Communication: Homocysteine, Thioretinaco Ozonide, Oxidative Phosphorylation, Biosynthesis of Phosphoadenosine Phosphosulfate and the Pathogenesis of Atherosclerosis.

The formation of phosphoadenosine phosphosulfate (PAPS) is accomplished by the action of the enzyme 3'-phosphoadenosine 5'-phosphosulfate synthase (PAPSS) in two sequential reactions, consisting of (1) reaction of inorganic sulfate with adenosine triphosphate (ATP) to form adenosine phosphosulfate (APS) and pyrophosphate and (2) reaction of APS with inorganic phosphate to form PAPS and adenosine diphosphate (ADP). The hydrolysis of guanosine triphosphate (GTP) is coordinated with synthesis of APS in a reaction sequence which provides the chemical energy for synthesis of APS. The present proposal is that the active site of oxidative phosphorylation, thioretinaco ozonide oxygen (TR2CoO3O2), functions as the source of APS synthesis from nicotinamide adenine dinucleotide (NAD+) and hydrosulfate (HSO4-) by reduction of the complex with electrons from electron transport complexes, releasing APS and thioretinaco hydroperoxide (TR2CoO3O2H) upon protonation. Subsequently, APS reacts with GTP, which is produced from the active site of oxidative phosphorylation, TR2CoO3O2ATP, to phosphorylate APS to PAPS. These proposed reactions for PAPS synthesis in atherosclerosis explain the metabolic pathway for formation of PAPS from homocysteine through the intermediate formation of thioretinamide (TR) and explain how hyperhomocysteinemia stimulates production of sulfated glycosaminoglycans (GAG), which are essential components of atherosclerotic plaques.