Phenylalanine Hydroylase (PAH) functions to keep the essential amino acid phenylalanine (Phe) below levels that cause irreversible brain damage in infancy/childhood and behavioral problems throughout life. Mutations to the PAH genes can disrupt this control function and cause phenylketonuria (PKU), which occurs in about 1:12000 live births. Due to mandatory screening, PKU is typically diagnosed at birth and successfully treated with strict dietary control of protein intake. However, adults living with PKU need a less restricted diet and new therapies are sought. Such therapies can come from understanding how PAH works.
Until very recently, the way that PAH controls Phe was poorly understood. However, new research reveals important details about how PAH changes its shape in order to control its enzymatic activity (1, 2). Our goal in this project is to use molecular simulation to understand the PAH shape changes that accompany activation in response to elevated levels of Phe and how this process is perturbed in disease.
This is a collaboration with Eileen K. Jaffe at Fox Chase Cancer Center.
(1) Arturo EC, Gupta K, Heroux A, Stith L, Cross PJ, Parker EJ, Loll PJ, Jaffe EK. First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer. Proc Natl Acad Sci U S A. 2016;113(9):2394-9
(2) Patel D, Kopec J, Fitzpatrick F, McCorvie TJ, Yue WW. Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. Scientific reports. 2016;6:23748
List of Contributors
This project is managed by Prof. Vincent Voelz at Temple University.
Dr. Voelz's research focuses on using new simulation methods to unravel the mysteries of how proteins self-assemble into their functional folds, and to design folding and binding properties of proteins and peptide mimetics from first principles. The Voelz Lab participates in the Folding@home project, hosting two servers at Temple University. Dr. Voelz was formerly a postdoctoral scholar in the Vijay Pande lab at Stanford University.
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