Hmp. Wilson et al., STRUCTURAL BASIS OF THE PHOSPHOLIPID ACYLTRANSFERASE ENZYME-SUBSTRATESPECIFICITY - A COMPUTER MODELING STUDY OF THE PHOSPHOLIPID ACCEPTOR MOLECULE, Journal of lipid research, 36(3), 1995, pp. 429-439
The activity of the 1-acyl-sn-glycero-3-phosphocholine acyltransferase
enzyme (E.C. 2.3.1.??) was measured with three radically different ac
ceptor 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 enzym
e had similar activity with P-sn-G3PC, the natural acceptor substrate,
and with P-sn-G2PC. The enzyme showed no detectable activity toward H
e-sn-G3PC. These results are much different than would be expected fro
m simple examination of the structures. Computer-assisted molecular mo
deling was done to study the geometrical configurations and to focus u
pon the similarities and differences of the three substrate acceptor m
olecules. Three bond distances were selected as important for enzyme r
ecognition: the distance between the oxygen of the acceptor hydroxyl g
roup and 1) the phosphorus; 2) the nitrogen; and 3) the oxygen bridge
to the hydrocarbon chain. There were striking similarities for the bon
d distances of two of the three acceptor substrates, P-sn-G3PC and P-s
n-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-5n-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 consist
ent with the experimental observation that He-sn-G3PC is not an inhibi
tor.