GTP cyclohydrolase I feedback regulatory protein-dependent and -independent inhibitors of GTP cyclohydrolase I.
GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates the feedback inhibition of GTP cyclohydrolase I activity by (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) through protein complex formation. Since guanine and BH4 have a common pyrimidine ring structure, we examined the inhibitory effect of guanine and its analogs on the enzyme activity. Guanine, 8-hydroxyguanine, 8-methylguanine, and 8-bromoguanine inhibited the enzyme activity in a GFRP-dependent and pH-dependent manner and induced complex formation between 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 contrast, inhibition by 8-azaguanine and 8-mercaptoguanine was GFRP-independent and pH-independent. The type of inhibition by 8-azaguanine and 8-mercaptoguanine was a competitive type. The two compounds did not induce complex formation between the enzyme and GFRP. These results demonstrate that guanine compounds of the first group bind to the BH4-binding site of the GTP cyclohydrolase I/GFRP complex, whereas 8-azaguanine and 8-mercaptoguanine bind to the active site of the enzyme. Finally, the possible implications in Lesch-Nyhan syndrome and Parkinson diseases of the inhibition of GTP cyclohydrolase I by guanine and 8-hydroxyguanine are discussed.
Yoneyama
T
T
Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
Wilson
L M
LM
Hatakeyama
K
K
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001375:Azaguanine / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002850:Chromatography, Gel; D004305:Dose-Response Relationship, Drug; D006136:GTP Cyclohydrolase / Q000737:chemistry* / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007926:Lesch-Nyhan Syndrome / Q000378:metabolism; D008956:Models, Chemical; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D013872:Thionucleosides / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000964:Antimetabolites, Antineoplastic; D013872:Thionucleosides; D006151:Guanosine; C066771:8-methylguanine; C035169:8-bromoguanosine; C024829:8-hydroxyguanine; D006147:Guanine; D006160:Guanosine Triphosphate; C037031:8-thioguanosine; D006136:GTP Cyclohydrolase; D001375:Azaguanine