Regulation of Phenylalanine Catabolism

  • Fitzpatrick, Paul F (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The liver enzyme phenylalanine hydroxylase is responsible for catabolism of excess phenylalanine in the diet. Deficiencies in levels of the enzyme result in the metabolic disorder phenylketonuria, a disease with devastating neurological consequences if untreated, demonstrating the physiological importance of the enzyme. Central to the proper function of phenylalanine hydroxylase is the regulation of the enzyme by its substrates, phenylalanine and tetrahydrobiopterin, and by phosphorylation. Both forms of regulation require the N-terminal ~117 residue regulatory domain. In the generally-accepted model for regulation, the resting form of the enzyme is inactive and allosteric binding of phenylalanine at a regulatory site converts the enzyme to an active form. Tetrahydrobiopterin stabilizes the inactive form, while phosphorylation potentiates the conversion to the active form. The goal of the research proposed here is to understand the structural and dynamic basis for the allosteric regulation. The proposed experiments will combine modern structural approaches (e.g., NMR and mass spectroscopy) with measurement of intrinsic rate constants for binding and catalysis in order to provide a more complete understanding of the allosteric regulation of phenylalanine hydroxylase. PUBLIC HEALTH RELEVANCE: This is a proposal to study the regulation of the liver enzyme phenylalanine hydroxylase. An inherited deficiency in this enzyme unless the affected individual is placed on a restricted diet from birth. A better understanding of the regulation will improve our ability to develop better treatments for PKU.
StatusFinished
Effective start/end date9/20/115/31/16

Funding

  • National Institutes of Health: $279,180.00
  • National Institutes of Health: $336,010.00
  • National Institutes of Health: $42,505.00
  • National Institutes of Health: $271,223.00
  • National Institutes of Health: $280,590.00

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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