4 research outputs found
Discovery of Bisubstrate Inhibitors of Nicotinamide <i>N</i>âMethyltransferase (NNMT)
Nicotinamide <i>N</i>-methyltransferase
(NNMT) catalyzes
the N-methylation of pyridine-containing compounds using the cofactor <i>S</i>-5â˛-adenosyl-l-methionine (SAM) as the
methyl group donor. Through the regulation of the levels of its substrates,
cofactor, and products, NNMT plays an important role in physiology
and pathophysiology. Overexpression of NNMT has been implicated in
various human diseases. Potent and selective small-molecule NNMT inhibitors
are valuable chemical tools for testing biological and therapeutic
hypotheses. However, very few NNMT inhibitors have been reported.
Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734
(<b>6</b>) and characterization of this inhibitor in biochemical,
biophysical, kinetic, and structural studies. Importantly, we obtained
the first crystal structure of human NNMT in complex with a small-molecule
inhibitor. The structure of the NNMTâ<b>6</b> complex
has unambiguously demonstrated that <b>6</b> occupied both substrate
and cofactor binding sites. The findings paved the way for developing
more potent and selective NNMT inhibitors in the future
Global Profiling of Acetyltransferase Feedback Regulation
Lysine acetyltransferases
(KATs) are key mediators of cell signaling. Methods capable of providing
new insights into their regulation thus constitute an important goal.
Here we report an optimized platform for profiling KATâligand
interactions in complex proteomes using inhibitor-functionalized capture
resins. This approach greatly expands the scope of KATs, KAT complexes,
and CoA-dependent enzymes accessible to chemoproteomic methods. This
enhanced profiling platform is then applied in the most comprehensive
analysis to date of KAT inhibition by the feedback metabolite CoA.
Our studies reveal that members of the KAT superfamily possess a spectrum
of sensitivity to CoA and highlight NAT10 as a novel KAT that may
be susceptible to metabolic feedback inhibition. This platform provides
a powerful tool to define the potency and selectivity of reversible
stimuli, such as small molecules and metabolites, that regulate KAT-dependent
signaling
Sinefungin Derivatives as Inhibitors and Structure Probes of Protein Lysine Methyltransferase SETD2
Epigenetic regulation is involved in numerous physiological
and
pathogenic processes. Among the key regulators that orchestrate epigenetic
signaling are over 50 human protein lysine methyltransferases (PKMTs).
Interrogation of the functions of individual PKMTs can be facilitated
by target-specific PKMT inhibitors. Given the emerging need for such
small molecules, we envisioned an approach to identify target-specific
methyltransferase inhibitors by screening privileged small-molecule
scaffolds against diverse methyltransferases. In this work, we demonstrated
the feasibility of such an approach by identifying the inhibitors
of SETD2. <i>N</i>-propyl sinefungin (Pr-SNF) was shown
to interact preferentially with SETD2 by matching the distinct transition-state
features of SETD2âs catalytically active conformer. With Pr-SNF
as a structure probe, we further revealed the dual roles of SETD2âs
post-SET loop in regulating substrate access through a distinct topological
reconfiguration. Privileged sinefungin scaffolds are expected to have
broad use as structure and chemical probes of methyltransferases
DS_DISC766278 â Supplemental material for Discovery of Small-Molecule Antagonists of the H3K9me3 Binding to UHRF1 Tandem Tudor Domain
<p>Supplemental material, DS_DISC766278 for Discovery of Small-Molecule Antagonists of the H3K9me3 Binding to UHRF1 Tandem Tudor Domain by Guillermo Senisterra, Hugh Y. Zhu, Xiao Luo, Hailong Zhang, Guoliang Xun, Chunliang Lu, Wen Xiao, Taraneh Hajian, Peter Loppnau, Irene Chau, Fengling Li, Abdellah Allali-Hassani, Peter Atadja, Counde Oyang, En Li, Peter J. Brown, Cheryl H. Arrowsmith, Kehao Zhao, Zhengtian Yu, and Masoud Vedadi in SLAS Discovery</p