Asymmetric dimethylarginine (ADMA) targets nitric oxide synthase (NOS) (competitive inhibitor)[1]

In many pathological circumstances, asymmetric dimethylarginine is a sign of endothelial dysfunction and an endogenous activator of nitric oxide synthase (NOS). When HIV-1 is present, there is an increase in asymmetric dimethylarginine (ADMA) [1].

Asymmetric dimethylarginine (ADMA) is significantly elevated in plasma of asymptomatic, untreated HIV-1-infected patients compared to healthy controls; the median plasma ADMA concentration is 0.68 μmol/L in HIV patients versus 0.52 μmol/L in controls[1]
ADMA levels correlate positively with markers of immune activation in HIV-1-infected patients, including plasma TNF-α, IL-6, soluble CD14 (sCD14), and soluble CD40 ligand (sCD40L) levels[1]
ADMA levels correlate negatively with CD4+ T cell counts in HIV-1-infected patients; patients with CD4+ T cell counts <500 cells/μL have significantly higher ADMA levels than those with CD4+ T cell counts ≥500 cells/μL[1]
Elevated ADMA levels are associated with increased risk of disease progression in asymptomatic HIV-1 infection, serving as a potential prognostic marker[1]

For plasma ADMA detection assay: Collect fasting venous blood from HIV-1-infected patients and healthy controls; separate plasma by centrifugation and store at -80°C until analysis; thaw samples and prepare dilutions in assay buffer; measure ADMA concentration using a validated immunoassay (competitive enzyme-linked immunosorbent assay); quantify via absorbance measurement at 450 nm, with results calibrated against a standard curve[1]

Metabolism / Metabolites
Uremic toxins often accumulate in the blood due to overeating or poor kidney filtration. Most uremic toxins are metabolic waste products that are normally excreted through urine or feces.

Toxicity Summary
Uremic toxins, such as asymmetric dimethylarginine, can be actively transported to the kidneys via organic ion transporters, particularly OAT3. Elevated uremic toxin levels can stimulate the production of reactive oxygen species (ROS). This appears to be mediated by the direct binding of uremic toxins to or inhibition of NADPH oxidases, particularly NOX4, which is abundant in the kidneys and heart (A7868). ROS can induce a variety of different DNA methyltransferases (DNMTs) involved in the silencing of the KLOTHO protein. KLOTHO has been shown to play an important role in anti-aging, mineral metabolism, and vitamin D metabolism. Multiple studies have shown that in acute or chronic kidney disease, KLOTHO mRNA and protein levels are decreased due to elevated local ROS levels (A7869).

[1]. The cardiovascular risk marker asymmetric dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression. Ann Clin Biochem. 2014 Sep;51(Pt 5):568-75.

N(ω),N(ω)-dimethyl-L-arginine is a derivative of L-arginine, with two methyl groups attached to the primary amino group of its guanidine group. It is an EC 1.14.13.39 (nitric oxide synthase) inhibitor. It is a non-protein L-α-amino acid, belonging to the guanidine group, and is a derivative of L-arginine, as well as a dimethylarginine. It is the conjugate base of N(ω),N(ω)-dimethyl-L-arginine (1+). Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical substance found in blood plasma. It is a metabolic byproduct of the ongoing protein modification process in the cytoplasm of all human cells and is closely related to the conditionally essential amino acid L-arginine. ADMA interferes with the production of nitric oxide from L-arginine, a key chemical for maintaining endothelial cell and cardiovascular health. N,N-dimethylarginine has been reported to be present in fruit flies, fission yeast, and other organisms with relevant data.
Asymmetric dimethylarginine (ADMA) is a dimethylated derivative of L-arginine, in which two methyl groups are asymmetrically linked to arginine residues. ADMA is a competitive inhibitor of NOS (nitric oxide), formed when S-adenosylmethionine protein N-methyltransferase transfers two methyl groups from S-adenosylmethionine to one of the two guanidino nitrogen atoms of the arginine residue in a protein. ADMA is released during protein degradation and is a substrate of dimethylarginine dimethylaminohydrolase (DDAH). Free ADMA in plasma competes with L-arginine for binding to heme in NOS, thereby inhibiting nitric oxide (NO) synthesis. Reduced NO synthesis inhibits vasodilation, leading to endothelial dysfunction. Elevated plasma ADMA levels can be caused by certain types of cancer, cardiovascular disease, hypertension, hyperlipidemia, type 2 diabetes, and increased oxidative stress.
Asymmetric dimethylarginine is a uremic toxin. Based on their chemical and physical properties, uremic toxins can be divided into three main categories: 1) small molecule, water-soluble, non-protein-bound compounds, such as urea; 2) small molecule, lipid-soluble and/or protein-bound compounds, such as phenols; and 3) larger so-called medium-molecule compounds, such as β2-microglobulin. Long-term exposure to uremic toxins can lead to a variety of diseases, including kidney damage, chronic kidney disease, and cardiovascular disease. Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical substance found in blood plasma. It is a metabolic byproduct of a continuous protein modification process in the cytoplasm of all human cells. It is closely related to the conditionally essential amino acid L-arginine. ADMA interferes with the formation of nitric oxide from L-arginine, a key chemical substance for maintaining endothelial cell and cardiovascular health. Asymmetric dimethylarginine is produced during protein methylation, a common post-translational modification mechanism of proteins. This reaction is catalyzed by a group of enzymes called S-adenosylmethionine protein N-methyltransferases (protein methyltransferases I and II). The methyl group used to generate ADMA is derived from the methyl donor S-adenosylmethionine, an intermediate in homocysteine metabolism. (Homocysteine is an important blood chemical as it is also a marker of cardiovascular disease). After synthesis, ADMA migrates into the extracellular space and then enters the plasma. Asymmetric dimethylarginine was determined using high-performance liquid chromatography. Dimethyl-L-arginine is a metabolite found or produced in Saccharomyces cerevisiae. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor formed by the methylation of arginine residues in proteins and released upon proteolysis. In this reaction, S-adenosylmethionine is the methyl donor, and S-adenosylhomocysteine is the demethylation product. Therefore, ADMA and homocysteine are biochemically related. Both plasma homocysteine and ADMA concentrations are elevated in patients with renal insufficiency, likely due to impaired metabolic clearance (rather than urinary clearance). Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease in patients with end-stage renal disease, particularly in patients without malnutrition and inflammation. In addition, plasma ADMA levels are associated with cardiovascular disease in patients with renal failure. Both homocysteine and ADMA are thought to mediate their adverse vascular effects by impairing endothelial cell-dependent nitric oxide function, leading to decreased vasodilation, increased smooth muscle cell proliferation, platelet dysfunction, and increased monocyte adhesion. Asymmetric dimethylarginine (ADMA) is an endogenous methylated derivative of L-arginine and is also a recognized marker of cardiovascular risk [1]. In HIV-1 infection, elevated ADMA levels reflect impaired nitric oxide (NO) bioavailability due to NOS inhibition, which may lead to immune activation and vascular dysfunction [1].
The positive correlation between ADMA and immune activation markers (sCD14, sCD40L) suggests that there is a link between ADMA-mediated NO reduction and immune dysregulation induced by microbial translocation in HIV-1 infection [1].

C8H18N4O2

202.25412

202.143

30315-93-6

Asymmetric-dimethylarginine-d6 dihydrochloride;1313730-20-9;Asymmetric dimethylarginine dihydrochloride;220805-22-1;Asymmetric dimethylarginine-d7 hydrochloride hydrate

123831

White to off-white solid powder

1.239g/cm3

372.555°C at 760 mmHg

195 - 197 °C

179.115°C

0.455

3

4

6

14

215

1

CN(C)C(=NCCC[C@@H](C(=O)O)N)N

YDGMGEXADBMOMJ-LURJTMIESA-N

InChI=1S/C8H18N4O2/c1-12(2)8(10)11-5-3-4-6(9)7(13)14/h6H,3-5,9H2,1-2H3,(H2,10,11)(H,13,14)/t6-/m0/s1

(2S)-2-amino-5-[[amino(dimethylamino)methylidene]amino]pentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~494.44 mM)
H2O : ~100 mg/mL (~494.44 mM)

Solubility in Formulation 1: 100 mg/mL (494.44 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)