My watch list  

Dimethylarginine dimethylaminohydrolase

dimethylarginine dimethylaminohydrolase 1
Symbol DDAH1
Entrez 23576
HUGO 2715
OMIM 604743
RefSeq NM_012137
UniProt O94760
Other data
EC number
Locus Chr. 1 p22
dimethylarginine dimethylaminohydrolase 2
Symbol DDAH2
Entrez 23564
HUGO 2716
OMIM 604744
RefSeq NM_013974
UniProt O95865
Other data
EC number
Locus Chr. 6 p21

Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme found in all mammalian cells. Two isoforms exist, DDAH I and DDAH II, with some differences in tissue distribution of the two isoforms[1]). The enzyme degrades methylarginines, specifically asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (MMA). The methylarginines ADMA and MMA inhibit the production of nitric oxide synthase.[2] Accordingly, DDAH is important in removing methylarginines, generated by protein degradation, from accumulating and inhibiting the generation of nitric oxide.

Inhibition of DDAH activity causes methylarginines to accumulate, blocking nitric oxide(NO) synthesis and causing vasoconstriction.[3] An impairment of DDAH activity appears to be involved in the elevation of plasma ADMA, and impairment of vascular relaxation observed in humans with cardiovascular disease or risk factors (such as hypercholesterolemia, diabetes mellitus, and insulin resistance). The activity of DDAH is impaired by oxidative stress, permitting ADMA to accumulate. A wide range of pathologic stimuli induce endothelial oxidative stress such as oxidized LDL-cholesterol, inflammatory cytokines, hyperhomocysteinemia, hyperglycemia and infectious agents. Each of these insults attenuates DDAH activity in vitro and in vivo.[4][5][6][7] The attenuation of DDAH allows ADMA to accumulate, and to block NO synthesis. The adverse effect of these stimuli can be reversed in vitro by antioxidants, which preserve the activity of DDAH.

The sensitivity of DDAH to oxidative stress is conferred by a critical sulfhydryl in the active site of the enzyme that is required for the metabolism of ADMA. This sulfhydryl can also be reversibly inhibited by NO in an elegant form of negative feedback.[8] Homocysteine (a putative cardiovascular risk factor) mounts an oxidative attack on DDAH to form a mixed disulfide, inactivating the enzyme.[5] By oxidizing a sulfhydryl moiety critical for DDAH activity, homocysteine and other risk factors cause ADMA to accumulate and to suppress nitric oxide synthase (NOS) activity.

The critical role of DDAH activity in regulating NO synthesis in vivo was demonstrated using a transgenic DDAH mouse.[9] In this animal, the activity of DDAH is increased, and plasma ADMA levels are reduced by 50%. The reduction in plasma ADMA is associated with a significant increase in NOS activity, as plasma and urinary nitrate levels are doubled. The increase in NOS activity translates into a 15mmHg reduction in systolic blood pressure in the transgenic mouse. This study provides evidence for the importance of DDAH activity and plasma ADMA levels in the regulation of NO synthesis. Subsequent studies have shown that DDAH transgenic animals also manifest improvements in endothelial regeneration and angiogenesis, and reduced vascular obstructive disease, in association with the reduced plasma levels of ADMA.[10][11] These findings are consistent with evidence from a number of groups that nitric oxide plays a critical role in vascular regeneration. By contrast, elevations in ADMA impair angiogenesis. These insights into the role of DDAH in degrading endogenous inhibitors of NOS, and thereby maintaining vascular NO production, may have important implications in vascular health and therapy for cardiovascular disease.


  1. ^ Leiper JM, Santa Maria J, Chubb A et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J. 1999; 343: 209-214.
  2. ^ Cooke JP: Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004 Apr 20;109(15):1813-8.
  3. ^ MacAllister RJ, Parry H, Kimoto M et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996; 119: 1533-1540.
  4. ^ Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel Mechanism for Endothelial Dysfunction : Dysregulation of Dimethylarginine Dimethylaminohydrolase Circulation 1999 Jun 22;99(24): 3092-5).
  5. ^ a b Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation. 2001; 104:2569-2575.
  6. ^ Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven G, Cooke JP: Impaired nitric oxide synthase pathway in diabetes mellitus: Role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002 Aug 20;106(8):987-92
  7. ^ Weis M, Kledal TN, Lin KY, Panchal SN, Gao SZ, Valantine HA, Mocarski ES, Cooke JP: Cytomegalovirus infection impairs the NOS pathway. Role of ADMA in transplant arteriosclerosis. Circulation 2004 Feb 3;109(4):500-5.
  8. ^ Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13527-32. Epub 2002 Oct 07.
  9. ^ Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger M, Wang B, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP: DDAH Regulates NO Synthesis: Genetic and physiological evidence. Circulation 2003; 108: 1043-1048
  10. ^ Jacobi J, Sydow K, von Degenfeld G, Zhang Y, Dayoub H, Wang B, Patterson AJ, Kimoto M, Blau HM, Cooke JP: Overexpression of Dimethylarginine Dimethylaminohydrolase (DDAH) Reduces Tissue ADMA Levels and Enhances Angiogenesis. Circulation 2005 Mar 22;111(11):1431-8.
  11. ^ Tanaka M, Sydow K, Gunawan F, Jacobi J, Tsao PS, Robbins RC and Cooke JP: DDAH overexpression suppresses graft coronary artery disease in murine cardiac allografts. Circulation 2005 Sep 13;112(11):1549-56. Epub 2005 Sep 6.
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Dimethylarginine_dimethylaminohydrolase". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE