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peptidyl-arginine methylation, to asymmetrical-dimethyl arginine

Definition

Target type: biologicalprocess

The process of methylation of peptidyl-arginine to form peptidyl-N(omega),N(omega)-dimethyl-L-arginine. [RESID:AA0068, RESID:AA0069]

Peptidyl-arginine methylation to asymmetrical-dimethyl arginine, also known as ADMA, is a post-translational modification involving the enzymatic transfer of two methyl groups to a specific arginine residue within a protein. This process is catalyzed by a family of enzymes called protein arginine methyltransferases (PRMTs).

PRMTs utilize S-adenosyl methionine (SAM) as a methyl donor, transferring the methyl group to the guanidino nitrogen of the arginine residue. In the case of asymmetrical dimethylation, PRMTs transfer two methyl groups to different nitrogens on the guanidino group of arginine.

The process of ADMA formation involves several key steps:

1. **Recognition and Binding:** The PRMT enzyme recognizes and binds to a specific sequence within the target protein, often in the context of a specific structural motif. This interaction brings the arginine residue into close proximity to the active site of the enzyme.
2. **Methylation:** The PRMT catalyzes the transfer of a methyl group from SAM to the guanidino nitrogen of the arginine residue. This results in the formation of monomethylarginine (MMA).
3. **Second Methylation:** The PRMT then catalyzes a second methylation event, transferring another methyl group to a different nitrogen on the guanidino group. This results in the formation of ADMA.

The specific PRMTs responsible for ADMA formation are PRMT1 and PRMT4. These enzymes have distinct substrate specificities and play important roles in a variety of cellular processes.

ADMA formation has significant biological implications. It can modulate protein function, alter protein-protein interactions, and impact signaling pathways. For instance, ADMA has been implicated in cardiovascular disease, inflammation, and cancer.

In summary, peptidyl-arginine methylation to ADMA is a complex process that involves specific enzymes, substrates, and regulatory mechanisms. It plays a crucial role in cellular processes and is associated with a range of biological and pathological conditions.'
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Proteins (5)

ProteinDefinitionTaxonomy
Protein arginine N-methyltransferase 1A protein arginine N-methyltransferase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q99873]Homo sapiens (human)
Protein arginine N-methyltransferase 7A protein arginine N-methyltransferase 7 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9NVM4]Homo sapiens (human)
Histone-arginine methyltransferase CARM1A histone-arginine methyltransferase CARM1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q86X55]Homo sapiens (human)
Protein arginine N-methyltransferase 6A protein arginine N-methyltransferase 6 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96LA8]Homo sapiens (human)
Protein arginine N-methyltransferase 3A protein arginine N-methyltransferase 3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:O60678]Homo sapiens (human)

Compounds (23)

CompoundDefinitionClassesRoles
fluorescitefluorescein (acid form) : A xanthene dye that is highly fluorescent and commonly used as a fluorescent tracer.benzoic acids;
cyclic ketone;
hydroxy monocarboxylic acid;
organic heterotricyclic compound;
phenols;
xanthene dye
fluorescent dye;
radioopaque medium
pentamidinepentamidine : A diether consisting of pentane-1,5-diol in which both hydroxyl hydrogens have been replaced by 4-amidinophenyl groups. A trypanocidal drug that is used for treatment of cutaneous leishmaniasis and Chagas disease.

Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of PNEUMOCYSTIS pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects.
aromatic ether;
carboxamidine;
diether
anti-inflammatory agent;
antifungal agent;
calmodulin antagonist;
chemokine receptor 5 antagonist;
EC 2.3.1.48 (histone acetyltransferase) inhibitor;
NMDA receptor antagonist;
S100 calcium-binding protein B inhibitor;
trypanocidal drug;
xenobiotic
saccharinsaccharin : A 1,2-benzisothiazole having a keto-group at the 3-position and two oxo substituents at the 1-position. It is used as an artificial sweetening agent.

Saccharin: Flavoring agent and non-nutritive sweetener.
1,2-benzisothiazole;
N-sulfonylcarboxamide
environmental contaminant;
sweetening agent;
xenobiotic
sulfathiazolesulfathiazole : A 1,3-thiazole compound having a 4-aminobenzenesulfonamido group at the 2-position.

Sulfathiazole: A sulfathiazole compound that is used as a short-acting anti-infective agent. It is no longer commonly used systemically due to its toxicity, but may still be applied topically in combination with other drugs for the treatment of vaginal and skin infections, and is still used in veterinary medicine.
1,3-thiazoles;
substituted aniline;
sulfonamide;
sulfonamide antibiotic
antiinfective agent;
drug allergen;
EC 2.5.1.15 (dihydropteroate synthase) inhibitor;
environmental contaminant;
xenobiotic
suraminsuramin : A member of the class of phenylureas that is urea in which each of the amino groups has been substituted by a 3-({2-methyl-5-[(4,6,8-trisulfo-1-naphthyl)carbamoyl]phenyl}carbamoyl)phenyl group. An activator of both the rabbit skeletal muscle RyR1 and sheep cardiac RyR2 isoform ryanodine receptor channels, it has been used for the treatment of human African trypanosomiasis for over 100 years.

Suramin: A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties.
naphthalenesulfonic acid;
phenylureas;
secondary carboxamide
angiogenesis inhibitor;
antinematodal drug;
antineoplastic agent;
apoptosis inhibitor;
EC 2.7.11.13 (protein kinase C) inhibitor;
GABA antagonist;
GABA-gated chloride channel antagonist;
purinergic receptor P2 antagonist;
ryanodine receptor agonist;
trypanocidal drug
alizarindihydroxyanthraquinonechromophore;
dye;
plant metabolite
7-amino-4-hydroxy-2-naphthalenesulfonic acid7-amino-4-hydroxy-2-naphthalenesulfonic acid : An aminonaphthalenesulfonic acid that is 2-naphthalenesulfonic acid substituted by an amino group at position 7 and a hydroxy group at position 4 respectively.

7-amino-4-hydroxy-2-naphthalenesulfonic acid: structure given in first source
aminonaphthalenesulfonic acid;
naphthols
metabolite
1-naphthol-8-amino-3,6-disulfonic acid1-naphthol-8-amino-3,6-disulfonic acid: dye and found in industrial waste
methyl redmethyl red : An azo dye consisting of benzoic acid substituted at position 2 by a 4-[(dimethylamino)phenyl]diazenyl group.

methyl red: RN given refers to parent cpd; structure
s-adenosylmethionineacylcarnitine: structure in first source

S-adenosyl-L-methioninate : A sulfonium betaine that is a conjugate base of S-adenosyl-L-methionine obtained by the deprotonation of the carboxy group.
sulfonium betainehuman metabolite
hexamidinehexamidine : A polyether that is the bis(4-guanidinophenyl) ether of hexane-1,6-diol.aromatic ether;
guanidines;
polyether
antimicrobial agent;
antiseptic drug
sinefunginadenosines;
non-proteinogenic alpha-amino acid
antifungal agent;
antimicrobial agent
fluorone blackfluorone Black: structure
c.i. direct red 23C.I. Direct Red 23: azo dye; structure in first source
furamidinefuramidine: RN given refers to parent cpd; WR 199385 refers to di-HCl; pafuramidine is a prodrug of this
s-adenosylhomocysteineS-adenosyl-L-homocysteine : An organic sulfide that is the S-adenosyl derivative of L-homocysteine.

S-Adenosylhomocysteine: 5'-S-(3-Amino-3-carboxypropyl)-5'-thioadenosine. Formed from S-adenosylmethionine after transmethylation reactions.
adenosines;
amino acid zwitterion;
homocysteine derivative;
homocysteines;
organic sulfide
cofactor;
EC 2.1.1.72 [site-specific DNA-methyltransferase (adenine-specific)] inhibitor;
EC 2.1.1.79 (cyclopropane-fatty-acyl-phospholipid synthase) inhibitor;
epitope;
fundamental metabolite
stilbamidinestilbamidine: RN given refers to parent cpd
mbx 1090
unc 03217-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine: a G9a antagonist; structure in first sourcequinazolines
epz004777N-glycosyl compound
gsk343GSK343 : A member of the class of indazoles that is 1-isopropyl-1H-indazole-4-carboxamide in which the nitrogen of the carboxamide group is substituted by a (6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl group and in which the indazole ring is substituted at position 6 by a 2-(4-methylpiperazin-1-yl)pyridin-4-yl group. A highly potent and selective EZH2 inhibitor (IC50 = 4 nM).

GSK343: an EZH2 methyltransferase inhibitor
aminopyridine;
indazoles;
N-alkylpiperazine;
N-arylpiperazine;
pyridone;
secondary carboxamide
antineoplastic agent;
apoptosis inducer;
EC 2.1.1.43 (enhancer of zeste homolog 2) inhibitor
6,7-dimethoxy-2-(pyrrolidin-1-yl)-n-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine: a SETD8 inhibitor; structure in first source
sgc707