Aromatic Amino Acid Metabolism

Question 1

What is phenylalanine catabolized to

Answer 1

Tyrosine

Question 2

What can tyrosine form into

Answer 2

Question 3

When does tyrosine become an essential amino acid

Answer 3

When the body is not getting enough phenylalanine (an actual essential amino acid)

Question 4

What enzyme converts phenylalanine to tyrosine

Answer 4

Phenylalanine hydroxylase

Question 5

Features of the Phenylalanine hydroxylase reaction

Answer 5

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.

Question 6

What is unique about Dihydrobiopterin

Answer 6

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.

Question 7

What is Hyperphenylalaninemia

Answer 7

Hyperpheylalaninemia is defined as having abnormally high levels of phenylalanine in the blood. Greater than 2 mg/dL

Question 8

What causes Classic Phenylketonuria

Answer 8

a deficiency of phenylalanine hydroxylase

Classic PKU is considered likely when plasma phenylalanine levels exceed 20 mg/dL when untreated.

Question 9

Clinical features of classic PKU

Answer 9

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

Question 10

Pathopysiology of Classic PKU

Answer 10

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.

Question 11

What causes intellectual disabilities in PKU

Answer 11

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

Question 12

Therapy for PKU

Answer 12

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

Question 13

Monitoring of PKU

Answer 13

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.

Question 14

PKU outcomes

Answer 14

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.

Question 15

Non-nutrition intervention for PKU

Answer 15

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).

Question 16

What is NeoPhe

Answer 16

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

Question 17

What is maternal PKU

Answer 17

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.

Question 18

Risks of maternal PKU

Answer 18

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.

Question 19

Features/pathophys of Tetrahydrobiopterin Deficiency

Answer 19

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.

Question 20

Clinical manifestations of tetrahydrobiopterin deficiency

Answer 20

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

Question 21

Full catabolism of phenylalanine/tyrosine

Answer 21

Question 22

What is alcaptonuria

Answer 22

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).

Question 23

Complications of Alcaptonuria

Answer 23

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.

Question 24

What is Type I Tyrosinemia (pathophys)

Answer 24

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.

Question 25

Treatment for Type I Tyrosinemia

Answer 25

The major problem in type I tyrosinemia is the accumulation of the toxic metabolite, succinylacetone.

Type I tyrosinemia can be treated with an inhibitor of hydroxyphenylpyruvate dioxygenase reducing levels of fumarylacetoacetate and thereby succinylacetone.

Question 26

What is Type II Tyrosinemia

Answer 26

The enzyme tyrosine aminotransferase, AKA tyrosine transaminase, is defective in tyrosinemia type II

Tyrosinemia type II results in eye and skin lesions and intellectual disabilities.

Question 27

Tyrosinemia type II treatment

Answer 27

diet low in phenylalanine and tyrosine.

Question 28

What is Type III Tyrosinemia

Answer 28

The enzyme hydroxyphenylpyruvate dioxigenase is defective in type II tyrosinemia.

Type III is the rarest form of the tyrosinemias.

Clinical features include intellectual disability, seizures, and periodic loss of balance and coordination (intermittent ataxia).

Question 29

Treatment for Type III Tyrosinemia

Answer 29

diet low in phenylalanine and tyrosine.

Question 30

Catabolism of trytophan and lysine

Answer 30

Question 31

What are the metabolic fates of tryptophan in primary degradation pathway

Answer 31

The primary degradative pathway for tryptophan involves the enzyme indolamine dioxygenase and proceeds through α-ketoadipate to pyruvate and acetoacetate

Question 32

Trytophan fates from the normal degradative pathway beginning with the enzyme indoamine dioxygenase

Answer 32

This pathway is a source of formate in cells, which can enter one-carbon metabolism as 5-formyl-tetrahydrofolate (used in purine synthesis).

Kynurenine can be converted to kynurenate, which is an antagonist for glutamate receptors in the brain and is thought to be neuroprotective.

Another branchpoint in the pathway of tryptophan catabolism synthesizes quinolic acid, which is an agonist for NMDA-sensitive glutamate receptors and is thought to be neurotoxic.

Imbalances in the ratio of kynurenate and quinolinic acid are thought to contribute to the pathogenesis of several neurological diseases (relevant to upcoming neurology section of HSHD2) .

Importantly, quinolinic acid can go on to produce niacin, yes, niacin. Approximately 50% of the body’s requirement for niacin is derived from the metabolism of tryptophan.

Question 33

Products of trytophan alternative pathway

Answer 33

The enzyme tryptophan hydroxylase diverts tryptophan from its normal degradative pathway into an alternative pathway leading to serotonin and melatonin.

Tryptophan hydroxylase requires tetrahydrobiopterin as a coenzyme and so this pathway involved in the synthesis of the neurotransmitters serotonin and melatonin would be disrupted in patients with tetrahydrobiopterin deficiency.

Question 34

Two major fates of Histidine breakdown

Answer 34

Degradation and histamine synthesis

Question 35

Process of histidine degradation

Answer 35

The α -amino group of histidine is lost as ammonia in the first step of histidine degradation.

The bulk of the histidine molecule ends up as glutamate which can be converted to α - ketoglutarate by transamination and used for glucose synthesis (histidine is therefore glucogenic).

The remaining carbon and nitrogen atoms from the histidine side chain get transferred as a formimino group to tetrahydrofolate.

This carbon enters the pool for one carbon metabolism as N5-formamino-tetrahydrofolate and is subsequently converted to N 5 ,N 10 -methenyl tetrahydrofolate (used as a substrate for thymidylate synthase).

Measurements of FIGLU levels in the urine has been used as an indicator of folic acid deficiency.

Question 36

Process of histamine formation

Answer 36

Histidine is converted to histamine via a decarboxylation reaction catalyzed by histidine decarboxylase