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

Arch Biochem Biophys. 2001 Apr 1;388(1):67-73. doi: 10.1006/abbi.2001.2288.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Azaguanine / pharmacology
  • Binding Sites
  • Binding, Competitive
  • Chromatography, Gel
  • Dose-Response Relationship, Drug
  • GTP Cyclohydrolase / chemistry*
  • GTP Cyclohydrolase / metabolism*
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Guanine / pharmacology
  • Guanosine / analogs & derivatives*
  • Guanosine / pharmacology
  • Guanosine Triphosphate / metabolism
  • Hydrogen-Ion Concentration
  • Inhibitory Concentration 50
  • Kinetics
  • Lesch-Nyhan Syndrome / metabolism
  • Models, Chemical
  • Parkinson Disease / metabolism
  • Rats
  • Thionucleosides / pharmacology

Substances

  • Adjuvants, Immunologic
  • Antimetabolites, Antineoplastic
  • Thionucleosides
  • Guanosine
  • 8-methylguanine
  • 8-bromoguanosine
  • 8-hydroxyguanine
  • Guanine
  • Guanosine Triphosphate
  • 8-thioguanosine
  • GTP Cyclohydrolase
  • Azaguanine