Platelet-activating factor acetylhydrolases in health and disease

The platelet-activating factor (PAF) acetylhydrolases catalyze hydrolysis o f the sn-2 ester bond of PAF and related proinflammatory phospholipids and thus attenuate their bioactivity. One secreted (plasma) and four intracellu lar isozymes have been described. The intracellular isozymes are distinguis hed by differences in primary sequence, tissue localization, subunit compos ition, and substrate preferences. The most thoroughly characterized intrace llular 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 p roduct of the LISI gene, mutations of which cause Miller-Dieker lissencepha ly. Isoform II is a single polypeptide that is homologous to the plasma PAF acetylhydrolase and has antioxidant activity in several systems. Plasma PA F acetylhydrolase is also a single polypeptide with a catalytic triad of am ino acids that is characteristic of the alpha/beta hydrolases. Deficiency o f this enzyme has been associated with a number of pathologies. The most co mmon inactivating mutation, V279F, is found ill > 30% of randomly surveyed Japanese subjects (4% homozygous, 27% heterozygous). The prevalence of the mutant allele is significantly greater in patients with asthma, stroke, myo cardial infarction, brain hemorrhage, and nonfamilial cardiomyopathy, Precl inical studies have demonstrated that recombinant plasma PAF acetylhydrolas e can prevent or attenuate pathologic inflammation in a number of animal mo dels. In addition, preliminary clinical results suggest that the recombinan t 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 pathologi c inflammation. (C) 2000 Elsevier Science B.V. All rights reserved.