Effects of Oncohistone Mutations and PTM Crosstalk on the N‑Terminal Acetylation Activities of NatD

Acetylation at the α-N-terminus (Nα) is the most abundant modification detected on histone H4 and H2A, which is catalyzed by N-terminal acetyltransferase D (NatD or NAA40). Histone H4 and H2A contain an identical N-terminal SGRGK sequence that is enriched with post-translational modifications (PTMs) and frequently occurred oncogenic mutations known as “oncohistone” mutations. However, there is a lack of information on how oncohistone mutations and other PTMs affect NatD-catalyzed acetylation. Herein, we determined how the local chemical environment on the N-terminal SGRGK sequence impacts NatD-catalyzed Nα-acetylation on histone H4/H2A. Our studies indicate that all oncohistone mutations at SGRG suppressed NatD-catalyzed acetylation. Meanwhile, H4 Ser1 phosphorylation and Arg3 methylation negatively impact the NatD-mediated acetylation, but the Lys5 acetylation only has a marginal effect. This work reveals the impacts of oncohistone mutations on NatD activity and unravels the crosstalk between NatD and PTMs, implying potential regulatory mechanism of NatD and highlighting different avenues to interrogate the NatD-mediated pathway in the future

PCR results of strain D5 <i>nodA</i> gene.

<p>PCR results of strain D5 <i>nodA</i> gene.</p

Nodulation of strain D5 inoculated plants.

<p>A. <i>Acacia confusa</i>, B. <i>Acacia crassicarpa</i>, C. <i>Acacia mangium</i>, D. <i>Glycine max,</i> and E. Control.</p

PCR results of strain D5 <i>nifH</i> gene.

<p>PCR results of strain D5 <i>nifH</i> gene.</p

Phylogenetic dendrogram of strain D5 based on 16S rRNA gene sequence.

<p>Phylogenetic dendrogram of strain D5 based on 16S rRNA gene sequence.</p

Structure–Activity Relationship Studies on Cell-Potent Nicotinamide <i>N</i>‑Methyltransferase Bisubstrate Inhibitors

Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme implicated in multiple diseases, making it a promising therapeutic target. Building upon our recently reported NNMT inhibitor II399, we systematically investigate the structure–activity relationship by designing and synthesizing a series of analogues. Among them, two top inhibitors II559 (Ki = 1.2 nM) and II802 (Ki = 1.6 nM) displayed over 5000-fold selectivity for NNMT over closely related methyltransferases. Moreover, II559 and II802 showed enhanced cellular inhibition, with a cellular IC50 value of approximately 150 nM, making them the most cell-potent bisubstrate inhibitors reported to date. Furthermore, both inhibitors reduced the cell viability with a GI50 value of ∼10 μM and suppressed the migration of aggressive clear cell renal cancer cell carcinoma cell lines. Overall, II559 and II802 would serve as valuable probes to investigate the enzymatic function of NNMT in health and diseases

The nodulation rates of strain D5 inoculated <i>Acacia confusa</i>, <i>A. crassicarpa, A. mangium</i>, and <i>Glycine max</i>, and the corresponding nitrogenase activities of root nodules.

<p>The nodulation rates of strain D5 inoculated <i>Acacia confusa</i>, <i>A. crassicarpa, A. mangium</i>, and <i>Glycine max</i>, and the corresponding nitrogenase activities of root nodules.</p

Additional file 1 of Exploring the training of chinese medical staff oriented to the need for clinical drug information services: from the perspective of drug information patients obtained and need

Supplementary Material

PCR results of 16S rRNA of strain D5.

<p>PCR results of 16S rRNA of strain D5.</p

PPh₃‑Mediated [4 + 2]- and [4 + 1]-Annulations of Maleimides with Azoalkenes: Access to Fused Tetrahydropyridazine/Pyrrolidinedione and Spiro-dihydropyrazole/Pyrrolidinedione Derivatives

Unprecedented PPh₃-mediated [4 + 2]- and [4 + 1]-annulation of maleimides with in situ formed azoalkenes have been successfully developed, affording fused tetrahydropyridazine/pyrrolidinedione and spiro-dihydropyrazole/pyrrolidinedione derivatives in good yields under mild reaction conditions. Maleimides serve as C2 synthons in the [4 + 2]-annulation using 1,2-dichloroethane as the solvent in the presence of 20 mol % of PPh₃. With a stoichiometric amount of PPh₃ in acetone, maleimides serve as C1 synthons, and the in situ formed phosphorus ylide is the key intermediate to realize this [4 + 1]-annulation