Biology:Phospholipase A2

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Short description: Peripheral membrane protein


phospholipase A2
Phospholipases2.svg
Phospholipase Cleavage Sites. Note that an enzyme that displays both PLA1 and PLA2 activities is called a Phospholipase B
Identifiers
EC number3.1.1.4
CAS number9001-84-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Phospholipase A2
1poc.png
Bee 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.
Identifiers
SymbolPhospholip_A2_1
PfamPF00068
InterProIPR001211
PROSITEPDOC00109
SCOP21bbc / SCOPe / SUPFAM
OPM superfamily82
OPM protein1g4i

The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse 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 phospholipase specifically recognizes the sn2 acyl bond of phospholipids and catalytically hydrolyzes the bond, releasing arachidonic acid and 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.[2] Venom from bees 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]

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 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[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 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,[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 asthma[11] and ocular surface inflammation (dry eye).[12]

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.[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 cell signaling processes, such as inflammatory response. They release arachidonic acid from membrane phospholipids. Arachidonic acid is both a 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 page: Biology: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 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.[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 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.[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 inflammatory responses, regulation of the enzyme is essential. cPLA2 is regulated by phosphorylation and calcium concentrations. cPLA2 is phosphorylated by a 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 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.[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 schizophrenia and pervasive developmental 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

  • Paul Sigler

References

  1. ↑ "Diversity of group types, regulation, and function of phospholipase A2". The Journal of Biological Chemistry 269 (18): 13057–13060. May 1994. doi:10.1016/S0021-9258(17)36794-7. PMID 8175726. 
  2. ↑ "Localization of structural elements of bee venom phospholipase A2 involved in N-type receptor binding and neurotoxicity". The Journal of Biological Chemistry 272 (11): 7173–7181. March 1997. doi:10.1074/jbc.272.11.7173. PMID 9054413. 
  3. ↑ "Facilitation of phospholipase A2 activity by mastoparans, a new class of mast cell degranulating peptides from wasp venom". The Journal of Biological Chemistry 258 (22): 13697–13702. November 1983. doi:10.1016/S0021-9258(17)43973-1. PMID 6643447. 
  4. ↑ Lehninger principles of biochemistry (4th ed.). San Francisco: W.H. Freeman. 2005. ISBN 0-7167-4339-6. https://archive.org/details/lehningerprincip00lehn_0. 
  5. ↑ "The chemistry of snake venom and its medicinal potential". Nature Reviews. Chemistry 6 (7): 451–469. 2022-06-10. doi:10.1038/s41570-022-00393-7. PMID 35702592. 
  6. ↑ "Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice". The Journal of Clinical Investigation 120 (5): 1400–1414. May 2010. doi:10.1172/JCI40493. PMID 20424323. 
  7. ↑ "Group X phospholipase A2 is released during sperm acrosome reaction and controls fertility outcome in mice". The Journal of Clinical Investigation 120 (5): 1415–1428. May 2010. doi:10.1172/JCI40494. PMID 20424324. 
  8. ↑ "Lipoprotein-associated and secreted phospholipases A2₂ in cardiovascular disease: roles as biological effectors and biomarkers". Circulation 122 (21): 2183–2200. November 2010. doi:10.1161/CIRCULATIONAHA.110.936393. PMID 21098459. 
  9. ↑ "Secretory phospholipase AA2 pathway during pediatric acute respiratory distress syndrome: a preliminary study". Pediatric Critical Care Medicine 12 (1): e20–e24. January 2011. doi:10.1097/PCC.0b013e3181dbe95e. PMID 20351613. 
  10. ↑ "Circulating phospholipase-A2 activity in obstructive sleep apnea and recurrent tonsillitis". International Journal of Pediatric Otorhinolaryngology 76 (4): 471–474. April 2012. doi:10.1016/j.ijporl.2011.12.026. PMID 22297210. 
  11. ↑ "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". The Journal of Biological Chemistry 286 (32): 28049–28055. August 2011. doi:10.1074/jbc.M111.235812. PMID 21652694. 
  12. ↑ "sPLA2-IIa amplifies ocular surface inflammation in the experimental dry eye (DE) BALB/c mouse model". Investigative Ophthalmology & Visual Science 52 (7): 4780–4788. July 2011. doi:10.1167/iovs.10-6350. PMID 21519031. 
  13. ↑ "Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease". Journal of Alzheimer's Disease 25 (3): 505–515. January 2011. doi:10.3233/JAD-2011-101959. PMID 21471645. 
  14. ↑ "Pla2g12b and Hpn are genes identified by mouse ENU mutagenesis that affect HDL cholesterol". PLOS ONE 7 (8): e43139. August 2012. doi:10.1371/journal.pone.0043139. PMID 22912808. Bibcode: 2012PLoSO...743139A. 
  15. ↑ "Hepatocyte nuclear factor-4 α regulates liver triglyceride metabolism in part through secreted phospholipase AA2 GXIIB". Hepatology 53 (2): 458–466. February 2011. doi:10.1002/hep.24066. PMID 21274867. 
  16. ↑ "Hepatocyte nuclear factor 4α and downstream secreted phospholipase A2 GXIIB regulate production of infectious hepatitis C virus". Journal of Virology 88 (1): 612–627. January 2014. doi:10.1128/JVI.02068-13. PMID 24173221. 
  17. ↑ "The expanding superfamily of phospholipase A(2) enzymes: classification and characterization". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1488 (1–2): 1–19. October 2000. doi:10.1016/S1388-1981(00)00105-0. PMID 11080672. 
  18. ↑ "Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development". Nature Medicine 14 (10): 1059–1066. October 2008. doi:10.1038/nm.1870. PMID 18806801. 
  19. ↑ "The role of lipoprotein-associated phospholipase A2 in atherosclerosis may depend on its lipoprotein carrier in plasma". Biochimica et Biophysica Acta 1791 (5): 327–338. May 2009. doi:10.1016/j.bbalip.2009.02.015. PMID 19272461. 
  20. ↑ 20.0 20.1 "Interfacial enzymology: the secreted phospholipase A(2)-paradigm". Chemical Reviews 101 (9): 2613–2654. September 2001. doi:10.1021/cr990139w. PMID 11749391. "See page 2640". 
  21. ↑ PDB: 1FXF​; "Five coplanar anion binding sites on one face of phospholipase A2: relationship to interface binding". Biochemistry 40 (3): 609–617. January 2001. doi:10.1021/bi002514g. PMID 11170377. 
  22. ↑ "Pharmacological study of phospholipase A2-induced histamine release from rat peritoneal mast cells". Journal of Pharmacobio-Dynamics 12 (9): 517–522. September 1989. doi:10.1248/bpb1978.12.517. PMID 2482349. 
  23. ↑ "Role of phospholipase A2 activation in histamine release from human basophils". Allergy 38 (6): 413–418. August 1983. doi:10.1111/j.1398-9995.1983.tb05084.x. PMID 6194706. 
  24. ↑ "Properties and regulation of cytosolic phospholipase A2". The Journal of Biological Chemistry 272 (27): 16709–16712. July 1997. doi:10.1074/jbc.272.27.16709. PMID 9201969. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. 2003. p. 103. ISBN 1-4160-2328-3. 
  26. ↑ "Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders". Pharmacological Reviews 58 (3): 591–620. September 2006. doi:10.1124/pr.58.3.7. PMID 16968951. 
  27. ↑ "Essential fatty acids and phospholipase A2 in autistic spectrum disorders". Prostaglandins, Leukotrienes, and Essential Fatty Acids 71 (4): 201–204. October 2004. doi:10.1016/j.plefa.2004.03.008. PMID 15301788. 
  28. ↑ "The role of phospholipases A2 in schizophrenia". Molecular Psychiatry 11 (6): 547–556. June 2006. doi:10.1038/sj.mp.4001819. PMID 16585943. 

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