Aromatic Amino Acid Metabolism Flashcards
What is phenylalanine catabolized to
Tyrosine
What can tyrosine form into
When does tyrosine become an essential amino acid
When the body is not getting enough phenylalanine (an actual essential amino acid)
What enzyme converts phenylalanine to tyrosine
Phenylalanine hydroxylase
Features of the Phenylalanine hydroxylase reaction
Hydroxylation of phenylalanine is irreversible so phenylalanine cannot be derived from tyrosine.
Phenylalanine hydroxylase uses the co-enzyme tetrahydrobiopterin (BH4) to supply reducing equivalents for the hydroxylation reaction.
Over the course of the phenylalanine hydroxylase reaction tetrahydrobiopterin is oxidized to dihydrobiopterin.
Tetrahydrobiopterin is regenerated from dihydrobiopterin by dihydrobiopterin reductase in a reaction involving the oxidation of NADPH.
What is unique about Dihydrobiopterin
Dihydrobiopterin is unusual as an co-enzyme in that it is NOT derived from a vitamin precursor.
Instead, dihydrobiopterin is synthesized from GTP in a series of steps catalyzed by dihydrobiopterin synthetase.
What is Hyperphenylalaninemia
Hyperpheylalaninemia is defined as having abnormally high levels of phenylalanine in the blood. Greater than 2 mg/dL
What causes Classic Phenylketonuria
a deficiency of phenylalanine hydroxylase
Classic PKU is considered likely when plasma phenylalanine levels exceed 20 mg/dL when untreated.
Clinical features of classic PKU
Neurologic abnormalities include
tremors
ataxia
seizures
Neuropsychiatric issues include
attention and concentration problems
hyperactivity
anxiety
depression
Physical findings include:
fair hair and complexion
dry skin
eczema
Pathopysiology of Classic PKU
Excess phenylalanine caused by a deficiency of phenylalanine hydroxylase is converted to phenylpyruvate by transamination.
Phenylpyruvate is then decarboxylated to phenylacetate giving urine a musty smell, a tell tale feature of classic PKU.
Phenylpyruvate can also be reduced to phenyllactate, another metabolite that accumulates in the blood of phenylketonurics.
What causes intellectual disabilities in PKU
increased amounts of phenylalanine in the circulation inhibit the transport of tryptophan and tyrosine across the blood brain barrier since all three amino acids utilize the large neutral amino acid transporter to cross this barrier.
The reduced amounts of tryptophan and tyrosine reaching the brain, interfere with the synthesis of a number of neurotransmitters, contributing in part to the clinical manifestations of the disease
Therapy for PKU
Low protein, low phenylalanine diet - not just vegetarian diet as other foods (grains, some vegetables and fruits) can have significant phenylalanine content.
Medical formula - phenylalanine is restricted or absent, tyrosine is added
Monitoring of PKU
Phenylalanine levels are monitored to assess treatment effectiveness with a goal of keeping phenylalanine levels in the range of 2-6 mg/dL; frequency of monitoring depends on age and compliance.
Tyrosine levels are monitored to assure patients are getting adequate amounts of tyrosine from a diet restricted in phenylalanine.
PKU outcomes
Outcome is best if control is achieved before 1 month of age and maintained throughout a patient’s lifetime.
When treated early and consistently, IQ is typically in the normal range though it can be lower than unaffected siblings.
With ineffective control, risks are similar to untreated patients though generally less severe.
Non-nutrition intervention for PKU
Kuvan - a synthetic form of tetrahydrobiopterin
~40% of patients with PKU will show a response to Kuvan (assuming the phenylalanine hydroxylase in these patients has a relatively high Km for the coenzyme).
What is NeoPhe
NeoPhe (many other commercially available formulations) - a mixture of large neutral amino acidsDietary supplementation with large neutral amino acids (Tyr, Trp, Thr, Met, Val, Ile, Leu, and His).
All of these amino acids compete with phenylalanine for crossing the blood brain barrier and for the uptake of phenylalanine from the diet into the circulation.
Studies have shown some efficacy in reducing brain and circulating phenylalanine levels when combining supplements of large neutral amino acid with standard phenylalanine-restricted diets and with diets composed of natural protein
What is maternal PKU
Phe is a teratogen.
If the mother’s PKU is poorly controlled, more phenylalanine crosses the placenta and harms the fetus.
Thus, a baby can be affected by maternal PKU (mPKU) even though the baby itself does not have PKU.
Risks of maternal PKU
Signs and symptoms that maternal PKU has comprised fetal growth and development include microcephaly and growth retardation; congenital heart disease; neurologic abnormalities including hypertonia, hyperactivity, and cognitive impairment; and dysmorphic features including round face, broad flat nasal bridge, and short palpebral fissures.
The risks of these abnormalities are proportional to the degree of phenylalanine elevation in the mother during fetal development.
Features/pathophys of Tetrahydrobiopterin Deficiency
Defects in enzymes involved in the synthesis of dihydrobiopterin or the recycling of dihydrobiopterin to tetrahydrobiopterin can lead to a reduction in phenylalanine hydroxylase activity and elevated levels of phenylalanine.
Hyperphenylalaninemia caused by defects in dihydrobiopterin synthesis or recycling are identified by monitoring dihydrobiopterin reductase levels in the blood or tetrahydrobiopterin or its metabolites in the urine.
Clinical manifestations of tetrahydrobiopterin deficiency
Defects in tetrabiopterin synthesis account for only a small fraction of patients with elevated phenylalanine (~ 2%).
Hyperphenylalaninemia caused by tetrahydrobiopterin deficiency has been referred to as non-classical phenylketonuria or malignant phenylketonuria.
Individuals with tetrahydrobiopterin deficiency have clinical manefestations beyond those observed in classical phenylketonuria because tetrahydrobiopterin is a cofactor for hydroxylase enzymes involved in the formation of catecholamines/dopamine and serotonin, respectively.
Treat with Kuvan
Full catabolism of phenylalanine/tyrosine
What is alcaptonuria
The disease alcaptonuria is caused by a deficiency of homogentisate dioxygenase, which leads to the accumulation homogentisate.
Alcaptonurics have no clinical symptoms early in life except for a darkening of urine with time from the oxidation of homogentisic acid (staining of diapers).
Complications of Alcaptonuria
Although alcaptonurics do not have clinical symptoms early in life, as they age, pigmented homogentisic acid derivatives accumulate in connective tissues (ochronosis) leading to arthritis.
What is Type I Tyrosinemia (pathophys)
Type I tyrosinemia is the most severe form of the tyrosinemias.
The enzyme fumarylacetoacetase is defective in tyrosinemia type I.Furmarylacetoacetae accumulates and is converted to succinylacetone which is a mitochondrial toxin in the kidney that leads to renal tubular dysfunction.
Succinylacetone is also an inhibitor of heme synthesis and is a liver toxin.
Succinylacetone is also known to inhibit DNA repair enzymes and children with type I tyrosinemia have an elevated incidence of liver and other types of cancer.
Children with tyrosinemia I typically die within the first year of life.
Patients with tyrosinemia I have a characteristic cabbage-like odor.
