Phenylketonuria (PKU)TAM NGUYEN

CHEM 4700

Introduction

PKU is a common inborn metabolic disorder caused by a deficiency of the liver enzyme phenylalanine hydroxylase.

It prevents normal metabolization of phenylalanine (Phe), one of the essential amino acids that cannot be manufactured by the body and must therefore be consumed in protein rich foods.

Untreated individuals may give off a musty odor and they excrete large amounts of phenylalanine in their urine.

Cause

The most common cause of PKU is a mutation in the gene coding for the enzyme phenylalanine hydroxylase (PAH).

The mutation causes a deficiency in the activity of this enzyme and leads to aberrant amino acid metabolism.

Localized misfolding occurs, in which the misfolding spreads until the entire four-subunit enzyme can no longer function

The buildup of phenylalanine hinders the development of the brain and causes mental retardation

Symptoms

Severe intellectual and developmental disabilities

Behavioral or social problems

Stunted or slow growth

A musty odor in urine, breath, or skin that is a result of the extra phenylalanine in the body

Fair skin and blue eyes, due to the body’s failure to transform phenylalanine into melanin (the pigment responsible for a person’s coloring).

Structure

The structure of PAH. (A) The modeled structure of full-length tetrameric PAH (composite model prepared by combining the structures of tetrameric human PAH (residues 118-452; PDB 2PAH) and dimeric rat PAH (residues 19-427; PDB 2PHM)). (B) Detailed structure of PAH including thienylalanine and BH4 (PDB 1KW0).

Biochemical Nature

Phenylalanine hydroxylase in complex with cofactor tetrahydrobiopterin (BH4)

The structure of PAH is shown along with its interaction points to the cofactor bound to the active site proving an ideal basis for structure-based drug design.

Phenylalanine to Tyrosine

Enzymes are structures that allow amino acids to combine by acting on a substrate and producing a new product.

Individuals with PKU have a deficiency in the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine.

The enzyme catalyzes the hydroxylation of phenylalanine on the phenyl ring at the 4 position, to make tyrosine.

Metabolic Pathways

Individuals with PKU, phenylalanine could not converted into tyrosine, phenylalanine accumulates and tyrosine is deficient.

Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate.

Metabolites include phenylacetate, phenylpyruvate, and phenethylamine.

Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic.

Phenylalanine vs. Tyrosine

The coiled-coil motif is visible in the center of each tetramer. The iron bound in the active sites are shown as red spheres

NMR Structure

http://www.drugbank.ca/spectra/nmr_one_d/1177

Treatment

The only treatment available for PKU is a diet where phenylalanine levels are strictly limited.

Meat, fish, eggs, cheese, milk products, legumes, and bread are all foods that have high levels of phenylalanine.

Artificial protein substitutes are given which contain amino acids without phenylalanine

Permanent monitoring of blood phenylalanine levels.

Screening Test

Newborn screening allows early identification and early implementation of treatment.

Usually a few drops of blood are obtained by a small prick on the heel, placed on a card and then sent for measurement.

Blood tested for excess phenylalanine, in which blood was placed on agar plate with bacteria that need phenylalanine to grow.

References

Leandro, João, Nina Simonsen, Jaakko Saraste, Paula Leandro, and Torgeir Flatmark. "Phenylketonuria as a Protein Misfolding Disease: The Mutation PG46S in Phenylalanine Hydroxylase Promotes Self-association and Fibril Formation." Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease (2010): 106-20. Print.

Fusetti, F. "Structure of Tetrameric Human Phenylalanine Hydroxylase and Its Implications for Phenylketonuria." Journal of Biological Chemistry (1998): 16962-6967. Print.

Underhaug, Jarl, Oscar Aubi, and Aurora Martinez. "Phenylalanine Hydroxylase Misfolding and Pharmacological Chaperones." Current Topics in Medicinal Chemistry (2013): 36-42. Print.

“What Are Common Symptoms of Phenylketonuria (PKU)?” Web. 16 Mar. 2015. <http://www.nichd.nih.gov/health/topics/pku/conditioninfo/Pages/symptoms.aspx>.

"Introduction to Phenyketonuria." Faq. Web. 16 Mar. 2015. <https://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa metab cases/PKU Cases/faq.htm>.