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-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes / drug effects
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Adipocytes / metabolism
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Amine Oxidase (Copper-Containing) / chemistry*
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Amine Oxidase (Copper-Containing) / drug effects
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Amine Oxidase (Copper-Containing) / metabolism*
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Amines / metabolism
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Amino Acid Sequence
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Animals
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Benzylamines / metabolism
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Benzylamines / pharmacology
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Binding Sites
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Biological Transport
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Catalytic Domain
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Cell Adhesion Molecules / chemistry*
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Cell Adhesion Molecules / drug effects
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Cell Adhesion Molecules / metabolism*
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Cells, Cultured
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Drug Evaluation, Preclinical / methods
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Glucose / metabolism
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Humans
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Insulin / metabolism*
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Insulin / pharmacology
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Male
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Methylamines / chemistry
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Methylamines / metabolism
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Methylamines / pharmacology
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Mice
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Models, Molecular
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Molecular Sequence Data
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Naphthalenes / chemistry
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Naphthalenes / metabolism
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Naphthalenes / pharmacology
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Protein Conformation
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Rats
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Rats, Wistar
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Sequence Homology, Amino Acid
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Substrate Specificity
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Vanadates / metabolism
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Vanadates / pharmacology
Substances
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Amines
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Benzylamines
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C-6,7-dimethylnaphthalen-1-yl-methylamine
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Cell Adhesion Molecules
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Insulin
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Methylamines
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Naphthalenes
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Vanadates
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benzylamine
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Amine Oxidase (Copper-Containing)
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semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse
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Glucose