Structure-function relationships of 3β-hydroxysteroid dehydrogenase: Contribution made by the molecular genetics of 3β-hydroxysteroid dehydrogenase deficiency

• Published in: Steroids Vol. 62; no. 1; pp. 176 - 184
• Main Authors: Morel, Yves, Mébarki, Farida, Rhéaume, Eric, Sanchez, Rocio, Forest, Maguelone G., Simard, Jacques
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 1997; Elsevier Science
• Subjects: 3-Hydroxysteroid Dehydrogenases - deficiency; 3-Hydroxysteroid Dehydrogenases - genetics; 3-Hydroxysteroid Dehydrogenases - metabolism; 3β-hydroxysteroid dehydrogenase; Adolescent; Amino Acid Sequence; Animals; Binding Sites; Biological and medical sciences; Cattle; Cell Membrane - enzymology; Child; Child, Preschool; Cricetinae; Disorders of Sex Development - genetics; Disorders of Sex Development - metabolism; Female; Fundamental and applied biological sciences. Psychology; Humans; Infant, Newborn; Isoenzymes; isomerase; Male; Metabolic Diseases - genetics; Mice; Molecular Sequence Data; Mutagenesis; Mutation; NAD; Phenotype; Rats; Sequence Homology, Amino Acid; short-chain alcohol dehydrogenase; Steroid hormones. Cholecalciferol derivatives; Steroids - metabolism; Structure-Activity Relationship; Vertebrates: endocrinology; Virilism - genetics; Virilism - metabolism; Δ5-steroid; NAD; Δ5-steroid; 3β-hydroxysteroid dehydrogenase; short-chain alcohol dehydrogenase; isomerase; Human; Enzyme; Deficiency; Binding site; Steroidogenesis; Oxidoreductases; Mutation; Aminoacid sequence
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(96)00178-X

The transformation of Δ5-3β-hydroxysteroids into the corresponding Δ4-3-keto-steroids is an essential step for the biosynthesis of all classes of active steroids: progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. These steroid hormones play a crucial role in the differentiation, development, growth, and physiological function of most human tissues. The structures of several cDNAs encoding 3β-HSD isoenzymes have been characterized in human and several other vertebrate species: human types I and II; macaque; bovine; rat types I, II, III, and IV; mouse types I, II, III, IV, V, and VI; hamster types I, II, and III; and rainbow trout. Their transient expression reveals that 3β-HSD and Δ5-Δ4-isomerase activities reside within a single protein. Distinct approaches have been used for a better understanding of the structure-function relationships of these 3β-HSD enzymes: i) affinity radiolabeling studies of the human type I 3β-HSD; ii) identification and the functional consequences of the human type-II 3β-HSD mutations detected in patients with 3β-HSD deficiency. Taken together, all of these data were examined to determine whether the relationship between the genotype and the phenotype of these patients were consistent with in vitro mutagenesis studies. 3β-HSD deficiency, transmitted in an autosomic recessive disorder, is characterized by varying degrees of salt wasting; in genetic males, fetal testicular 3β-HSD deficiency causes an undervirilized male genitalia (male pseudohermaphroditism); females exhibit either normal sexual differentiation or mild virilization. All mutations were detected in the type II 3β-HSD gene, which is expressed almost exclusively in the adrenals and gonads. No mutation was detected in the type I 3β-HSD gene, which is expressed in peripheral tissues. The finding of a normal type I 3β-HSD gene explains the elevated Δ5-steroids and mild virilization of affected girls at birth. To date, 24 mutations have been identified in 25 distinct families with 3β-HSD deficiencies. All nonsense and frameshift mutations introducing a premature termination codon were associated with the classical salt-losing form. The locations of these nonsense mutations suggest that at least the first 318 amino acids out of 371 are required for 3β-HSD activity. The consequences of the missense mutations on some domains of the 3β-enzyme, such as membrane-spanning domains, cofactor-binding site, and steroid-binding site, were reviewed. The future crystallization of the overexpressed normal and mutant-type II-3β-HSD enzymes should contribute to a better understanding of the structure-function relationships of this enzyme, especially for missense mutations located outside the putative functional regions.