Dimethylargininase

dimethylargininase
Ribbon diagram of human DDAH1.[1]
Identifiers
EC no.	3.5.3.18
CAS no.	123644-75-7
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

In the field of enzymology, a dimethylargininase, also known as a dimethylarginine dimethylaminohydrolase (DDAH), is an enzyme that catalyzes the chemical reaction:

N-omega,N-omega'-methyl-L-arginine + H₂O ${\displaystyle \rightleftharpoons }$ dimethylamine + L-citrulline

Thus, the two substrates of this enzyme are N-omega,N-omega'-methyl-L-arginine and H₂O, whereas its two products are dimethylamine and L-citrulline.

Isozymes

Dimethylarginine dimethylaminohydrolase 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[2]). The enzyme degrades methylarginines, specifically asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (MMA).

dimethylarginine dimethylaminohydrolase 1 Identifiers Symbol DDAH1 NCBI gene 23576 HGNC 2715 OMIM 604743 RefSeq NM_012137 UniProt O94760 Other data EC number 3.5.3.18 Locus Chr. 1 p22 Search for Structures Swiss-model Domains InterPro

dimethylarginine dimethylaminohydrolase 2 Identifiers Symbol DDAH2 NCBI gene 23564 HGNC 2716 OMIM 604744 RefSeq NM_013974 UniProt O95865 Other data EC number 3.5.3.18 Locus Chr. 6 p21 Search for Structures Swiss-model Domains InterPro

Function

The methylarginines ADMA and MMA inhibit the enzyme nitric oxide synthase.[3] As such, DDAH is important in removing methylarginines, generated by protein degradation, from accumulating and inhibiting the generation of nitric oxide.

Clinical significance

Inhibition of DDAH activity causes methylarginines to accumulate, blocking nitric oxide(NO) synthesis and causing vasoconstriction.[4] 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.[5][6][7][8] 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.[9] Homocysteine (a putative cardiovascular risk factor) mounts an oxidative attack on DDAH to form a mixed disulfide, inactivating the enzyme.[6] 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.[10] 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.[11][12] 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.

See also

• Protein detoxification

References

1. PDB: 3I2E​; Wang W, Monzingo AF, Hu S, Schaller TH, Robertus JD, Fast W (2009). "Developing Dual and Specific Inhibitors of Dimethylarginine Dimethylaminohydrolase-1 and Nitric Oxide Synthase: Toward a Targeted Polypharmacology To Control Nitric Oxide". Biochemistry. 48 (36): 8624–8635. doi:10.1021/bi9007098. PMC 2746464. PMID 19663506.; rendered via PyMOL.
2. 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.
3. Cooke JP (April 2004). "Asymmetrical dimethylarginine: the Uber marker?". Circulation. 109 (15): 1813–1818. doi:10.1161/01.CIR.0000126823.07732.D5. PMID 15096461.
4. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, Whitley GS, Vallance P (December 1996). "Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase". Br. J. Pharmacol. 119 (8): 1533–40. doi:10.1111/j.1476-5381.1996.tb16069.x. PMC 1915783. PMID 8982498.
5. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP (June 1999). "Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase". Circulation. 99 (24): 3092–5. doi:10.1161/01.cir.99.24.3092. PMID 10377069.
6. Stühlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP (November 2001). "Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine". Circulation. 104 (21): 2569–2575. CiteSeerX 10.1.1.584.9462. doi:10.1161/hc4601.098514. PMID 11714652.
7. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP (August 2002). "Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase". Circulation. 106 (8): 987–992. doi:10.1161/01.CIR.0000027109.14149.67. PMID 12186805.
8. Weis M, Kledal TN, Lin KY, Panchal SN, Gao SZ, Valantine HA, Mocarski ES, Cooke JP (February 2004). "Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis". Circulation. 109 (4): 500–505. CiteSeerX 10.1.1.576.1717. doi:10.1161/01.CIR.0000109692.16004.AF. PMID 14732750.
9. Leiper J, Murray-Rust J, McDonald N, Vallance P (October 2002). "S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13527–13532. Bibcode:2002PNAS...9913527L. doi:10.1073/pnas.212269799. PMC 129707. PMID 12370443.
10. Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP (December 2003). "Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence". Circulation. 108 (24): 3042–3047. doi:10.1161/01.CIR.0000101924.04515.2E. PMID 14638548. S2CID 196628.
11. Jacobi J, Sydow K, von Degenfeld G, Zhang Y, Dayoub H, Wang B, Patterson AJ, Kimoto M, Blau HM, Cooke JP (March 2005). "Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis". Circulation. 111 (11): 1431–1438. doi:10.1161/01.CIR.0000158487.80483.09. PMID 15781754.
12. Tanaka M, Sydow K, Gunawan F, Jacobi J, Tsao PS, Robbins RC, Cooke JP (September 2005). "Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease". Circulation. 112 (11): 1549–1556. doi:10.1161/CIRCULATIONAHA.105.537670. PMID 16144995.

Further reading

• Ogawa T, Kimoto M, Sasaoka K (1989). "Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney". J. Biol. Chem. 264 (17): 10205–9. doi:10.1016/S0021-9258(18)81786-0. PMID 2722865.

External links

• dimethylarginine+dimethylaminohydrolase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)