The structure and function of CYP26B variants in atherosclerosis development

All-trans retinoic acid is important for normal cardiovascular development and is involved in cardiovascular diseases. Levels of all-trans retinoic acid in blood vessels are under strict control by several cytochromes P450 (CYP) enzymes in for instance smooth muscle cells (SMCs) of blood vessels, particularly by CYP26B1, which our research consortium has discovered is present in two different splice variants, one full-length and one truncated. The truncated variant has been associated with atherosclerotic lesions but the functional differences between the two forms remain unsolved.

In the present project, we will characterize the enzymatic function of the two variants in terms of metabolism as well as their structural features and elucidate the basic physiological implications of these properties. Such information would be highly valuable in the understanding of basic mechanisms and helpful for design of new anti-atherosclerotic drugs, so called RAMBAs.

Biochemical characterization of the two splice variants of CYP26B1 is carried out with regards to structural and enzyme kinetics features, and by studies of atRA metabolism in cell lines transfected with expression constructs of the two variants. This means that we are crystallizing and solving the three-dimensional structures of the two splice variants of CYP26B1, determining their atRA affinities and their atRA catabolic kinetic constants, and examining the levels of atRA in cell lines expressing each of the two variants.

This project is partly connected to the project "Retinoic acid in acute ischemia and heart failure: from genes to left ventricular performance" and aspects of the project are the subjects for commercialization efforts.

Read about the project Retinoic acid in acute ischemia and heart failure: from genes to left ventricular performance.