Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin.

ABSTRACT: Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH₄) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH₄ in the precatalytic state. Crystal structures, solved at 3.18-Å resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH₄ BH₄ forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic

SUBMITTER: Flydal MI 

PROVIDER: S-EPMC6561269 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature