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A structure-activity study to identify novel and efficient substrates of the human semicarbazide-sensitive amine oxidase/VAP-1 enzyme
- Publication Year :
- 2010
-
Abstract
- Kinetic studies were performed with various alkanamines as "substrate probes" of the properties of the active site of the human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1). We found that the enzyme-substrate recognition step is mainly controlled by apolar interactions and that a "good" substrate has a molecular structure containing a long aliphatic chain and a second positive charge at a distance greater than 12 A from the reactive amino group. In this context, we identified a novel substrate for the human SSAO/VAP-1, 1,12-diaminododecane (DIADO), which is characterised by the highest catalytic efficiency reported to date in comparison to the prototypic substrate benzylamine. Computational docking studies revealed the structural basis of this behaviour, highlighting the key role played by Lys393 in hindering substrate docking. Maximum SSAO/VAP-1 activity is reached at relatively low concentrations of DIADO (10-30 microM), and, in these conditions, it has good selectivity: it is a good substrate of SSAO/VAP-1 but not of human adipocyte monoamine oxidases or pig kidney diamine oxidase. From these findings, it appears that DIADO can be used as a new substrate for human SSAO/VAP-1 to elicit glucose transport into adipocytes, and may consequently have potential pharmacological applications in the design of anti-diabetic agents.
- Subjects :
- Models, Molecular
Amine oxidase
Biochemistry
Structure-Activity Relationship
chemistry.chemical_compound
Benzylamine
Catalytic Domain
Drug Discovery
Adipocytes
Humans
Structure–activity relationship
Amines
pH dependence
chemistry.chemical_classification
biology
Chemistry
Cell Membrane
Osmolar Concentration
Amine oxidase (copper-containing)
Active site
Semicarbazide-sensitive amine oxidases
General Medicine
Hydrogen-Ion Concentration
Recombinant Proteins
Computational docking
Semicarbazides
Kinetics
Enzyme
Docking (molecular)
Butanes
biology.protein
Amine Oxidase (Copper-Containing)
SSAO/VAP-1 substrates
Structure-function relationships
Diamine oxidase
Cell Adhesion Molecules
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....1e3a7008ae45ce952424be05a81e44d6