Probing the Mechanism and Structure-Function Relations in Phenylalanine Hydroxylase

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This award by the Inorganic, Bioinorganic and Organometallic Chemistry program supports research by Professor Mahdi Abu-Omar of the University of California at Los Angeles to study the enzyme, phenylalanine hydroxylase from chromobacterium violaceum (cPAH). A genetic deficiency in the homologous human enzyme, hPAH, is responsible for the disease phenylketonuria. This research involves: 1) determining the rate-limiting step in the catalytic reaction of PAH by measuring 18O kinetic isotope effects; 2) trapping and characterizing intermediates involved in oxygen activation in PAH by kinetic and spectroscopic methods; 3) understanding the active site architecture and the origin of the substrate selectivity through site-specific mutants of the enzyme; and 4) establishing structure-function relationships by creating and exploring the reactivity of new PAH chimera composed of the regulatory domain of hPAH and the catalytic domain of cPAH.The function of an important enzyme, phenylalanine hydroxylase, which synthesizes an essential amino acid, tyrosine that is further metabolized to important neurotransmitters will be studied. The work will focus on how oxygen is activated at its iron-containing active site.