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J Biol Chem, Vol. 274, Issue 45, 31827-31832, November 5, 1999
From the Department of Health Chemistry, Graduate School of
Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113, Japan
Brain intracellular platelet-activating factor
acetylhydrolase (PAF-AH) isoform I is a member of a family of complex
enzymes composed of mutually homologous 
1 and
2 subunits, both of which account for catalytic
activity, and the 
subunit. We previously demonstrated that the
expression of one catalytic subunit, 1, is
developmentally regulated, resulting in a switching of the catalytic
complex from 1/2 to
2/2 during brain development (Manya, H.,
Aoki, J., Watanabe, M., Adachi, T., Asou, H., Inoue, Y., Arai, H., and
Inoue, K. (1998) J. Biol. Chem. 273, 18567-18572). In
this study, we explored the biochemical differences in three possible
catalytic dimers, 1/1,
1/2, and
2/2. The
2/2 homodimer exhibited different
substrate specificity from the 1/1 homodimer and the 1/2 heterodimer, both
of which showed similar substrate specificity. The
2/2 homodimer hydrolyzed PAF and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylethanolamine
(AAGPE) most efficiently among
1-O-alkyl-2-acetyl-phospholipids. In contrast, both
1/1 and 1/2
hydrolyzed
1-O-alkyl-2-acetyl-sn-glycero-3-phosphoric acid
more efficiently than PAF. AAGPE was the poorest substrate for these
enzymes. The subunit bound to all three catalytic dimers but
modulated the enzyme activity in a catalytic dimer composition-dependent manner. The subunit strongly
accelerated the enzyme activity of the
2/2 homodimer but rather suppressed the
activity of the 1/1 homodimer and had
little effect on that of the 1/2
heterodimer. The (His149 to Arg) mutant , which has been
recently identified in isolated lissencephaly sequence patients, lost
the ability to either associate with the catalytic complexes or
modulate their enzyme activity. The enzyme activity of PAF-AH isoform I
may be regulated in multiple ways by switching the composition of the
catalytic subunit and by manipulating the subunit.
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