Gladiolic acid and related aromatic ortho-dialdehydes, a novel class of mitochondrial inhibitors. Inactivation of cytochrome c

Abstract

Gladiolic acid (4-methoxy-5-methyl-o-phthalaldehyde-3-carboxylic acid), an antifungal metabolite produced by Penicillium gladioli (McCull. & Thom), was found to inactivate the catalytic properties of horse heart cytochrome c by reacting with functionally-critical lysine residues in the heme protein. Cyclopaldic acid, quadrilineatin, flavipin and 3-formylopianic acid, aromatic o-dialdehydes structurally related to gladiolic acid (GA), also inactivated cytochrome c. Dihydrogladiolic acid did not complex with cytochrome c. Three moles of GA reacted per mole of cytochrome c reduced the ability of the protein to function with beef heart cytochrome oxidase and pig heart NADH-cytochrome c reductase by 85% and 100%, respectively. The ferricytochrome c-GA complex weakly inhibited the interaction of ferrocytochrome c with the acidic protein of cytochrome oxidase. The reaction between GA and cytochrome c appeared to proceed further than a simple Schiff base formation and the complex was not reversed by dialysis. Gladiolic acid acted as an “apparent” inhibitor of cytochrome oxidase of sweet potato mitochondria by inactivating cytochrome c in situ . Oxidative phosphorylation associated with cytochrome oxidase activity (Site III) was strongly inhibited.