Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function.
The present study was designed to investigate the interaction between 5-methyltetrahydrofolate and tetrahydrobiopterin in modulating endothelial function. Tetrahydrobiopterin is a critical cofactor for nitric oxide synthase and maintains this enzyme as a nitric oxide- versus superoxide-producing enzyme. The structure of 5-methyltetrahydrofolate is similar to tetrahydrobiopterin and both agents have been shown to improve endothelium-dependent vasodilatation. We hypothesized that 5-methyltetrahydrofolate interacts with nitric oxide synthase in a fashion analogous, yet independent, of tetrahydrobiopterin to improve endothelial function. We demonstrate that 5-methyltetrahydrofolate binds the active site of nitric oxide synthase and mimics the orientation of tetrahydrobiopterin. Furthermore, 5-methyltetrahydrofolate attenuates superoxide production (induced by inhibition of tetrahydrobiopterin synthesis) and improves endothelial function in aortae isolated from tetrahydrobiopterin-deficient rats. We suggest that 5-methyltetrahydrofolate directly interacts with nitric oxide synthase to promote nitric oxide (vs. superoxide) production and improve endothelial function. 5-Methyltetrahydrofolate may represent an important strategy for intervention aimed at improving tetrahydrobiopterin bioavailability.
Hyndman
Mathew Eric
ME
Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Verma
Subodh
S
Rosenfeld
Robin J
RJ
Anderson
Todd J
TJ
Parsons
Howard G
HG
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001665:Binding Sites; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005456:Fluorescent Dyes; D005609:Free Radicals; D007150:Immunohistochemistry; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011621:Pteridines / Q000494:pharmacology; D011622:Pterins; D017382:Reactive Oxygen Species / Q000378:metabolism; D012235:Rhodamines; D013481:Superoxides / Q000378:metabolism; D013763:Tetrahydrofolates / Q000378:metabolism / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D005456:Fluorescent Dyes; D005609:Free Radicals; D011621:Pteridines; D011622:Pterins; D017382:Reactive Oxygen Species; D012235:Rhodamines; D013763:Tetrahydrofolates; C058319:dihydrorhodamine 123; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D000109:Acetylcholine; C005984:5-methyltetrahydrofolate