title: The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor.
abstract: The mitogen-activated protein kinase-activated protein kinase MK5 is ubiquitously expressed in vertebrates and is implicated in cell proliferation, cytoskeletal remodeling, and anxiety behavior. This makes MK5 an attractive drug target. We tested several diterpenoid alkaloids for their ability to suppress MK5 kinase activity. We identified noroxoaconitine as an ATP competitor that inhibited the catalytic activity of MK5 in vitro (IC₅₀ = 37.5 μM; K(i) = 0.675 μM) and prevented PKA-induced nuclear export of MK5, a process that depends on kinase active MK5. MK5 is closely related to MK2 and MK3, and noroxoaconitine inhibited MK3- and MK5- but not MK2-mediated phosphorylation of the common substrate Hsp27. Molecular docking of noroxoaconitine into the ATP binding sites indicated that noroxoaconitine binds more strongly to MK5 than to MK3. Noroxoaconitine and derivatives may help in elucidating the precise biological functions of MK5 and may prove to have therapeutic values.
authors.affiliation: University of Tromsø, Norway.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Kostenko
authors.forename: Mahmud Tareq Hassan
authors.initials: MT
authors.lastname: Khan
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.forename: Ugo
authors.initials: U
authors.lastname: Moens
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000470:Alkaloids; D004224:Diterpenes; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C555605:noroxoaconitine; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000157:Aconitine