Natural and pharmacological chaperones against accelerated protein degradation: uroporphyrinogen III synthase and congenital erythropoietic porphyria

Abstract Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease derived from a deficient activity in the fourth enzyme of the heme biosynthetic pathway, uroporphyrinogen III synthase (UROIIIS). The impossibility of a correct heme production results in the accumulation of intermediate metabolites known as uroporhyrins, leading to pathological consequences such as skin photosensitivity and phototoxic cutaneous injuries. In this chapter, we discuss the importance of protein homeostasis in the heme pathway and its regulation, as well as how many of the CEP-causing mutations impair UROIIIS homeostasis, affecting thermodynamic stability but preserving normal or near-normal activity. As a proof of concept, we show how UROIIIS proteostasis can be restored by use of a proteasomal inhibitor in animal models. Finally, a new line of therapeutic intervention against CEP is presented, which involves the use of a pharmacological chaperone known as ciclopirox (CPX) to improve UROIIIS stability, reverting most of the CEP symptoms in mice models.