GTP cyclohydrolase I feedback regulatory protein-dependent and -independent inhibitors of GTP cyclohydrolase I

GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates the feedba ck inhibition of GTP cyclohydrolase I activity by (6R)-L-erythro-5,6,7,8-te trahydrobiopterin (BH4) through protein complex formation. Since guanine an d BH4 have a common pyrimidine ring structure, we examined the inhibitory e ffect of guanine and its analogs on the enzyme activity. Guanine, 8-hydroxy guanine, 8-methylguanine, and 8-bromoguanine inhibited the enzyme activity in a GFRP-dependent and pa-dependent manner and induced complex formation b etween GTP cyclohydrolase I and GFRP. The type of inhibition by this group is a mixed type. All these properties were shared with BH4. In striking con trast, inhibition by 8-azaguanine and 8-mercaptoguanine was GFRP-independen t and pH-independent. The type of inhibition by 8-azaguanine and 8-mercapto guanine was a competitive type. The two compounds did not induce complex fo rmation between the enzyme and GFRP. These results demonstrate that guanine compounds of the first group bind to the BH4-binding site of the GTP cyclo hydrolase I/GFRP complex, whereas 8-azaguanine and 8-mercaptoguanine bind t o the active site of the enzyme. Finally, the possible implications in Lesc h-Nyhan syndrome and Parkinson diseases of the inhibition of GTP cyclohydro lase I by guanine and 8-hydroxyguanine are discussed. (C) 2001 Academic Pre ss.