The aminopeptidase (AP) activity of LTA4H contributes to an anti-inflammatory phenotype in multiple murine models by catalyzing the hydrolysis of the tripeptide proline-glycine-proline (PGP). Previously, we reported that 4MDM activated LTA4H AP activity. Orning and co-workers showed that tripeptides with an arginine residue at the N-terminus were better substrates for LTA4H-mediated hydrolysis. Since alanine-pNA has been primarily used to assess LTA4H AP activity, we decided to investigate the kinetic mechanisms for LTA4H hydrolysis of other substrates such as Arg-pNA and Pro-pNA by LTA4H in the presence of 4MDM to determine substrate selectivity with respect to the amino acid residue. Our study demonstrated that 4MDM could either activate the hydrolysis of Pro-pNA by LTA4H with one mechanism or inhibit the hydrolysis of Arg-pNA with a different mechanism.Herein, we present distinctive mechanisms in which LTA4H enzymatic activity can be modulated by 4MDM depending on the substrate.

Substrate-dependent hydrolysis by the leukotriene A4 hydrolase in the presence of 4MDM

2019 Spring National Meeting

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