Tunneling in tocopherol-mediated peroxidation of 7-dehydrocholesterol

Abstract

The peroxidation of 7-dehydrocholesterol (7-DHC), a biosynthetic precursor to vitamin D₃ and cholesterol, has been linked to the pathophysiology of Smith–Lemli–Optiz syndrome (SLOS), a devastating human disorder. In SLOS, 7-DHC plasma and tissue levels are elevated because of defects in the enzyme that convert it to cholesterol. α-Tocopherol can mediate the peroxidation of 7-DHC under certain circumstances and this prompted us to investigate the kinetic isotope effect (KIE) during this process. Thus, 9,14-d₂-7-DHC was synthesized using a photochemical cyclization of deuterium-reinforced previtamin D₃ (retro to its biosynthesis). Subsequently, we carried out co-oxidation of 9,14-h₂-25,26,26,26,27,27,27-d₇- and 9,14-d₂-7-DHC in the presence of α-tocopherol under conditions that favor TMP. By monitoring the products formed from each precursor using mass spectrometry, the KIE for the hydrogen (deuterium) atom removal at C9 was found to be 21 ± 1. This large KIE value indicates that tunneling plays a role in the hydrogen atom transfer step in the tocopherol-mediated peroxidation of 7-DHC.