University of the People

Written Assignment Unit 7

Introduction to Biochemistry

 
 

 
The metabolic disease I will be discussing is phenylketonuria.

A brief background on phenylketonuria

Asbjorn Folling, in 1934, discovered phenylpyruvic acid in the urine samples of 10 mentally

deficient patients (Phenylketonuria, 1967). Ferric chloride reacts with the compound

phenylpyruvic acid to form a greenish-blue color (Phenylketonuria, 1967). This became the

standard test for detecting phenylketonuria (Phenylketonuria, 1967).

Phenylketonuria (PKU) is an autosomal recessive disorder that affects the way the body

processes an amino acid called phenylalanine (Phenylketonuria, 1967). The heterozygous parents

of the children affected by this disorder are clinically normal, and they lack phenylpyruvic acid

in their urine (Phenylketonuria, 1967). The disorder is caused by a defect in the gene that

produces an enzyme called phenylalanine hydroxylase, which is needed to break down

phenylalanine (Phenylketonuria, 1967).

According to Justice & Smith (1975), they stated in an article that when someone with PKU eats

foods that contain protein, the body cannot break down the phenylalanine properly. This leads to

a buildup of phenylalanine and its byproducts in the blood and brain, which can cause brain

damage, intellectual and developmental disabilities, behavioral problems, seizures, skin

problems, and other health complications.

PKU is typically diagnosed in newborns through routine newborn screening tests. Treatment

involves following a strict low-phenylalanine diet, which limits the intake of high-protein foods

such as meat, poultry, fish, dairy products, and eggs, as well as artificial sweeteners and certain

grains and vegetables. PKU patients also need to take a special phenylalanine-free formula that
provides them with the necessary nutrients. Without treatment, PKU can lead to permanent

intellectual disability and developmental delays (Sumaily, 2017). However, with early diagnosis

and treatment, many people with PKU can lead normal lives and avoid the serious health

complications associated with the disorder (Sumsily, 2017).

Mechanism of the Phenylketonuria Pathway

Phenylalanine is converted into another amino acid called tyrosine through a series of enzymatic

reactions. However, people with PKU lack an enzyme called phenylalanine hydroxylase (PAH)

which is necessary for the conversion of phenylalanine to tyrosine (Sumaily, 2017). As a result,

phenylalanine builds up in the blood and can cause brain damage and other health problems

(Sumaily, 2017).

The pathway for phenylalanine metabolism involves several steps. First, phenylalanine is

transported into cells and converted to tyrosine by the enzyme PAH (Sumaily, 2017). This

reaction requires the cofactor tetrahydrobiopterin (BH4), which is produced from guanosine

triphosphate (GTP) through a series of enzymatic reactions (Sumaily, 2017). In people with

PKU, mutations in the gene that codes for PAH or other enzymes involved in the pathway can

result in a reduction or complete loss of enzyme activity, leading to a buildup of phenylalanine

and a deficiency of tyrosine (Sumaily, 2017). This can cause a range of symptoms, including

intellectual disability, seizures, behavioral problems, and skin disorders (Sumaily, 2017).

Characteristics of Phenylalanine (Phe) and Tyrosine (Tyr)

An important amino acid with a nonpolar side chain is phe (C9H11NO2). Phe is an electrically

neutral amino acid that promotes interactions between hydrophobic molecules, much like all
other nonpolar amino acids (Sumaily, 2017). Tyr is a precursor to Phe, demonstrating Tyr's

significance in cellular functions. Tyr, which has the chemical formula C9H11NO3, is a non-

essential -amino acid, in contrast to Phe (Sumaily, 2017). Despite being uncharged, this

proteinogenic amino acid has a polar side chain. Tyr serves a variety of purposes, making it an

essential amino acid (Sumaily, 2017).

Phenylalanine hydroxylase (PAH)

PAH catalyzes the hydroxylation of Phe to produce Tyr. Pterin-dependent amino acid

hydroxylases, of which PAH, tryptophan hydroxylase, and tyrosine hydroxylase are three

members, are a class of monooxygenases that catalyze reactions using tetrahydrobiopterin 4

(BH4), a pteridine cofactor, and non-heme iron (Sumaily, 2017).

Discuss which gene or genes are aberrantly regulated and by what epigenetic mechanisms.

Phenylketonuria (PKU) is caused by mutations in the gene that encodes phenylalanine

hydroxylase (PAH), which is needed to break down the amino acid phenylalanine (Sumaily,

2017). These mutations result in reduced or absent PAH activity, leading to the buildup of

phenylalanine and its byproducts in the blood and brain. However, it is not well understood how

these mutations lead to aberrant regulation of the PAH gene and what epigenetic mechanisms are

involved (Sumaily, 2017).

According to a study by Dobrowolski et al. (2016), epigenetic modifications such as DNA

methylation and histone modifications may play a role in the regulation of the PAH gene in

PKU. DNA methylation is a process by which methyl groups are added to DNA, which can

affect gene expression by blocking the binding of transcription factors and other regulatory
proteins (Dobrowolski et al., 2016). In PKU, it has been suggested that the PAH gene may be

hypermethylated, resulting in reduced PAH expression and activity (Dobrowolski et al., 2016).

According to Bollatti & Baccarrelli (2010), histone modifications, such as acetylation and

methylation, can also affect gene expression by altering the accessibility of chromatin to

transcription factors and other regulatory proteins. Evidence suggests that histone modifications

may be involved in the regulation of the PAH gene in PKU (Bollatti & Baccarrelli, 2010).

According to Bollatti & Baccarrelli (2010), their study showed that the PAH gene is associated

with certain histone modifications that are indicative of active transcription and that these

modifications are reduced in PKU patients.

Describe how this alters a pathway, resulting in the disorder/disease.

The altered regulation of the PAH gene in phenylketonuria (PKU) leads to reduced or absent

activity of the PAH enzyme (Sumaily, 2017). This results in the accumulation of the amino acid

phenylalanine and its byproducts in the blood and brain (Sumaily, 2017). The accumulation of

phenylalanine and its byproducts is what damages the brain and results in the various symptoms

of PKU (Sumaily, 2017).

The PAH enzyme is essential in the metabolic pathway that converts phenylalanine to another

amino acid called tyrosine. In the absence or reduction of PAH activity, the conversion of

phenylalanine to tyrosine is impaired, leading to the accumulation of phenylalanine in the body

(Sumaily, 2017). Increased levels of phenylalanine can have toxic effects on the brain, disrupting

the formation and functioning of neural connections. This can cause intellectual and
developmental disabilities, behavioral problems, and other neurological complications that are

characteristic of PKU.

Overall, the aberrant regulation of the PAH gene and the resulting reduction in PAH activity

disrupt the metabolic pathway that converts phenylalanine to tyrosine, leading to the

accumulation of phenylalanine and its toxic byproducts. This accumulation ultimately causes the

characteristic symptoms and complications of PKU.

References

Bollati, V., & Baccarelli, A. A. (2010). Environmental epigenetics. Heredity, 105(1), 105–112.

https://doi.org/10.1038/hdy.2010.2

Dobrowolski, S., Lyons-Weiler, J., Spridik, K., Vockley, J., Skvorak, K. J., & Biery, A. (2016).

DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAH enu2 mouse

model of phenylketonuria. Molecular Genetics and Metabolism, 119(1–2), 1–7.

https://doi.org/10.1016/j.ymgme.2016.01.001

Justice, P., & Smith, G. F. (1975). PKU: Phenylketonuria. The American Journal of Nursing,

75(8), 1303–1305. https://doi.org/10.2307/3423603

Phenylketonuria. (1967). The British Medical Journal, 3(5558), 124–125.

http://www.jstor.org/stable/20388747

Sumaily, K. M. (2017, December 1). Phenylketonuria: A new look at an old topic, advances in

laboratory diagnosis, and therapeutic strategies. PubMed Central (PMC).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669513/
Widaman, K. F. (2009). Phenylketonuria n Children and Mothers: Genes, Environments,

Behavior. Current Directions in Psychological Science, 18(1), 48–52.

http://www.jstor.org/stable/20695993