LNCaP
Lymph node carcinoma of the prostate, prostate cancer cell line
MCF7
Michigan Cancer Foundation-7, breast cancer cell line
MCL
Mantle cell lymphoma
MEP50
Methylosome protein 50
MLL
Mixed lineage leukaemia
MMA
Monomethylated arginine
MTA
Methylthioadenosine
MTAP
5-Methylthioadenosine phosphorylase
PABP1
Poly(A)-binding protein-1
PAD
Protein arginine deiminase
PGM
Proline, glycine, methionine-rich
PK/PD
Pharmacokinetic/pharmacodynamic
PRMT
Protein arginine N-methyltransferase
RNA
Ribonucleic acid
RSF1
Repressor splicing factor
SAH
S-adenosyl-L-homocysteine
SAHH
S-adenosyl-L-homocysteine hydrolase
SAM
S-adenosyl-L-methionine
SAR
Structure-activity relationship
sDMA
Symmetrically dimethylated arginine
SET7
SET domain containing protein 7
SGC
Structural genomics consortium
Tat
Trans-activator of transcription
1 Introduction
The methylation of arginine residues in proteins is an important post-translational
modification, performed by the family of protein arginine N-methyltransferases
(PRMTs). The enzymes use nature’s ubiquitous methyl donor S-adenosyl-L-methionine (AdoMet, also known as SAM) as a cofactor to form the methylated protein
product with concomitant release of S-adenosyl-L-homocysteine (AdoHcy, also
known as SAH) as a byproduct. Mechanistically, target arginine residues are first
monomethylated by all types of PRMTs and subsequently dimethylated asymmetrically by type I PRMTs and symmetrically by type II PRMTs. Type III PRMTs
produce only monomethylated arginine (MMA). The PRMTs share highly conserved active site sequences, including a number of residues involved in AdoMet
cofactor recognition as well as two glutamate residues that hydrogen bond with the
guanidine moiety of the substrate peptide. These glutamate residues are part of the
so-called double E-loop which ensures that the guanidine group is positioned in
close proximity to the AdoMet cofactor to facilitate the methyl transfer via an SN2like substitution reaction (Fig. 1).
PRMT Inhibitors
161
Lymph node carcinoma of the prostate, prostate cancer cell line
MCF7
Michigan Cancer Foundation-7, breast cancer cell line
MCL
Mantle cell lymphoma
MEP50
Methylosome protein 50
MLL
Mixed lineage leukaemia
MMA
Monomethylated arginine
MTA
Methylthioadenosine
MTAP
5-Methylthioadenosine phosphorylase
PABP1
Poly(A)-binding protein-1
PAD
Protein arginine deiminase
PGM
Proline, glycine, methionine-rich
PK/PD
Pharmacokinetic/pharmacodynamic
PRMT
Protein arginine N-methyltransferase
RNA
Ribonucleic acid
RSF1
Repressor splicing factor
SAH
S-adenosyl-L-homocysteine
SAHH
S-adenosyl-L-homocysteine hydrolase
SAM
S-adenosyl-L-methionine
SAR
Structure-activity relationship
sDMA
Symmetrically dimethylated arginine
SET7
SET domain containing protein 7
SGC
Structural genomics consortium
Tat
Trans-activator of transcription
1 Introduction
The methylation of arginine residues in proteins is an important post-translational
modification, performed by the family of protein arginine N-methyltransferases
(PRMTs). The enzymes use nature’s ubiquitous methyl donor S-adenosyl-L-methionine (AdoMet, also known as SAM) as a cofactor to form the methylated protein
product with concomitant release of S-adenosyl-L-homocysteine (AdoHcy, also
known as SAH) as a byproduct. Mechanistically, target arginine residues are first
monomethylated by all types of PRMTs and subsequently dimethylated asymmetrically by type I PRMTs and symmetrically by type II PRMTs. Type III PRMTs
produce only monomethylated arginine (MMA). The PRMTs share highly conserved active site sequences, including a number of residues involved in AdoMet
cofactor recognition as well as two glutamate residues that hydrogen bond with the
guanidine moiety of the substrate peptide. These glutamate residues are part of the
so-called double E-loop which ensures that the guanidine group is positioned in
close proximity to the AdoMet cofactor to facilitate the methyl transfer via an SN2like substitution reaction (Fig. 1).
PRMT Inhibitors
161