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We probed the efficacy of DPI on two well\u2010known drug targets, the human monoamine oxidases MAO A and B. UV\u2010visible spectrophotometry and steady\u2010state kinetics experiments demonstrate that DPI acts as a competitive and reversible MAO inhibitor with <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values of 1.7 and 0.3\u2005\u03bcM 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\u2010site 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 that the inhibition mechanism does not involve a reaction with the reduced flavin. This binding and inhibitory activity against the MAOs, two major reactive oxygen species (ROS)\u2010producing enzymes, will have to be carefully considered when interpreting experiments that rely on DPI for target validation and chemical biology studies on ROS functions.<\/jats:p>","DOI":"10.1002\/cmdc.202000264","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T15:25:12Z","timestamp":1590593112000},"page":"1394-1397","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Diphenylene Iodonium Is a Noncovalent MAO Inhibitor: A Biochemical and Structural Analysis"],"prefix":"10.1002","volume":"15","author":[{"given":"Luca G.","family":"Iacovino","sequence":"first","affiliation":[{"name":"Department of Biology and Biotechnology \u201cLazzaro Spallanzani\u201d University of Pavia, Via Ferrata 9  27100 Pavia Italy"}]},{"given":"Joana","family":"Reis","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cLazzaro Spallanzani\u201d University of Pavia, Via Ferrata 9  27100 Pavia Italy"}]},{"given":"Antonello","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry and Technologies Sapienza University of Rome  P.le A. Moro 5 00185 Rome Italy"}]},{"given":"Claudia","family":"Binda","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cLazzaro Spallanzani\u201d University of Pavia, Via Ferrata 9  27100 Pavia Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9523-7128","authenticated-orcid":false,"given":"Andrea","family":"Mattevi","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cLazzaro Spallanzani\u201d University of Pavia, Via Ferrata 9  27100 Pavia Italy"}]}],"member":"311","published-online":{"date-parts":[[2020,6,10]]},"reference":[{"key":"e_1_2_2_1_1","unstructured":"\u00a0"},{"key":"e_1_2_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101466"},{"key":"e_1_2_2_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9823481"},{"key":"e_1_2_2_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp990681o"},{"key":"e_1_2_2_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205432200"},{"key":"e_1_2_2_6_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2900041"},{"key":"e_1_2_2_7_2","doi-asserted-by":"publisher","DOI":"10.1042\/0264-6021:3420465"},{"key":"e_1_2_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2017.07.007"},{"key":"e_1_2_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101272"},{"key":"e_1_2_2_10_2","author":"Konat\u00e9 M. 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