogo, P.; Capoluongo, E.D.; Conti, G.; Pietrini, D.; Carnielli, V.P.; Piastra, M. (January 2011). Secretory phospholipase A₂ pathway during pediatric acute respiratory distress syndrome: a. 
  9. ^ Ezzeddini, Rana; Darabi, Masoud; Ghasemi, Babollah; Jabbari, Yalda; Abdollahi, Shahin; Rashtchizadeh, Nadereh; Gharahdaghi, Abasaad; Darabi, Maryam; Ansarin, Masoud; Shaaker, Maghsood; Samadi, Akbar; Karamravan, Jamal (2012). "Circulating phospholipase-A2 activity in obstructive sleep apnea". International Journal of Pediatric Otorhinolaryngology 76 (4): 471–4. doi:10.1016/j.ijporl.2011.12.026. PMID 22297210. 
  10. ^ Henderson, W.R. Jr.; Oslund, R.C.; Bollinger, J.G.; Ye, X.; Tien, Y.T.; Xue, J.; Gelb, M.H. (August 2011). "Blockade of Human Group X Secreted Phospholipase A2 (GX-sPLA2)-induced Airway Inflammation and Hyperresponsiveness in a Mouse Asthma Model by a Selective GX-sPLA2 Inhibitor". Journal of Biological Chemistry 286 (32): 28049–55. doi:10.1074/jbc.M111.235812. PMC 3151050. PMID 21652694. 
  11. ^ Wei, Y.; Epstein, S.P.; Fukuoka, S.; Birmingham, N.P.; Li, X.M.; Asbell, P.A. (July 2011). "sPLA2-IIa Amplifies Ocular Surface Inflammation in the Experimental Dry Eye (DE) BALB/c Mouse Model". Investigative Ophthalmology and Visual Science 52 (7): 4780–8. doi:10.1167/iovs.10-6350. PMC 3175946. PMID 21519031. 
  12. ^ Chalbot, S.; Zetterberg, H.; Blennow, K.; Fladby, T.; Andreasen, N.; Grundke-Iqbal, I.; Iqbal, K. (January 2011). "Blood-Cerebrospinal Fluid Barrier Permeability in Alzheimer's Disease". Journal of Alzheimer's disease 25 (3): 505–15. doi:10.3233/JAD-2011-101959 (inactive 2014-03-22). PMC 3139450. PMID 21471645. 
  13. ^ Six DA, Dennis EA (2000). "The expanding superfamily of phospholipase A(2) enzymes: classification and characterization". Biochim. Biophys. Acta 1488 (1–2): 1–19. doi:10.1016/S1388-1981(00)00105-0. PMID 11080672. 
  14. ^ 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.1870. PMC 2885134. PMID 18806801. 
  15. ^ 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" 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ 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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Phospholipase A2 Provide feedback

Phospholipase A2 releases fatty acids from the second carbon group of glycerol. Perhaps the best known members are secreted snake venoms, but also found in secreted pancreatic and membrane-associated forms. Structure is all-alpha, with two core disulfide-linked helices and a calcium-binding loop. This alignment represents the major family of PLA2s. A second minor family, defined by the honeybee venom PLA2 PDB:1POC and related sequences from Gila monsters (Heloderma), is not recognised. This minor family conserves the core helix pair but is substantially different elsewhere. The PROSITE pattern PA2_HIS, specific to the first core helix, recognises both families.

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001211

Phospholipase A2 (EC) (PLA2) is a small lipolytic enzyme that releases fatty acids from the second carbon group of glycerol. It is involved in a number of physiologically important cellular processes, such as the liberation of arachidonic acid from membrane phospholipids [PUBMED:7664098]. It plays a pivotal role in the biosynthesis of prostaglandin and other mediators of inflammation. PLA2 has four to seven disulphide bonds and binds a calcium ion that is essential for activity. Within the active enzyme, the alpha amino group is involved in a conserved hydrogen-bonding network linking the N-terminal region to the active site. The side chains of two conserved residues, His and Asp, participate in the catalytic network.

Many PLA2's are widely distributed in snakes, lizards, bees and mammals. In mammals there are at least four forms: pancreatic, membrane-associated as well as two less well characterised forms. The venom of most snakes contains multiple forms of PLA2. Some of them are presynaptic neurotoxins which inhibit neuromuscular transmission by blocking acetylcholine release from the nerve termini.

Some of the proteins in this family are allergens. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed of the first three letters of the genus; a space; the first letter of the species name; a space and an arabic number. In the event that two species names have identical designations, they are discriminated from one another by adding one or more letters (as necessary) to each species designation.

The allergens in this family include allergens with the following designations: Api m 1.

Gene Ontology

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Domain organisation

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Seed source: Overington and HMM_iterative_training
Previous IDs: phoslip;
Type: Domain
Author: Eddy SR
Number in seed: 37
Number in full: 1645
Average length of the domain: 114.20 aa
Average identity of full alignment: 33 %
Average coverage of the sequence by the domain: 69.11 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.7 20.7
Trusted cut-off 20.7 20.7
Noise cut-off 20.5 20.6
Model length: 116
Family (HMM) version: 14
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Species distribution

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Phospholip_A2_1 Kunitz_BPTI


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Phospholip_A2_1 domain has been found. There are 390 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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