Platelet-activating factor acetylhydrolases in health and disease.
The platelet-activating factor (PAF) acetylhydrolases catalyze hydrolysis of the sn-2 ester bond of PAF and related pro-inflammatory phospholipids and thus attenuate their bioactivity. One secreted (plasma) and four intracellular isozymes have been described. The intracellular isozymes are distinguished by differences in primary sequence, tissue localization, subunit composition, and substrate preferences. The most thoroughly characterized intracellular isoform, Ib, is a G-protein-like complex with two catalytic subunits (alpha1 and alpha2) and a regulatory beta subunit. The beta subunit is a product of the LIS1 gene, mutations of which cause Miller-Dieker lissencephaly. Isoform II is a single polypeptide that is homologous to the plasma PAF acetylhydrolase and has antioxidant activity in several systems. Plasma PAF acetylhydrolase is also a single polypeptide with a catalytic triad of amino acids that is characteristic of the alpha/beta hydrolases. Deficiency of this enzyme has been associated with a number of pathologies. The most common inactivating mutation, V279F, is found in >30% of randomly surveyed Japanese subjects (4% homozygous, 27% heterozygous). The prevalence of the mutant allele is significantly greater in patients with asthma, stroke, myocardial infarction, brain hemorrhage, and nonfamilial cardiomyopathy. Preclinical studies have demonstrated that recombinant plasma PAF acetylhydrolase can prevent or attenuate pathologic inflammation in a number of animal models. In addition, preliminary clinical results suggest that the recombinant enzyme may have pharmacologic potential in human inflammatory disease as well. These observations underscore the physiological importance of the PAF acetylhydrolases and point toward new approaches for controlling pathologic inflammation.
Tjoelker
L W
LW
ICOS Corporation, Bothell, WA 98021, USA. ltjoelker@icos.com
Stafforini
D M
DM
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D002318:Cardiovascular Diseases / Q000201:enzymology; D002460:Cell Line; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004912:Erythrocytes / Q000201:enzymology; D005060:Europe; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007564:Japan; D009154:Mutation; D010741:Phospholipases A / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D007527:Isoenzymes; D010743:Phospholipids; D010972:Platelet Activating Factor; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase