Abstract
Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.
Highlights
The finding that structurally-related sPLA2 enzymes could have opposing effects in a model of inflammation has significant implications for the development of clinically effective inhibitors of hGIIA enzyme activity
With dose-response relationships reported for ACR20 responses (a 20% reduction in severity scores) and C-reactive protein at 1 week, these signals were lost in subsequent weeks due to ACR20 response increasing in all groups including placebo, leading investigators to conclude the treatment was ineffective in combination with DMARD treatment
The last 30 years of research has demonstrated the complexity of Phospholipase A2 (PLA2) function with the discovery of a superfamily of PLA2 enzymes
Summary
It is well-established that hGIIA function is not limited to its catalytic activity. Many of the observed effects of hGIIA on biological systems, in pathological settings characterized by persistent aberrant expression of hGIIA, may be attributed to direct or indirect perturbation of intracellular cell signaling pathways mediated through proteinprotein interactions. Other studies in astrocytoma cells suggest that PGE2 upregulation is a result of hGIIA’s ability to increase cPLA2-α function In this case, evidence suggests that exogenous hGIIA binds to a PLA2 receptor (PLA2R) on the cell surface which initiates activation of two separate pathways; the MAP kinase cascade which activates cPLA2-α, and activation of PLCγ and release of calcium from intracellular stores [85,86]. Evidence suggests that exogenous hGIIA binds to a PLA2 receptor (PLA2R) on the cell surface which initiates activation of two separate pathways; the MAP kinase cascade which activates cPLA2-α, and activation of PLCγ and release of calcium from intracellular stores [85,86] This effect is not mitigated with the addition of p-bromophenacyl bromide (BPB) which halts enzymatic activity of hGIIA, confirming that this mechanism is independent of catalysis. 55. .PPhhaarrmmaaccoolologgicicaallIInnhhibibitiitoionnooffhhGGIIIIAAFFuunnccttiioonn mfumnanuoludtnltlotiCosipCtnpyoloollnenyenntsdhdlsiiyidineisdsteioioenarcrrrlidliadniennelgevlgrherisstiva,thb,thiiiiieatttnetoiirgissrrnooscgcldlelloeieedsfoaaeiohfsrrafeGsthtahhheGIsaGaIesAIttyIIsiIiAmddyAhemeapinnnvitnpttoeiitpfmfopibihccmhesayae,ytsstinsbii,oooiubnoinldutolooeotgafgnfaylpystlpiosoafooainteitnenidednndn.tdidttiiHestniesfnfohidinhdwinybiiyinbseinstrgivorgteeoerghhrgsru,GsGuoaloIalfIsaIItfhAtiAdiohGoenGffnIsuuIcIaAnnIrasAicscsbmtstoieimooocadcninyaia.aay.tbbteNeNeboddaevuatwestuuwu,esirfirtneatuhah-olll ahnGdIIsAynitnhheitbiictoinrshhibaivtoercsuorrfehnGtlyIIAbehenavaeppberoevneiddednuteiftioedto. xHicoiwtyecvoenrc,earsnsd.eIsnchriibbietdorasboofvheG, InIoA hhGaIvIeAbienehnibpirteovrisouhsalvyerecvuirerwenetdly[6b4e,1e4n2]a. pOprriogvineadllyduheGtIoIAtoinxhiciibtiytocros nwceerrensc.laIsnshifiibeidtobrassoedf hoGnItIhAeirhsapveecifbiceecnhempriceavliocounslfyormreavtiioewnsebdut[6re4c,1e4n2tl]y. aOfruingcintiaolnlyal bhaGsiIsIAof cinlahsisbifiitcoartsionwweraes introduced by Lee et al [111], viz. inhibitors which are selective for (a) the catalysis-dependent mechanism or (b) the catalysis-independent mechanism or (c) dual function inhibitors
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