Characterization of human S-adenosyl-homocysteine hydrolase in vitro and identification of its potential inhibitors

Abstract

Human S-adenosyl-homocysteine hydrolase (SAHH, E.C.3.3.1.1) has been considered to be an attractive target for the design of medicines to treat human disease, because of its important role in regulating biological methylation reactions to catalyse the reversible hydrolysis of S-adenosylhomocysteine (SAH) to adenosine (Ado) and l-homocysteine (Hcy). In this study, SAHH protein was successfully cloned and purified with optimized, Pichia pastoris (P. pastoris) expression system. The biological activity results revealed that, among the tested compounds screened by ChemMapper and SciFinder Scholar, 4-(3-hydroxyprop-1-en-1-yl)-2-methoxyphenol (coniferyl alcohol, CAS: 458-35-5, ZINC: 12359045) exhibited the highest inhibition against rSAHH (IC₅₀= 34 nM). Molecular docking studies showed that coniferyl alcohol was well docked into the active cavity of SAHH. And several H-bonds formed between them, which stabilized coniferyl alcohol in the active site of rSAHH with a proper conformation.

Keywords:

• S-adenosyl-homocysteine hydrolase (SAHH)
• l-homocysteine (Hcy)
• Pichia pastoris
• inhibitors
• coniferyl alcohol

Acknowledgements

We thank Dr Weifeng Liu’s laboratory of Shandong University for the contribution of the vector pPIC9K and P. pastoris.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (NSFC) [grant numbers 31370090, 2150704], and Project of Key R&D of Shandong Province in China [grant numbers 2015GSF121006, BS2015SWSW023].