The biology and therapeutic potential of the DDAH/ADMA pathway.
Asymmetric dimethylarginine (ADMA) is an endogenously produced molecule that inhibits nitric oxide synthase and consequently may have adverse effects on physiology, in particular in the cardiovascular system. This review highlights the mechanisms involved in the synthesis and metabolism of ADMA and their role in the control of nitric oxide (NO) synthesis. We describe how the effects of both cellular and circulating ADMA can alter physiological function involving both NO dependent and independent pathways and go on to describe how the metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH) is the major endogenous mechanism by which ADMA levels are regulated. Furthermore, we discuss the association of ADMA concentrations with cardiovascular disease and how ADMA levels can be modulated therapeutically by altering its production and/or metabolism. Finally we discuss the effects of some of the current pharmaceutical therapies used to treat cardiovascular disease and their involvement in the modulation of the ADMA/DDAH pathway.
School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston-Upon-Thames, Surrey, KT1 2QJ.
F
F
Arrigoni
B
B
Ahmetaj
J
J
Leiper
D000581:Amidohydrolases / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase