Inhibitory mechanisms of lipoxygenase by garlic sulfides: “adsorption-embolism” effect of DAS and DADS and “quasi-domain-separation” effect of DATS and Allicin

Lipoxygenase (LOX) catalyzes the dioxygenation of polyunsaturated fatty acids containing 1,4-cis,cis-pentadiene, contributing to oxidative stress and food rancidity. This study examined the molecular mechanisms of LOX inhibition by four garlic sulfides: diallyl monosulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), and diallyl thiosulfinate (Allicin). We proposed the “Adsorption-Embolism” effect of DAS and DADS and the “Quasi-Domain-Separation” effect of DATS and Allicin, enhancing the bioactivity theory of natural sulfides as enzyme inhibitors based on protein modification. DAS and DADS formed an “adsorption embolism” in the substrate channel “W-cavity”, reducing its diameter and inhibiting LOX activity. DAS covalently modified Cys492, reinforcing the embolism, while DADS maintained it reversibly through hydrogen bonds and hydrophobic interactions. DATS and Allicin targeted the common boundary between the N- and C-terminal domains, modifying Cys127, disrupting non-covalent interactions. These effects led to looser connections or relative movement between the two domains. The “Catalytic-Fe Coordination Cycle” mechanism for LOX-catalyzed linolenic acid oxidation was also illustrated, supporting electron transfer between DAS and Catalytic-Fe and thereby promoting the biochemistry of 1,4-pentadiene conversion. Further studies are needed to explore the structural changes of LOX induced by these garlic sulfides under higher resolution and varied conditions.