Essential role of the N-terminal autoregulatory sequence in the regulation of phenylalanine hydroxylase

FEBS Lett. 2001 Jan 19;488(3):196-200. doi: 10.1016/s0014-5793(00)02426-1.

Abstract

Phenylalanine hydroxylase (PAH) is activated by its substrate phenylalanine and inhibited by its cofactor tetrahydrobiopterin (BH(4)). The crystal structure of PAH revealed that the N-terminal sequence of the enzyme (residues 19-29) partially covered the enzyme active site, and suggested its involvement in regulation. We show that the protein lacking this N-terminal sequence does not require activation by phenylalanine, shows an altered structural response to phenylalanine, and is not inhibited by BH(4). Our data support the model where the N-terminal sequence of PAH acts as an intrasteric autoregulatory sequence, responsible for transmitting the effect of phenylalanine activation to the active site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Biopterins / analogs & derivatives*
  • Biopterins / metabolism
  • Biopterins / pharmacology
  • Chymotrypsin / metabolism
  • Enzyme Activation / drug effects
  • Models, Molecular
  • Phenylalanine / antagonists & inhibitors
  • Phenylalanine / metabolism
  • Phenylalanine / pharmacology
  • Phenylalanine Hydroxylase / antagonists & inhibitors
  • Phenylalanine Hydroxylase / chemistry*
  • Phenylalanine Hydroxylase / genetics
  • Phenylalanine Hydroxylase / metabolism*
  • Phosphorylation / drug effects
  • Protein Conformation
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Deletion / genetics

Substances

  • Recombinant Proteins
  • Biopterins
  • Phenylalanine
  • Phenylalanine Hydroxylase
  • Chymotrypsin
  • sapropterin