Congenital erythropoietic porphyria (CEP) is a rare autosomal disease ultimately related to deleterious mutations in
uroporphyrinogen III synthase (UROIIIS), the fourth
enzyme of the biosynthetic route of the
heme group. UROIIIS catalyzes the cyclization of the linear tetrapyrrol
hydroxymethylbilane (HMB), inverting the configuration in one of the aromatic rings. In the absence of the
enzyme (or when ill-functioning), HMB spontaneously degrades to the by-product uroporphyrinogen I, which cannot lead to the
heme group and accumulates in the body, producing some of the symptoms observed in CEP patients. In the present chapter, clinical, biochemical, and biophysical information has been compiled to provide an integrative view on the molecular basis of CEP. The high-resolution structure of UROIIIS sheds light on the
enzyme reaction mechanism while thermodynamic analysis revealed that the
protein is thermolabile. Pathogenic missense mutations are found throughout the primary sequence of the
enzyme. All but one of these is rarely found in patients, whereas C73R is responsible for more than one-third of the reported cases. Most of the
mutant proteins (C73R included) retain partial catalytic activity but the mutations often reduce the
enzyme's stability. The stabilization of the
protein in vivo is discussed in the context of a new line of intervention to
complement existing treatments such as
bone marrow transplantation and gene therapy.