Vitamin-D is turned "on" and "off" within the body. My name is Natalie Jay. I am a third year PhD candidate at UB conducting research in Dr. Estrada's lab. Dr. Estrada's lab focuses on the structure and function of cytochrome P450 enzymes. My project focuses on the final enzyme in the vitamin-D metabolism pathway CYP24A1 which is involved in turning vitamin-D "off". There is very little known about how CYP24A1 turns "off" vitamin-D. CYP24A1 works in conjunction with its reduction- oxidation partner adrenodoxin. By using a fusion construct of CYP24A1 and adrenodoxin I am able to investigate the structure/function relationship of CYP24A1. Understanding what causes vitamin-D to turn "off" will help with development of more efficient treatment.
Vitamin-D insufficiency is associated with rickets, cardiovascular disease, and chronic kidney disease affecting nearly 50% of the population. In humans, vitamin-D is metabolized by a series of cytochrome P450 enzymes, including inactivation by the mitochondrial P450, CYP24A1. CYP24A1 in humans first hydroxylates either the carbon-23 or carbon-24 position of 1,25-(OH)2D3. The human isoform of CYP24A1 is not easily expressed and purified recombinantly. Therefore, most current structural studies are based on rat CYP24A1, which does not display carbon-23 hydroxylation. As a way to study the human isoform, we have initiated use of a fusion construct of human CYP24A1 with its reduction-oxidation protein partner adrenodoxin. This construct provides a platform for interrogating the structural effects of an Adx-CYP24A1 complex on ligand binding in CYP24A1. Notably, we've observed that when Adx is present, titration with 1,25(OH)2D3 primarily populates a low-spin state, which is removed upon separation of Adx. This finding points toward close structural coupling between substrate binding and redox partner recognition in mitochondrial P450 enzymes.
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