In vitro inactivation of mammalian methionine synthase by nitric oxide.
The research described here provides one mechanism of uniting current effects of nitric oxide (NO) with the elevated levels of homocysteine detected in patients with cardiovascular and other disease. Time- and dose-dependent studies of the inhibition of purified mammalian methionine synthase by NO were performed. The in vitro study gave an effective IC50 value of 3 mu mol L-1. Methionine synthase converts cellular homocysteine to methionine and is a major enzyme in the biosynthetic pathways for folates, S-adenosylmethionine and biological methylations, sulphur amino acids and polyamines. Nitric oxide-induced inactivation of methionine synthase alters the levels of these metabolites and could therefore provide a connection between the cardiovascular effects of NO, the plasma homocysteine levels and cardiovascular diseases that is complementary to the more traditional NO-induced stimulation of guanylate cyclase and the convertion of homocysteine to oxidized sulphur amino acids.
University-Industry Centre for Pharmaceutical Research, The School of Pharmacy, University of London, UK.
A
A
Nicolaou
S H
SH
Kenyon
J M
JM
Gibbons
T
T
Ast
W A
WA
Gibbons
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors*; D000818:Animals; D006710:Homocysteine / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D006710:Homocysteine; D009569:Nitric Oxide; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase