IMSR Public Seminar - "Understanding aldosterone biosynthesis for enhanced treatment of hypertension"

Friday 9 October 2020 (14:00-15:00)

James Durrant

Simone Brixius-Anderko

This online talk is part of the IMSR Seminar Series

Primary aldosteronism is the most common form of secondary hypertension and is often associated with cardiac disease. Primary aldosteronism develops due to excessive amounts of the steroid hormone aldosterone, the most potent human mineralocorticoid. Aldosterone synthesized by cytochrome P450 11B2 (CYP11B2, aldosterone synthase) regulates blood pressure and mineral homeostasis. CYP11B2 is 93% identical to the cortisol-producing CYP11B1. Thus, treatment of aldosterone-derived hypertension is impeded due to the lack of drugs specifically targeting CYP11B2. We use a structure/function approach to examine CYP11B2 interaction with both drugs and its redox partner protein adrenodoxin. The X-ray structure of CYP11B2 was determined with the drug LCI699. LCI699 was initially developed as CYP11B2 inhibitor but is now the first FDA-approved drug for the treatment of Cushing’s disease. LCI699 positioning in the CYP11B2 active site and comparison with CYP11B1 with similar compounds provides valuable clues for enhanced drug design. Second, we focused on CYP11B2 interaction with its redox partner protein adrenodoxin. An X-ray structure of an adrenodoxin/CYP11B2 complex identified the adrenodoxin binding site on the proximal face of CYP11B2 and specific interactions. Overall these studies improve our understanding of the aldosterone biosynthetic system and support the design of selective drugs for primary aldosteronism.

Dr Brixius-Anderko earned a diploma in biology and a PhD in biochemistry at Saarland University (Germany) studying steroidogenic cytochrome P450 enzymes for biotechnological applications. I then transitioned to the University of Michigan to study the structure/function relationships of cytochrome P450 enzymes involved in cortisol and aldosterone synthesis.