Review
Structural and functional aspects of thyroid peroxidase

https://doi.org/10.1016/j.abb.2005.06.023Get rights and content

Abstract

Thyroperoxidase (TPO) is the enzyme involved in thyroid hormone synthesis. Although many studies have been carried out on TPO since it was first identified as being the thyroid microsomal antigen involved in autoimmune thyroid disease, previous authors have focused more on the immunological than on the biochemical aspects of TPO during the last few years. Here, we review the latest contributions in the field of TPO research and provide a large reference list of original publications. Given this promising background, scientists and clinicians will certainly continue in the future to investigate the mechanisms whereby TPO contributes to hormone synthesis and constitutes an important autoantigen involved in autoimmune thyroid disease, and the circumstances under which the normal physiological function of this enzyme takes on a pathological role.

Section snippets

Gene expression

The human TPO gene spans more than 150 kbp, is located on chromosome 2, and consists of 17 exons and 16 introns [2], [3]. It encodes a 933 amino-acid residue (aa) molecule with a single membrane-spanning region. The closely related human myeloperoxidase (MPO) gene is much smaller (it is only 10 kbp in size) and only the first 735 aa of TPO show 42% similarity with the MPO sequence [4]. TPO has also been found to have a 197-aa extension at the extracellular C-terminal end of the molecule, which

Protein structure

Porcine TPO was first purified after treating thyroid membrane with trypsin and detergent [28], [29], [30], [31], yielding in fine a 90-kDa, enzymatically active, solubilized TPO fragment [32]. Human TPO was subsequently purified from detergent-solubilized thyroid membrane by performing monoclonal antibody (mAb)-assisted affinity chromatography [33], [34], [35], [36], yielding a 105–110-kDa enzymatically active doublet. Glycosylation was not responsible for this molecular heterogeneity [37],

Physiological function

TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues and the coupling of iodotyrosine residues in Tg, resulting in the formation of T3 and T4. The iodination and coupling reactions are not TPO specific because lactoperoxidase [74] and MPO [75] also catalyze these processes. The enzymatic process requires the presence of iodide, H2O2, and Tg. H2O2 is produced at the apical plasma

Immunological structure

In 1985, we identified the thyroid “microsomal antigen” as being TPO [33], [105]. Autoantibodies (aAb) present in the serum of patients with autoimmune thyroid disease (AITD) were found to react with a protein doublet 105–110 kDa in size and to immunoprecipitate TPO [106], [107], [108], [109]. Several patients’ sera against native, denatured, and denatured and reduced TPO recognized numerous B-cell epitopes on the surface of the human TPO molecule [110]. In pioneering studies, we established,

Pathological role

TPO is one of the main thyroid autoantigens. Using a specific, sensitive in-house immunoassay, we found TPO aAb to be present in 88% of all the patients with a thyroid disorder tested [155]. Interestingly, the three main antigens involved in AITD, namely Tg, TPO, and the TSH receptor, are all involved in the production of thyroid hormones. This feature may account for the tissue-specificity of the autoimmune response. These antigens are specific to the thyroid gland, although fatty tissue and

Conclusion

The wide range of TPO data compiled here often raise more questions than they answer. The questions focusing on the 3-D protein structure of TPO and how it is arranged to form a dimer at the membrane surface of thyrocytes still remain to be solved. This gap in our knowledge greatly impedes all efforts to identify the conformational IDR of TPO and its constitutive B- and T-cell epitopes. No data have been published so far on how TPO works with H2O2 to accommodate its two substrates, iodine and

References (189)

  • V. Estienne et al.

    J. Biol. Chem.

    (1999)
  • G. Damante et al.

    Biochim. Biophys. Acta

    (1994)
  • E. Zanelli et al.

    Biochem. Biophys. Res. Commun.

    (1990)
  • M. Ferrand et al.

    J. Biol. Chem.

    (2003)
  • P. Niccoli et al.

    J. Biol. Chem.

    (1997)
  • L. Fayadat et al.

    J. Biol. Chem.

    (2000)
  • V. Le Fourn et al.

    Biochim. Biophys. Acta

    (2004)
  • M.L. Coval et al.

    J. Biol. Chem.

    (1967)
  • A. Taurog et al.

    Arch. Biochem. Biophys.

    (1970)
  • J. Pommier et al.

    Biochimie

    (1972)
  • B. Czarnocka et al.

    FEBS Lett.

    (1985)
  • H. Nakagawa et al.

    Biochem. Biophys. Res. Commun.

    (1985)
  • A. Gardas et al.

    Biochem. Biophys. Res. Commun.

    (1997)
  • J. Hata et al.

    Biochem. Biophys. Res. Commun.

    (1989)
  • S. Kimura et al.

    FEBS Lett.

    (1989)
  • D.L. Kendler et al.

    Mol. Cell. Endocrinol.

    (1993)
  • P. Seto et al.

    Mol. Cell. Endocrinol.

    (1993)
  • J.L. Fan et al.

    J. Autoimmun.

    (1996)
  • A. Gardas et al.

    Biochim. Biophys. Acta

    (1999)
  • R.P. Magnusson et al.

    J. Biol. Chem.

    (1987)
  • A.B. Rawitch et al.

    Arch. Biochem. Biophys.

    (1992)
  • K. Morishita et al.

    J. Biol. Chem.

    (1987)
  • C. Kiser et al.

    Gene

    (1996)
  • K. Sakamaki et al.

    J. Biol. Chem.

    (1989)
  • R. Fenna et al.

    Arch. Biochem. Biophys.

    (1995)
  • T.D. Rae et al.

    J. Biol. Chem.

    (1998)
  • J. Zeng et al.

    J. Mol. Biol.

    (1992)
  • R.P. Ferrari et al.

    J. Inorg. Biochem.

    (1997)
  • A. Taurog et al.

    Arch. Biochem. Biophys.

    (1992)
  • A. Virion et al.

    Mol. Cell. Endocrinol.

    (1984)
  • C. Dupuy et al.

    J. Biol. Chem.

    (1999)
  • X. De Deken et al.

    J. Biol. Chem.

    (2000)
  • S. Ohtaki et al.

    J. Biol. Chem.

    (1982)
  • S. Ohtaki et al.

    J. Biol. Chem.

    (1982)
  • M.M. Krinsky et al.

    J. Biol. Chem.

    (1971)
  • B. Davidson et al.

    Biochim. Biophys. Acta

    (1978)
  • S. Ohtaki et al.

    J. Biol. Chem.

    (1981)
  • R.P. Magnusson et al.

    J. Biol. Chem.

    (1984)
  • R.P. Magnusson et al.

    J. Biol. Chem.

    (1984)
  • R.E. Huber et al.

    J. Biol. Chem.

    (1989)
  • J.E. Roberts et al.

    J. Biol. Chem.

    (1981)
  • F. Bjorksten

    Biochim. Biophys. Acta

    (1970)
  • D. Deme et al.

    Biochim. Biophys. Acta

    (1978)
  • A. Virion et al.

    Arch. Biochem. Biophys.

    (1985)
  • L. Lamas et al.

    J. Biol. Chem.

    (1974)
  • P. Carayon et al.

    Thyroperoxidase and Thyroid Autoimmunity

    (1990)
  • S. Kimura et al.

    Proc. Natl. Acad. Sci. USA

    (1987)
  • J.J.M. De Vijlder et al.

    Cytogenet. Cell Genet.

    (1988)
  • S. Kimura et al.

    Biochemistry

    (1989)
  • F. Libert et al.

    EMBO J.

    (1987)
  • Cited by (149)

    View all citing articles on Scopus
    View full text