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.