Liberty University
Master of Medical Science: Biopsychology
BCHM 551
Assignment 2
Faith Sola
L28844810
October 4, 2019
Words: 935
1. Phenylalanine (Phe) is a glucogenic and ketogenic essential aromatic amino acid that exists in
two arrangements: L-phenylalanine (PA) and D-phenylalanine. L- phenylalanine is an essential
amino acid, therefore its abundance in the human body is indicative of diet. Soy products, eggs,
seafood, and certain meats are rich in L- phenylalanine. In addition, L- phenylalanine can be
metabolized into proteins and signaling molecules. On the other hand, D- phenylalanine is
synthesized for medical applications. To know how the products of phenylalanine metabolism
are utilized, it is important to understand the fate of proteins when ingested. Proteins are ingested
and denatured in the stomach by protein pepsin into smaller peptides that travel through the
small intestine until they are hydrolyzed by other enzymes, transported intracellularly and
undergo hydrolysis, and transported in portal blood to liver or peripheral tissues where they can
be taken up and used or continue to pass through circulation until needed. In the liver,
phenylalanine is converted to tyrosine (i.e., L-tyrosine) by phenylalanine hydroxylase (PAH);
both phenylalanine and tyrosine are needed for melanogenesis and the synthesis of fumarate and
acetoacetate, thyroxine, catecholamines, and proteins. Phenylalanine can also be metabolically
disposed through transamination utilizing phenylpyruvate (PLP) to phenylpyruvate and further
metabolized to phenyllactate and phenylacetyl-CoA, the final metabolites in this pathway.
Phenylketonuria (PKU) and non-PKU hyperphenylalaninemia (HPA) are autosomal recessive
amino acid defects resulting from a full deficiency or partial deficiency of hepatic PAH,
respectively.1 The deficiency results in impaired hydroxylation of phenylalanine to tyrosine
manifested as elevated phenylalanine plasma levels and corresponding low tyrosine levels.
Normal serum levels of PA are less than 0.24mM; however, in individuals with HPA and PKU,
serum levels range from 0.24mM to 0.9mM and above 0.9mM, respectively. Both conditions
1
result from mutations to the PAH enzyme, therefore, severity and clinical presentation of
symptoms vary considerably between individuals. Variability can also result from the
demographics of the patient and their ingestion of PA-based on their diet.
2. PAH is coordinated with protein amino acid residues and molecular oxygen. BH cofactor is
4
likewise coordinated with molecular oxygen. The cofactor binding site represents a mutational
“hot spot” in which up to 400 different mutations could variably lower the affinity for the
cofactor, requiring an increased concentration of the cofactor to saturate the binding site and
therefore a higher than expected frequency of BH -responsive enzymes. The single-nucleotide
4
mutations, fluctuating in amino acid changes and location of the mutation, can determine
whether a patient might be responsive to BH therapy and is one possible explanation for a large
4
number of BH -therapy-responsive individuals in PAH deficient PKU and HAP patients.
4
3. Evaluation of urine can measure the levels of pterin metabolites such as biopterin. Low levels
of biopterin are indicative of a deficiency. A BH loading test in which infants suspected of BH
4 4
deficiency are administered BH can also be performed. In this case, PA levels will drop
42
significantly upon BH administration. Blood PA levels using the Guthrie bacterial inhibition
4
assay and a quantitative amino acid analysis can also be used as a screen test compared to
expensive genetic tests.1
4. For excess PA to be converted to tyrosine via PAH, PAH needs a dioxygen molecule and a
BH4 molecule. It was initially believed that all individuals with PKU or HPA had a primary
deficiency of PAH. It is now recognized that up to 2% of PKU cases are due to defects in the
BH4 recycling system. Patients with BH deficiency can still portray elevated PA levels and
4
develop neurological problems despite a low-PA diet. The poor outcome could be during in part
to the requirement of BH of two other enzymes, tryptophan hydroxylase, and tyrosine
4
hydroxylase, both of which are important for catecholamine and neurotransmitter synthesis.
1
Therefore, neurological problems in BH deficiency could potentially be caused by the decreased
4
formation of norepinephrine and serotonin. It’s also important to note that the severity of PA-
restriction in a diet is reduced in BH deficiency and some patients could even tolerate a normal
4
diet. On the other hand, patients with defective PAH enzymes will respond positively with a
substantial decrease in PA ingestion levels. Fortunately, BH supplementation therapy partnered
4
with a low-PA diet can effectively decrease serum PA levels in 41%-60% of HPA and PKU
patients with defective PAH enzymes.1
5. Impaired brain development with other neurological symptoms is the hallmark of untreated
PKU in diagnosed patients. Symptoms such as cerebral and basal ganglia dysfunction, rigidity,
hypotonia, hyperactivity seizures, gait abnormalities, unstable temperature regulation, and a
“mousy” odor of skin, hair, and urine are most common in patients with PKU and HPA. These
1
symptoms are first recognized in infants unable to meet early developmental milestones and if
not treated, symptoms can progress rapidly thereon.
As mentioned earlier, the metabolic disposal of excess PA involves two competitive
pathways: the first converts PA into phenyllactate and phenylacetyl-CoA through transamination,
and the second converts PA into tyrosine and later citric acid cycle intermediates utilizing PAH.
In PKU, PAH is ineffective, so the alternate transaminase pathway is the only available route.
However, PA cannot be further metabolized in that route, and PA and its metabolites accumulate
in the blood, urine, and tissues as a result. The precise cause of brain damage is unclear and
multifactorial. Possible causes of impaired brain development can be due to the accumulation of
aromatic metabolites of PA in neural tissues that can inhibit the synthesis of substances required
for normal brain growth, increased competitive inhibition of transport of other amino acids
required for protein synthesis in the brain, increased oxidative stress due an accumulation of
reactive oxygen species (ROS), and altered myelin structure and function.
References
1. Anderson W, Mitchell S. Phenylketonuria. In: Glew R, Rosenthal M, eds. Clinical Studies in
Medical Biochemistry. 3rd ed. Oxford University Press; 2007:204-215.
2. Blau N. Tetrahydrobiopterin Deficiency. National Organization for Rare Disorders.
https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/. Published 2018.
