Thyroid peroxidase (TPO) is the key
enzyme involved in
thyroid hormone synthesis.
Autoantibodies to TPO (TPOAbs) are a hallmark of autoimmune
thyroid disease (AITD). Here, we highlight recent progress over several years in understanding TPO biochemistry and function in various pathologies. TPO undergoes complex post-translational modifications as a dimer in endoplasmic reticulum during secretory pathway to apical membrane of thyrocytes. In silico modelling of TPO dimer has provided new information into the two
enzyme active site regions and autoantigenic determinants. TPO and
hydrogen peroxide generating DUOX and
caveolin-1 form a complex known as thyroxisome to bring together in close proximity the components of
hormone synthesis in apical membrane. Autoimmunity to TPO is characterised by
autoantibodies and T cell reactivity in
Hashimoto's disease and
Graves' disease. TPOAbs are directed predominantly to two
immunodominant determinants (IDR) termed IDR-A and IDR-B regions, with the latter
antibodies more predominant in
autoimmune disease. Strong genetic risk has been shown to be associated with TPOAbs for AITD development. A different antibody with unusual features of bispecificity for both TPO and
thyroglobulin may play protective role in
Hashimoto's disease. In the context of TPO biology in human
cancer, thyroid tumor tissue and
breast cancer differ in TPO expression and
isoform composition. In
thyroid cancer, TPO expression is decreased partly by the BRAF(V600E) mutation, with direct impact on significant
hormone production. TPOAbs may play a protective role in
breast cancer development. An understanding of TPO and its unique two enzymatic active sites and autoantigenic determinants continues to add new knowledge on the biochemistry and immunology of this
enzyme.