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Diphenylene iodonium is a non‐covalent MAO inhibitor: a biochemical and structural analysis

DOI: 10.1002/cmdc.202000264 DOI Help

Authors: Luca Giacinto Iacovino (Universita degli Studi di Pavia) , Joana Reis (Universita degli Studi di Pavia Facolta di Medicina e Chirurgia) , Antonello Mai (Universita degli Studi di Roma La Sapienza) , Claudia Binda (University of Pavia) , Andrea Mattevi (University of Pavia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 20221

Abstract: Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin‐ and heme‐dependent enzymes and is often used as an NADPH oxidase inhibitor. We probed the efficacy of DPI on two well‐known drug targets, the human monoamine oxidases MAO A and B. UV‐visible spectrophotometry and steady‐state kinetics experiments demonstrate that DPI acts as a competitive MAO inhibitor with Ki values of 1.7 µM and 0.3 µM for MAO A and MAO B, respectively. Elucidation of the crystal structure of human MAO B bound to the inhibitor revealed that DPI binds deeply in the active‐site cavity to establish multiple hydrophobic interactions with the surrounding side chains and the flavin. These data prove that DPI is a genuine MAO inhibitor and the inhibition mechanism does not involve a reaction with the reduced flavin. This binding and inhibitory activity against MAOs, two major ROS‐producing enzymes, will have to be carefully considered when interpreting experiments that rely on DPI for target validation and chemical biology studies on ROS functions.

Journal Keywords: Diphenylene iodonium; monoamine oxidases; flavoenzyme; ROS; iodonium compounds

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 10/06/2020 09:51

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)