Computer simulation of heterogeneous single nucleotide polymorphisms in the catalase gene indicates structural changes in the enzyme active site, NADPH-binding and tetramerization domains: a genetic predisposition for an altered catalase in patients with vitiligo?
Patients with vitiligo have low levels/activities of catalase in their lesional and non-lesional epidermis as well as in their epidermal melanocytes under in vitro conditions while the levels of catalase mRNA are unaltered. This defect leads to a build-up of hydrogen peroxide (H(2)O(2)) in the 10(-3) m range in the epidermis of these patients. In this context, it was realized that 10(-3) m H(2)O(2) deactivates catalase. Along this line, it was also suspected that catalase in patients with vitiligo possesses a special sensitivity to this reactive oxygen species (ROS), and indeed several heterozygous single nucleotide polymorphisms (SNPs) have been documented in the cat gene of these patients. Based on the 3D structure of human catalase monomer, we have modelled the influence of three selected SNPs on the enzyme active site, on the NADPH- as well as the tetramerization-binding domains. Our results show that these SNPs severely alter catalase structurally, which in turn should make the enzyme more susceptible to ROS compared with wild-type enzyme. Taken together, the work presented herein together with the earlier results on SNPs in the cat gene suggests a genetic predisposition for an altered catalase in patients with vitiligo.
Wood
John M
JM
Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, Bradford, UK.
Gibbons
Nicholas C J
NC
Chavan
Bhaven
B
Schallreuter
Karin U
KU
D019943:Amino Acid Substitution / Q000235:genetics; D001665:Binding Sites; D002374:Catalase / Q000737:chemistry / Q000235:genetics*; D003198:Computer Simulation; D030562:Databases, Protein; D020022:Genetic Predisposition to Disease; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008956:Models, Chemical; D009249:NADP / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D014820:Vitiligo / Q000201:enzymology / Q000235:genetics*
D009249:NADP; D006861:Hydrogen Peroxide; D002374:Catalase