Abstract: Reactive oxygen species (ROS) such as alkoxyl and peroxyl free radicals have been associated with a number of human disorders such as asthma, cardiovascular disease, diabetes, Alzheimer’s, Parkinson’s and cancer. Polyunsaturated fatty acids (PUFA) and their esters are particularly vulnerable to peroxyl radical chain oxidation reactions and the study of PUFA autoxidation has been central to understanding many of the features of ROS exposures. The mechanism of PUFA free radical oxidation is now reasonably well established1,2 and a strategy to determine the propagation rate constants of lipid substrates in chain oxidation has been established.3 Thus, a free radical clock based on the mechanism of oxidation of linoleate esters4 has been developed and propagation rate constants for several important lipids have been established.3,5 While the propagation rate constant for autoxidation of cholesterol (kp= 11 M-1s-1) is substantially less than that of linoleate (kp= 62 M-1s-1), the rate constant for 7-dehydrocholesterol propagation (7-DHC, kp= 2260 M-1s-1) is some 200 times that of cholesterol. Indeed, 7-DHC has the highest propagation rate constant reported to date of any organic molecule.
Elevated levels of 7-DHC are found in tissues and fluids of patients with a genetic disorder, Smith-Lemli-Opitz syndrome (SLOS),6 that is caused by mutations in the gene encoding 7-dehydrocholesterol reductase (DHCR7), the enzyme that converts 7-DHC to cholesterol.7 The high levels of 7-DHC found in SLOS tissues, the proclivity of this sterol to participate in autoxidation reactions and the formation of sterol electrophiles in the oxidation process has led to recent suggestions that SLOS is a lipid peroxidation disorder.8-12 In support of this suggestion, several studies have correlated oxysterol products found in tissues and fluids of SLOS animal and cell culture models with products of 7-DHC autoxidation. Strategies to investigate protein adduction by the highly reactive electrophiles derived from 7-DHC peroxidation have been developed13 and a high throughput screen of small molecules has identified to a number of pharmaceuticals that inhibit DHCR7 and cause elevated 7-DHC levels in tissues and fluids.14
1. Pratt, D. A.; Tallman, K. A.; Porter, N. A. Acc Chem Res 2011, 44, 458-467.
2. Yin, H.; Xu, L.; Porter, N. A. Chem Rev 2011, 111, 5944-5972.
3. Xu, L.; Davis, T. A.; Porter, N. A. J Am Chem Soc 2009, 131, 13037-13044.
4. Roschek, B.; Tallman, K. A.; Rector, C. L.; Gillmore, J. G.; Pratt, D. A.; Porter, N. A. J Org Chem 2006, 71, 3527-3532.
5. Xu, L.; Porter, N. A. Free Radical Res 2015, 49, 835-849.
6. Smith, D. W.; LemIi, L.; Opitz, J. M. J Pediatr 1964, 64, 210-217.
7. Porter, F. Eur J Hum Genet 2008, 16, 535-541.
8. Xu, L.; Korade, Z.; Rosado, D. A., Jr.; Mirnics, K.; Porter, N. A. J Lipid Res 2013, 54, 1135-1143.
9. Xu, L.; Liu, W.; Sheflin, L. G.; Fliesler, S. J.; Porter, N. A. J Lipid Res 2011, 52, 1810-1820.
10. Xu, L.; Mirnics, K.; Bowman, A. B.; Liu, W.; Da, J.; Porter, N. A.; Korade, Z. Neurobiol Disease 2012, 45, 923–929.
11. Windsor, K.; Genaro-Mattos, T. C.; Kim, H. Y.; Liu, W.; Tallman, K. A.; Miyamoto, S.; Korade, Z.; Porter, N. A. J. Lipid Res. 2013, 54, 2842-2850.
12. Xu, L.; Korade, Z.; Dale A Rosado, J.; Liu, W.; Lamberson, C. R.; Porter, N. A. J Lipid Res 2011, 52, 1222-1233.
13. Tallman, K. A., Kim, H.H.; Korade, Z.; Genaro-Mattos, T. C; Wages, P.A.; Liu, W.; Porter N.A. Redox Biol 2017, 12 182-190.
14. Wages, P. A.; Kim, H.H.; Korade, Z.; Porter N.A. J Lipid Res 2018, 59 1916-1926.