scholarly journals A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 854
Author(s):  
Iredia D. Iyamu ◽  
Ayad A. Al-Hamashi ◽  
Rong Huang
Keyword(s):  
Dna Damage ◽  
Kinetic Study ◽  
Maximal Inhibition ◽  
Arginine Methyltransferase ◽  
Protein Arginine Methyltransferases ◽  
Design And Synthesis ◽  
Damage Repair ◽  
Inhibition Concentration ◽  
Ic50 Value ◽  
Rna Biology

Protein arginine methyltransferases (PRMTs) play important roles in transcription, splicing, DNA damage repair, RNA biology, and cellular metabolism. Thus, PRMTs have been attractive targets for various diseases. In this study, we reported the design and synthesis of a potent pan-inhibitor for PRMTs that tethers a thioadenosine and various substituted guanidino groups through a propyl linker. Compound II757 exhibits a half-maximal inhibition concentration (IC50) value of 5 to 555 nM for eight tested PRMTs, with the highest inhibition for PRMT4 (IC50 = 5 nM). The kinetic study demonstrated that II757 competitively binds at the SAM binding site of PRMT1. Notably, II757 is selective for PRMTs over a panel of other methyltransferases, which can serve as a general probe for PRMTs and a lead for further optimization to increase the selectivity for individual PRMT.

scholarly journals Discovery of a Potent and Dual-Selective Bisubstrate Inhibitor for Protein Arginine Methyltransferase 4/5

2020 ◽  
Author(s):  
Ayad A. Al-Hamashi ◽  
Dongxing Chen ◽  
Youchao Deng ◽  
Guangping Dong ◽  
Rong Huang
Keyword(s):  
Structural Studies ◽  
High Potency ◽  
Maximal Inhibition ◽  
Arginine Methyltransferase ◽  
Protein Arginine Methyltransferases ◽  
Design And Synthesis ◽  
Inhibition Concentration ◽  
Future Drug ◽  
Bisubstrate Inhibitors ◽  
Guanidino Group

AbstractProtein arginine methyltransferases (PRMTs) have been implicated in the progression of many diseases. Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery. Herein, we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine (SAM) analogue moiety and a tripeptide through an alkyl substituted guanidino group. Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration (IC50) of 2.8 nM and <1.5 nM, respectively. Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases. This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs, providing valuable probes for future structural studies.

scholarly journals Non-Histone Arginine Methylation by Protein Arginine Methyltransferases

2020 ◽  
Vol 21 (7) ◽  
pp. 699-712 ◽  
Author(s):  
Ayad A. Al-Hamashi ◽  
Krystal Diaz ◽  
Rong Huang
Keyword(s):  
Rna Splicing ◽  
Arginine Methylation ◽  
Aberrant Expression ◽  
Histone Protein ◽  
Arginine Methyltransferase ◽  
Protein Arginine Methyltransferases ◽  
Protein Substrates ◽  
Damage Repair ◽  
Multiple Abnormalities ◽  
Histone Arginine Methylation

Protein arginine methyltransferase (PRMT) enzymes play a crucial role in RNA splicing, DNA damage repair, cell signaling, and differentiation. Arginine methylation is a prominent posttransitional modification of histones and various non-histone proteins that can either activate or repress gene expression. The aberrant expression of PRMTs has been linked to multiple abnormalities, notably cancer. Herein, we review a number of non-histone protein substrates for all nine members of human PRMTs and how PRMT-mediated non-histone arginine methylation modulates various diseases. Additionally, we highlight the most recent clinical studies for several PRMT inhibitors.

366-OR: TCF19 Promotes Functional Beta-Cell Mass and Proliferative Capacity by Regulating DNA Damage Repair Pathways

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 366-OR
Author(s):  
GRACE H. YANG ◽  
JEE YOUNG HAN ◽  
SUKANYA LODH ◽  
JOSEPH T. BLUMER ◽  
DANIELLE FONTAINE ◽  
...  
Keyword(s):  
Dna Damage ◽  
Beta Cell ◽  
Dna Damage Repair ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Proliferative Capacity ◽  
Damage Repair ◽  
Repair Pathways
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