Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: Identification of novel substrates with insulin-like activity

Luc Marti, Anna Abella, Xavier De La Cruz, Silvia García-Vicente, Mercedes Unzeta, Christian Carpéné, Manuel Palacín, Xavier Testar, Modesto Orozco, Antonio Zorzano

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates. The modeling of the catalytic domain revealed that aromatic residues Tyr384, Phe389, and Tyr394 define a pocket of stable size that may participate in the binding of apolar substrates. We identified a number of amines as substrates of human, rat, and mouse SSAO. The compounds PD0119035, 2,3-dimethoxybenzylamine, and C-naphthalen-1-yl-methylamine showed high affinity as substrates of rat SSAO. C-Naphthalen-1-yl-methylamine was the only substrate that showed high affinity for human SSAO. C-Naphthalen-1-yl-methylamine and 4-aminomethyl-benzenesulfonamide showed the highest capacity to stimulate glucose transport in isolated rat adipocytes. The impact of these findings on the development of new treatments for diabetes is discussed.
Original languageEnglish
Pages (from-to)4865-4874
JournalJournal of Medicinal Chemistry
Volume47
DOIs
Publication statusPublished - 23 Sep 2004

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