Biochemistry and structure of thyroid peroxidase

Thyroid peroxidase (TPO) is a membrane bound multidomain protein that is exclusively found in the thyroid gland. It is the key enzyme in the biosynthesis of thyroid hormones, which are essential for metabolism, growth and development of the human body. TPO catalyses the iodination and coupling of tyrosine residues in hormonogenic sites of the glycoprotein thyroglobulin in the luminal space of thyroid follicle cells. Oxidation of iodide by the heme co- factor located in the peroxidase domain requires hydrogen peroxide. How TPO catalyses the phenolic coupling of iodothyronines or what functions the other domains of TPO have is unknown. However, elucidation of the function of TPO would be highly relevant for the clinics, as it is at the core of two autoimmune thyroid diseases, Hashimotos disease and Graves disease, that together afflict nearly 2% of the worlds population. To date, only two TPO inhibitors are clinically approved, but they are not specific and thus target other enzymes in the human body as well. Furthermore, how exactly they block TPO activity is only poorly understood. The lack of biochemical and structural data on TPO hampers not only our understanding of hormone biosynthesis but also the development of more specific and potent inhibitors. This project aims to elucidate the biochemical and structural characteristics of TPO. The newly established recombinant expression system of the TPO extracellular domains is the basis for these investigations. The main goals are (I) understanding the kinetics and substrate specificity of TPO, (II) providing structural data of TPO alone and of relevant ligated states and (III) clarify the mode of action of TPO inhibitors. Together, this project aims to increase our understanding of the mechanism of hormone biosynthesis and provide a basis and the necessary structural information for future projects to design new TPO inhibitors with better selectivity.