Molecular pathomechanisms of steroidogenetic adrenal disorders
Adrenal steroid hormones are vitally important. Deficient adrenal steroid biosynthesis causing a lack of glucocorticoid and / or mineralocorticoid hormones leads to hypoglycaemia, hypotension, salt loss and death. Concomitant changes in adrenal androgen biosynthesis are responsible for virilisation in females or under-virilisation in males. Because of the importance of adrenal steroids for overall survival and reproduction, defects in steroidogenesis and steroid action are rare and have serious consequences. The steroidogenic enzymes belong to the cytochrome P450 enzymes and hydroxysteroid dehydrogenases. Cytochrome P450 enzymes can be subdivided into mitochondrial type 1 enzymes and endoplasmic type 2 proteins. The hydroxysteroid dehydrogenase are either aldo-keto reductases or short-chain dehydrogenases. Expression of the genes that mediate steroidogenesis is tightly controlled by numerous transcription factors such as NR5A and GATA family members. The enzymatic activity is further affected by posttranslational modifications or protein-protein interaction with cofactors, e.g. responsible for electron transfer. Naturally occurring sequence variations in steroidogenic enzymes are responsible for various forms of isolated or complex adrenal insufficiency. By studying the molecular genetics of these rare defects in vitro and in silico, the underlying molecular mechanisms can be described. Hereby, protein residues involved in heme positioning and binding, substrate access and product release, electron transfer and cofactor binding as well as regions inhibiting proteolysis have been detected. These analyses give further insights in the structure-function relationships of steroidogenic enzymes what is of fundamental importance for the understanding of adrenal diseases, disorders of sexual differentiation or reproduction.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.