Mode of Binding of the Antithyroid Drug Propylthiouracil to Mammalian Haem Peroxidases

Overview

Journal Acta Crystallogr F Struct Biol Commun

Specialty Chemistry

Date 2015 Mar 12

PMID 25760705

Citations 2

Authors

R P Singh

A Singh

G S Kushwaha

A K Singh

P Kaur

S Sharma

T P Singh

Affiliations

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Abstract

The mammalian haem peroxidase superfamily consists of myeloperoxidase (MPO), lactoperoxidase (LPO), eosinophil peroxidase (EPO) and thyroid peroxidase (TPO). These enzymes catalyze a number of oxidative reactions of inorganic substrates such as Cl(-), Br(-), I(-) and SCN(-) as well as of various organic aromatic compounds. To date, only structures of MPO and LPO are known. The substrate-binding sites in these enzymes are located on the distal haem side. Propylthiouracil (PTU) is a potent antithyroid drug that acts by inhibiting the function of TPO. It has also been shown to inhibit the action of LPO. However, its mode of binding to mammalian haem peroxidases is not yet known. In order to determine the mode of its binding to peroxidases, the structure of the complex of LPO with PTU has been determined. It showed that PTU binds to LPO in the substrate-binding site on the distal haem side. The IC50 values for the inhibition of LPO and TPO by PTU are 47 and 30 µM, respectively. A comparision of the residues surrounding the substrate-binding site on the distal haem side in LPO with those in TPO showed that all of the residues were identical except for Ala114 (LPO numbering scheme), which is replaced by Thr205 (TPO numbering scheme) in TPO. A threonine residue in place of alanine in the substrate-binding site may affect the affinity of PTU for peroxidases.

Citing Articles

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles.

Ramsbottom K, Carr D, Rigden D, Jones A PLoS One. 2020; 15(2):e0220754.

PMID: 32027661 PMC: 7004376. DOI: 10.1371/journal.pone.0220754.

Retraction: Mode of binding of the antithyroid drug propylthiouracil to mammalian haem peroxidases.

Acta Crystallogr F Struct Biol Commun. 2015; 71(Pt 6):804.

PMID: 26057817 PMC: 4461352. DOI: 10.1107/S2053230X15006962.

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