Journal of Lipid Research, Vol 36, 429-439, Copyright © 1995 by Lipid Research, Inc.
Structural basis of the phospholipid acyltransferase enzyme substrate specificity: a computer modeling study of the phospholipid acceptor molecule
HM Wilson, W Neumuller, H Eibl, WH Welch Jr and RC Reitz
Department of Biochemistry, University of Nevada, Reno 89557, USA.
The activity of the 1-acyl-sn-glycero-3-phosphocholine acyltransferase
enzyme (E.C. 2.3.1.??) was measured with three radically different acceptor
substrates: 1-palmitoyl-sn-glycero-3-phosphocholine (P-sn- G3PC),
1-palmitoyl-sn-glycero-2-phosphocholine (P-sn-G2PC), and 1-
hexadecyl-sn-glycero-3-phosphocholine (He-sn-G3PC). It was found that the
enzyme had similar activity with P-sn-G3PC, the natural acceptor substrate,
and with P-sn-G2PC. The enzyme showed no detectable activity toward
He-sn-G3PC. These results are much different than would be expected from
simple examination of the structures. Computer-assisted molecular modeling
was done to study the geometrical configurations and to focus upon the
similarities and differences of the three substrate acceptor molecules.
Three bond distances were selected as important for enzyme recognition: the
distance between the oxygen of the acceptor hydroxyl group and 1) the
phosphorus; 2) the nitrogen; and 3) the oxygen bridge to the hydrocarbon
chain. There were striking similarities for the bond distances of two of
the three acceptor substrates, P-sn-G3PC and P-sn-G2PC. These were the two
molecules that were shown to have activity with the enzyme. The bond
distances found for the enzymically inactive acceptor substrate,
He-sn-G3PC, differed significantly from P-sn-G3PC and P-sn-G2PC. Therefore,
this latter molecule probably does not fit into the active site of the
enzyme. The modeling data are also consistent with the experimental
observation that He-sn-G3PC is not an inhibitor.
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