Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.
The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.
Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
Nathan R
NR
Rose
Esther C Y
EC
Woon
Anthony
A
Tumber
Louise J
LJ
Walport
Rasheduzzaman
R
Chowdhury
Xuan Shirley
XS
Li
Oliver N F
ON
King
Clarisse
C
Lejeune
Stanley S
SS
Ng
Tobias
T
Krojer
Mun Chiang
MC
Chan
Anna M
AM
Rydzik
Richard J
RJ
Hopkinson
Ka Hing
KH
Che
Michelle
M
Daniel
Claire
C
Strain-Damerell
Carina
C
Gileadi
Grazyna
G
Kochan
Ivanhoe K H
IK
Leung
James
J
Dunford
Kar Kheng
KK
Yeoh
Peter J
PJ
Ratcliffe
Nicola
N
Burgess-Brown
Frank
F
von Delft
Susanne
S
Muller
Brian
B
Marsden
Paul E
PE
Brennan
Michael A
MA
McDonough
Udo
U
Oppermann
Robert J
RJ
Klose
Christopher J
CJ
Schofield
Akane
A
Kawamura
D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010937:Plant Growth Regulators / Q000494:pharmacology*; D011487:Protein Conformation; D013379:Substrate Specificity; D013386:Succinates / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010937:Plant Growth Regulators; D013386:Succinates; D056484:Jumonji Domain-Containing Histone Demethylases; C014499:daminozide