Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity.
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.
Marti
Luc
L
Parc Científic de Barcelona and Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain.
Abella
Anna
A
De La Cruz
Xavier
X
García-Vicente
Silvia
S
Unzeta
Mercedes
M
Carpéné
Christian
C
Palacín
Manuel
M
Testar
Xavier
X
Orozco
Modesto
M
Zorzano
Antonio
A
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D006631:Amine Oxidase (Copper-Containing) / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D000588:Amines / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001596:Benzylamines / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001692:Biological Transport; D020134:Catalytic Domain; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008744:Methylamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014638:Vanadates / Q000378:metabolism / Q000494:pharmacology
D000588:Amines; D001596:Benzylamines; C492679:C-6,7-dimethylnaphthalen-1-yl-methylamine; D015815:Cell Adhesion Molecules; D007328:Insulin; D008744:Methylamines; D009281:Naphthalenes; D014638:Vanadates; C030796:benzylamine; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse; D005947:Glucose