Mutagenesis and homology modeling reveal a predicted pocket of lysophosphatidylcholine acyltransferase 2 to catch Acyl-CoA.

Hamano, F.; Matoba, K.; Hashidate, T.; Suzuki, T.; Miura, K.; Hishikawa, D.; Harayama, T.; Yuki, K.; Kita, Y.; Noda, N. N.; Shimizu, T.; Shindou, H.

doi:10.1101/2020.10.31.363515

bioRxiv · 10.1101/2020.10.31.363515

Mutagenesis and homology modeling reveal a predicted pocket of lysophosphatidylcholine acyltransferase 2 to catch Acyl-CoA.

Hamano, F.·Matoba, K.·Hashidate, T.·Suzuki, T.·Miura, K.·Hishikawa, D.·Harayama, T.·Yuki, K.·Kita, Y.·Noda, N. N.·Shimizu, T.·Shindou, H.

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Abstract

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that elicits various cellular functions and promotes several pathological conditions, including anaphylaxis and neuropathic pain. PAF is biosynthesized by two types of lyso-PAF acetyltransferases: lysophosphatidylcholine acyltransferase 1 (LPCAT1) and LPCAT2, which are constitutive and inducible forms of lyso-PAF acetyltransferase, respectively. Because LPCAT2 mainly produces PAF under inflammatory conditions, understanding the structure of LPCAT2 is important for developing specific drugs against PAF-related inflammatory diseases. Although the structure of LPCAT2 has not been determined, the crystal structure was reported for Thermotoga maritima PlsC, an enzyme in the same enzyme family as LPCAT2. In this study, we identified residues in mouse LPCAT2 essential for its enzymatic activity and a potential acyl-coenzyme A (CoA)-binding pocket, based on homology modeling of mouse LPCAT2 with PlsC. We also found that Ala115 of mouse LPCAT2 was important for acyl-CoA selectivity. In conclusion, these results predict the structure of mouse LPCAT2. Our findings have implications for the future development of new drugs against PAF-related diseases.

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Hamano, F., Matoba, K., Hashidate, T., Suzuki, T., Miura, K., Hishikawa, D., Harayama, T., Yuki, K., Kita, Y., Noda, N. N., Shimizu, T., Shindou, H.. 2020-11-02. Mutagenesis and homology modeling reveal a predicted pocket of lysophosphatidylcholine acyltransferase 2 to catch Acyl-CoA.. https://doi.org/10.1101/2020.10.31.363515

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