Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cycle of protein-carboxyl methylation and demethylation was studied in intact blood platelets. Platelets rapidly incorporated L-[methyl-3H]methionine and after a delay of about 20 min, they evolved [3H]methanol. This evolution, and the amount of [3H] methanol liberated by treatment with base, was inhibited in a dose-dependent fashion by the cyclic nucleotide phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine, papaverine, dipyridamole, and RA233 (2,6-bis(diethanolamino)-4-piperidinopyrimido[5,4-d] pyrimidine). Each of these compounds increased the incorporation of [3H]methionine into platelets. The effects of RA233 were studied in more detail. Inhibition of [3H]methanol production was not potentiated by stimulators of the adenylate cyclase or the guanylate cyclase. The majority of the base-labile radioactivity was trichloroacetic acid precipitable. Thin layer chromatography of extracts of platelets incubated with L-[35S]methionine showed that RA233 did not induce a cellular accumulation of [35S]S-adenosylhomocysteine, and that it actually increased the amount of cellular [35S]S-adenosylmethionine. Discontinuous polyacrylamide gel electrophoresis at acid pH using the cationic detergent benzyldimethyl-n-hexadecylammonium chloride of platelets incubated with [3H]methionine showed incorporation of radioactivity into more than 30 protein bands, including one which co-migrates with calmodulin. The incorporation into the majority of these bands was inhibited by RA233 in a dose-dependent fashion. It is suggested that caution should be used in ascribing the pharmacological effects of known phosphodiesterase inhibitors to increases in cyclic nucleotides, because some of these effects could be due to inhibition of protein carboxyl methylation.
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PMID:Inhibitors of cyclic nucleotide phosphodiesterases inhibit protein carboxyl methylation in intact blood platelets. 619 23

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.
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PMID:In vitro inactivation of mammalian methionine synthase by nitric oxide. 890 27