Human aldosterone synthase and 11[beta]-hydroxylase: studies on the relationship of structure and function and their clinical implications.
PhD thesis, University of Glasgow.
Full text available as:
Abnormalities in adrenal steroid production have been implicated in certain forms of hypertension. Mutations in the CYP11B1 gene which result in complete loss of 11-hydroxylase function cause 11-hydroxylase deficiency and hypertension due to abnormally high levels of mineralocorticoid, DOC. Mutations have been identified which destroy aldosterone synthase 18-hydroxylase activity or 18-oxidase activity or both, resulting in lack of aldosterone. Structure-function studies have identified aldosterone synthase residues specifically involved in 18-hydroxylation and 18-OHDOC production respectively. Analogous mutations in the human CYP11B2 gene in exons 3 and 4 which result in amino acid substitutions, E136D and K251R have been shown to increase aldosterone production. In essential hypertension adrenal steroids have been implicated as a contributing factor in some cases and it is possible that mutations in aldosterone synthase and 11-hydroxylase may be responsible in part for abnormalities in steroid production. The studies reported in this thesis have investigated some of the residues which may be responsible for the special properties of these enzymes and also the effects of potential inhibitors on enzyme steroid production in vitro.
This thesis presents new studies on the relationship between structure and function of aldosterone synthase and 11-hydroxylase. Artificially induced changes, some relatively conservative and distant from centres of known functional importance, have been shown to alter activity significantly. A number of variations from consensus sequences of these enzymes have been identified in subjects with essential hypertension; whether these affect enzyme activity in such a way as to explain the clinical observations of mild 11-hydroxylase deficiency or suppressed renin or whether they might be used as diagnostic markers remains to be evaluated.
Actions (login required)