ALAD Porphyria Is a Conformational Disease

摘要: ALAD porphyria is a rare porphyric disorder, with five documented compound heterozygous patients, and it caused by profound lack of porphobilinogen synthase (PBGS) activity. PBGS, also called “δ-aminolevulinate dehydratase,” encoded the gene catalyzes second step in biosynthesis heme. recessive disorder; there are two common variant alleles, which encode K59 N59, eight known porphyria-associated mutations, F12L, E89K, C132R, G133R, V153M, R240W, A274T, V275M. Human PBGS exists as an equilibrium functionally distinct quaternary structure assemblies, “morpheeins,” one functional homo-oligomer can dissociate, change conformation, reassociate into different oligomer. In case human assemblies high-activity octamer low-activity hexamer. The current study quantifies morpheein forms for variants. Heterologous expression Escherichia coli, followed separation octameric hexameric on ion-exchange column, showed that percentage hexamer F12L (100%), R240W (80%), G133R (48%), C132R (36%), E89K (31%), A274T (14%) was appreciably larger than wild-type proteins N59 (0% 3%, respectively). All variants, including V153M V275M, increased propensity to form hexamer, according kinetic analysis. Thus, all variants found shift toward less active We propose disequilibrium broadens definition conformational diseases beyond prion disorders first example morpheein-based disease.