Fig. 6: A model for MBOAT7 catalytic function and comparison of general MBOAT classes.
a Hypothetical model for MBOAT7-catalyzed PI remodeling. The membrane-partitioned or soluble acyl-donor arachidonyl-CoA enters the reaction center at the MBOAT7’s cytosolic tunnel. The side pocket accommodates the long and kinked arachidonyl acyl chain. The acyl-acceptor lyso-PI enters the catalytic chamber through the connected lateral channel and ER lumenal tunnel, with the hydrophobic acyl chains enters through the lateral channel (gray dashed arrow), and the hydrophilic inositol headgroup slides in through the ER lumenal tunnel (green dashed arrow). The thioester bond and sn-2 hydroxy group of lyso-PI are positioned close to the catalytic Asn321 (N) and His356 (H). Once the catalysis is complete, CoA-SH is released into the cytosol, and PI is released to the ER lumenal leaflet of the membrane. The lateral gate is opened slightly wider to facilitate the rapid release of PI. b Putative chemical mechanism of MBOAT7-catalyzed PI remodeling. The backbone carbonyl of Ser352 forms hydrogen bonds with the N on the imidazole ring, which polarizes the other N to deprotonate the sn-2 hydroxyl group of lyso-PI glycerol. Deprotonated hydroxyl initiates a nucleophilic attack on the thioester bond of the arachidonyl-CoA. Finally, CoA-S– attracts the proton back from His356 to complete the catalytic cycle. c Phylogenetic analysis and structural comparison of MBOATs in different clusters. MBOATs with different substrate preferences were clustered and highlighted with different colors except the bacteria DltB. Red, blue and green indicate preference towards neutral lipids, polypeptide, and lyso-phospholipids, respectively. One representative structure from each cluster is shown with hydrophobicity surfaces. The key features for acyl acceptors to access are highlighted in dashed lines and labels. Cartoons are also shown on the right. Dashed circles denote the different entry sites of the acyl-acceptor substrates.
