Journal:Acta Cryst D:S2059798322007082

Native glycosylation and binding of the anti-depressant paroxetine in a low-resolution crystal structure of human myeloperoxidase

Lucas Krawczyk, Shubham Semwal, Jalal Soubhye, Salma Lemri Ouadriri, Martine Prévost, Pierre Van Antwerpen, Goedele Roos, & Julie Bouckaert ^[1]

Molecular Tour
The human enzyme myeloperoxidase (MPO in short) is a heme-dependent peroxidase. The peroxidases are a large group of enzymes playing roles in various biological processes. MPO is found in mammalian neutrophils, which is a type of with blood cells, and there it catalyzes the oxidation of halide ions and thiocyanate in the presence of hydrogen peroxide. This results in strong oxidizing agents and they are helping to eliminate the bacteria or viruses which were taken up by phagocytosis. So, MPO is a key protein in the human immune defense system.

In order for MPO to function correctly, sugar molecules need to be present on its protein surface. This is called the glycosylation pattern. Until now, only a part of the glycosylation of MPO could be seen from the crystal structures deposited in the Protein Data Bank, holding the collection of available structures of biomolecules. Human MPO has five glycosylation sites, identified at positions Asn323, Asn355, Asn391, Asn483 and Asn729. We present here a structure in which the glycan structures on these five glycosylation sites could be identified. The final model contains 8 polypeptide chains of mature MPO and 30 glycan chains on the Asn-binding sites. We compare these with the glycans identified in proteomics studies and from eighteen human MPO structures available in the PDB.

Our structure also contains bound paroxetine, a recently discovered inhibitor of MPO, previously used as anti-depressant. The bound paroxetine was always found in the presence of thiocyanate, a physiological substrate of MPO. A lot of effort has been undertaken into inhibitor design, as things can also go wrong with MPO. When things go wrong, MPO is released into the extracellular fluid. This circulating MPO damages host tissue as the reaction products of MPO can oxidize biomolecules (lipids, DNA and proteins). So, MPO is involved in a lot of pathologies, either as a source or to make the symptoms worse of existing pathologies, creating a large interest into the design of molecules in order to block this circulating MPO.

References

1. ↑ Krawczyk L, Semwal S, Soubhye J, Lemri Ouadriri S, Prevost M, Van Antwerpen P, Roos G, Bouckaert J. Native glycosylation and binding of the antidepressant paroxetine in a low-resolution crystal structure of human myeloperoxidase. Acta Crystallogr D Struct Biol. 2022 Sep 1;78(Pt 9):1099-1109. doi:, 10.1107/S2059798322007082. Epub 2022 Aug 9. PMID:36048150 doi:http://dx.doi.org/10.1107/S2059798322007082