Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity.
|Title||Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity.|
|Publication Type||Journal Article|
|Year of Publication||2004|
|Authors||Marti, Luc, Abella Anna, de la Cruz Xavier, García-Vicente Silvia, Unzeta Mercedes, Carpéné Christian, Palacín Manuel, Testar Xavier, Orozco Modesto, and Zorzano Antonio|
|Journal||J Med Chem|
|Date Published||2004 Sep 23|
|Keywords||Adipocytes, Amine Oxidase (Copper-Containing), Amines, Amino Acid, Amino Acid Sequence, Animals, Benzylamines, Binding Sites, Biological Transport, Catalytic Domain, Cell Adhesion Molecules, Cells, Cultured, Drug Evaluation, Glucose, Humans, Insulin, Male, Methylamines, Mice, Models, Molecular, Molecular Sequence Data, Naphthalenes, Preclinical, Protein Conformation, Rats, Sequence Homology, Substrate Specificity, Vanadates, Wistar|
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-dimethoxy-benzylamine, 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.