Asymmetric dimethylarginine (ADMA) — a naturally occurring amino acid that is a product of

protein breakdown — is released into the cytoplasm following the post-translational methylation
of arginine residues within proteins and the subsequent proteolysis of these arginine-methylated
proteins. ADMA inhibits all three isoforms of nitric oxide synthase and therefore has the
potential to produce diverse biological effects, particularly in the cardiovascular system. In
addition to its renal clearance, endogenously produced ADMA is metabolized to L-citrulline and
dimethylamine by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes.
Pharmacological modification of DDAH has therefore been proposed as a mechanism for
manipulating endogenous ADMA concentrations and regulating the production of nitric oxide in
situations where alterations in nitric oxide signalling have been shown to contribute to
pathophysiology. This Review describes the biology of ADMA and the potential therapeutic
utility of manipulating DDAH activity.

Key points

 Asymmetrically methylated arginines — principally asymmetric dimethylarginine

(ADMA; that is, ω-NG,NG-asymmetric dimethylargenine) — are endogenously produced
competitive inhibitors of nitric oxide synthase (NOS) enzymes. The concentration of
asymmetric methylarginines is actively regulated in vivo by the action of
dimethylarginine dimethylaminohydrolase (DDAH) enzymes that metabolize
methylarginines to L-citrulline and methylamine.

 Modulation of DDAH activity in experimental models has demonstrated that endogenous

inhibitors of NOS tonically inhibit the basal activity of NOS. Genetic or pharmacological
disruption of DDAH activity impairs cardiovascular homeostasis in vivo, whereas
overexpression of DDAH protects against cardiovascular disease in model systems.

 Genetic polymorphisms in human DDAH genes are associated with a variation in

circulating ADMA levels and disease progression in several cardiovascular diseases
including stroke, thrombosis and coronary artery disease. Increases in circulating plasma
 ADMA concentrations have been shown to strongly predict mortality in patients with
end-stage renal disease.

 Pharmacological elevation of ADMA concentration has been suggested to be

therapeutically useful in disease states in which excessive NO synthesis contributes to
disease (for example, septic shock). Consistent with this proposition, genetic or
pharmacological inhibition of DDAH has been shown to attenuate NO-dependent
hypotension that is induced in animals with sepsis.

Sinteza adma

Astfel, degradarea proteinei reprezintă sursa majoră intracelulară de metilarginine, deoarece nu

există în prezent niciun studiu sau dovadă care să ateste că L-Arginina liberă poate fi metilată .
În plus, proteoliza intracelulară a proteinelor metilate contribuie la nivelurile interstițiale și
plasmatice de dimetilarginină asimetrică , care sunt controlate în continuare prin degradarea și
importul de metilarginine.

Metilargininele sunt eliminate din organism prin excreţie renală și metabolism hepatic . Pe lângă
acestea, mono-metilarginina si dimetilarginina asimetrică , pot fi metabolizate mai departe în
citrulină și monometilamina sau dimetilamină, de către enzima denumită dimetilaminohidrolaza
de dimetilarginină.
Proteina metilarea argininei este efectuată de o clasă de enzime numite proteină arginine
metiltransferaze (PRMT), care metilă în mod specific reziduurile de arginină încorporate în
proteine la genera monometilarginina incorporata in proteine (MMA), dimetilarginina simetrica
(SDMA), sau dimetilarginină asimetrică (ADMA). La scindarea proteolitică a argininei-metilat
se generează proteine, MMA intracelulară liberă, SDMA sau ADMA, care, după secreție în
spațiul extracelular (inclusiv plasma) afectează direct concentrația de metilarginină în plasmă.
Methargininele libere sunt eliminate din organism prin excreție renală sau prin metabolizare
hepatică. În plus, MMA și ADMA, dar nu SDMA, pot fi degradate printr-o clasă de enzime
intracelulare numite dimetilaminohidrolaze de dimetilarginină (DDAH).