Putative Mechanism of Action of Proteasome Inhibitors and Pharmacologic Chaperones in Congenital Erythropoietic Porphyria. UROSC73R and UROSP248Q proteins are misfolded and subjected to premature degradation by the proteasome pathway, leading to deficiency of UROS enzymatic activity and accumulation of uroporphyrinogen I (URO I) and coproporphyrinogen I (COPRO I). Proteasome inhibitors such as bortezomib partially rescue UROSC73R and UROSP248Q expression and restore the metabolic heme biosynthetic pathway by preventing proteolysis. Conceivably, pharamacologic chaperone therapy could also be used to stabilize UROSP248Q and UROSC73R proteins and prevent premature degradation by the proteasome pathway.Blouin J et al. PNAS 2013;110:18238-18243 © 2013 by National Academy of Sciences