- Dimethylarginine dimethylaminohydrolase
protein
Name=dimethylarginine dimethylaminohydrolase 1
caption=
width=
HGNCid=2715
Symbol=DDAH1
AltSymbols=
EntrezGene=23576
OMIM=604743
RefSeq=NM_012137
UniProt=O94760
PDB=
ECnumber=3.5.3.18
Chromosome=1
Arm=p
Band=22
LocusSupplementaryData=protein
Name=dimethylarginine dimethylaminohydrolase 2
caption=
width=
HGNCid=2716
Symbol=DDAH2
AltSymbols=
EntrezGene=23564
OMIM=604744
RefSeq=NM_013974
UniProt=O95865
PDB=
ECnumber=3.5.3.18
Chromosome=6
Arm=p
Band=21
LocusSupplementaryData=Dimethylarginine dimethylaminohydrolase (DDAH) is an
enzyme found in allmammal ian cells. Two isoforms exist, DDAH I and DDAH II, with some differences in tissue distribution of the two isoforms [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.] ). The enzyme degradesmethylarginine s, specificallyasymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (MMA). The methylarginines ADMA and MMA inhibit the production ofnitric oxide synthase . [Cooke JP: Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004 Apr 20;109(15):1813-8.] 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, blockingnitric oxide (NO) synthesis and causingvasoconstriction . [MacAllister RJ, Parry H, Kimoto M et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996; 119: 1533-1540.] An impairment of DDAH activity appears to be involved in the elevation of plasma ADMA, and impairment of vascular relaxation observed in humans withcardiovascular disease or risk factors (such ashypercholesterolemia ,diabetes mellitus , andinsulin resistance ). The activity of DDAH is impaired byoxidative stress , permitting ADMA to accumulate. A wide range of pathologic stimuli induce endothelial oxidative stress such as oxidizedLDL-cholesterol ,inflammatory cytokines ,hyperhomocysteinemia ,hyperglycemia andinfectious agents . Each of these insults attenuates DDAH activity "in vitro" and "in vivo". [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).] 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.] [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] [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.] The attenuation of DDAH allows ADMA to accumulate, and to block NO synthesis. The adverse effect of these stimuli can be reversed in vitro byantioxidants , which preserve the activity of DDAH.The sensitivity of DDAH to oxidative stress is conferred by a critical
sulfhydryl in theactive site of the enzyme that is required for themetabolism of ADMA. This sulfhydryl can also be reversibly inhibited by NO in an elegant form ofnegative feedback . [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.]Homocysteine (a putative cardiovascular risk factor) mounts an oxidative attack on DDAH to form a mixeddisulfide , inactivating the enzyme. By oxidizing a sulfhydryl moiety critical for DDAH activity, homocysteine and other risk factors cause ADMA to accumulate and to suppressnitric oxide synthase (NOS) activity.The critical role of DDAH activity in regulating NO synthesis "in vivo" was demonstrated using a
transgenic DDAHmouse . [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] 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 urinarynitrate levels are doubled. The increase in NOS activity translates into a 15mmHg reduction insystolic 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 inendothelial regeneration andangiogenesis , and reduced vascular obstructive disease, in association with the reduced plasma levels of ADMA. [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.] [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.] 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.References
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