Differential studies of the kinetics, mechanisms, and active site structures for truncated and full-length phenylalanine hydroxylases

INOR 22

Gulbenk Anarat, anaratgu@bu.edu1, Marina S. Chow, marinac@stanford.edu2, SuzAnn M Hertzler, hertzler@bu.edu1, Supratim Datta, supratim@umich.edu3, Edward I. Solomon, edward.solomon@stanford.edu2, and John P. Caradonna, caradonn@bu.edu1. (1) Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, (2) Department of Chemistry, Stanford University, Stanford, CA 94305, (3) Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109
Phenylalanine hydroxylase (PAH) is a non-heme iron tetrahydrobiopterin-dependent monooxygenase that hydroxylates phenylalanine (L-Phe) to tyrosine (L-Tyr) in the rate-limiting step of L-Phe catabolism. Impaired function of PAH leads to the accumulation of toxic L-Phe metabolites, causing the clinical disorder phenylketonuria (PKU). Available crystal structures of PAH are of the truncated forms of the enzyme, missing all or part of the N-terminal regulatory domain and/or the C-terminal tetramerization domain. Studies of mammalian truncated (D1-117PAH) and full-length tetrameric PAH will be presented, allowing for a detailed discussion of their differential active site geometries, kinetics, mechanisms and structures. A comparison to monomeric bacterial PAH will also be presented. Evaluation of small molecule active site binding data for both full-length and truncated PAH will be discussed in relation to the available truncated crystal structures. These data indicate important differences in small molecule binding and consequently in the number of exchangeable iron site ligands for full length and truncated PAH.
 

Bioinorganic Chemistry: Enzymes and Coenzymes
8:30 AM-12:10 PM, Sunday, August 19, 2007 BCEC -- 208, Oral

Division of Inorganic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007