A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes.

Iredia D Iyamu,Rong Huang,Ayad A Al-Hamashi

doi:10.3390/biom11060854

Abstract

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.

Highlights

Protein arginine methyltransferases (PRMTs) are a group of enzymes that methylate the guanidino group of the arginine using S-adenosyl methionine (SAM) as a methyl donor, producing mono- or dimethylated arginine residues and S-adenosyl-L-homocysteine (SAH).To date, nine human PRMT members have been identified, which are classified into three types according to the characteristic of their products [1,2,3]
6f containing a phenyl group displayed an we examined the effect of the aromatic group on the PRMT1 inhibit pound 6f containing a phenyl group displayed an IC50 of 0.29 ± 0.01 μM to PRM
Kinetic analysis revealed that II757 is a SAM-competitive inhibitor for PRMT1, indicating that it can be tethered to a substrate-competitive inhibitor to further improve its inhibitory activity and selectivity for any specific member of the PRMT family

Summary

Introduction

Protein arginine methyltransferases (PRMTs) are a group of enzymes that methylate the guanidino group of the arginine using S-adenosyl methionine (SAM) as a methyl donor, producing mono- or dimethylated arginine residues and S-adenosyl-L-homocysteine (SAH). Nine human PRMT members have been identified, which are classified into three types according to the characteristic of their products [1,2,3]. As the only member in Type III, PRMT7 solely produces monomethylated arginine. Arginine methylation regulates diverse biological processes, including signal transduction, RNA splicing, DNA repair, cell proliferation, and differentiation [4]. Aberrant levels of PRMTs have been implicated in diverse diseases including cardiovascular diseases, cancers, inflammatory diseases, and diabetes [1,5,6,7,8]

Objectives

Methods

Findings

Conclusion