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Background and Purpose  6R‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin ( BH  4 ) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous  BH  4  restores vascular function in patients. Unfortunately, oral  BH  4  has limited efficacy. Therefore, orally bioavailable pharmacological activators of  endogenous  BH 4  biosynthesis hold significant therapeutic potential.  GTP ‐cyclohydrolase 1 ( GCH 1), the rate limiting enzyme in  BH  4  synthesis, forms a protein complex with  GCH 1 feedback regulatory protein ( GFRP ). This complex is subject to allosteric feed‐forward activation by  L ‐phenylalanine ( L ‐phe). We investigated the effects of  L ‐phe on the biophysical interactions of  GCH 1 and  GFRP  and its potential to alter BH 4  levels  in vivo .    Experimental Approach  Detailed characterization of  GCH 1– GFRP  protein–protein interactions were performed using surface plasmon resonance ( SPR ) with or without  L ‐phe. Effects on systemic and vascular BH 4  biosynthesis  in vivo  were investigated following L‐phe treatment (100 mg·kg −1 , p.o.).    Key Results   GCH 1 and  GFRP  proteins interacted in the absence of known ligands or substrate but the presence of  L ‐phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates.  In vivo , L‐phe challenge induced a sustained elevation of aortic  BH  4 , an effect absent in  GCH 1(fl/fl)‐ T ie2Cre mice.    Conclusions and Implications  Biophysical data indicate that  GCH 1 and  GFRP  are constitutively bound.  In vivo,  data demonstrated that  L ‐phe elevated vascular  BH  4  in an endothelial  GCH 1 dependent manner. Pharmacological agents which mimic the allosteric effects of L‐phe on the  GCH 1– GFRP  complex have the potential to elevate endothelial BH 4  biosynthesis for numerous cardiovascular disorders.

Validating the GTP ‐cyclohydrolase 1‐feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches