Singh R P, Singh A, Kushwaha G S, Singh A K, Kaur P, Sharma S, Singh T P
Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
Acta Crystallogr F Struct Biol Commun. 2015 Mar;71(Pt 3):304-10. doi: 10.1107/S2053230X15001806. Epub 2015 Feb 19.
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.
哺乳动物血红素过氧化物酶超家族由髓过氧化物酶（MPO）、乳过氧化物酶（LPO）、嗜酸性粒细胞过氧化物酶（EPO）和甲状腺过氧化物酶（TPO）组成。这些酶催化多种无机底物如Cl(-)、Br(-)、I(-)和SCN(-)以及各种有机芳香化合物的氧化反应。迄今为止，仅知晓MPO和LPO的结构。这些酶中的底物结合位点位于血红素远端一侧。丙硫氧嘧啶（PTU）是一种有效的抗甲状腺药物，其作用机制是抑制TPO的功能。研究还表明它能抑制LPO的作用。然而，其与哺乳动物血红素过氧化物酶的结合模式尚不清楚。为了确定其与过氧化物酶的结合模式，已测定了LPO与PTU复合物的结构。结果表明，PTU在血红素远端一侧的底物结合位点与LPO结合。PTU对LPO和TPO抑制作用的IC50值分别为47和30 μM。比较LPO和TPO中血红素远端一侧底物结合位点周围的残基发现，除了Ala114（LPO编号方案）外，所有残基均相同，在TPO中该残基被Thr205（TPO编号方案）取代。底物结合位点中苏氨酸残基取代丙氨酸可能会影响PTU对过氧化物酶的亲和力。
