Metabolic Pathway for Phenylalanine and Tyrosine
Conversion of Phenylalanine to Tyrosine
- Phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine
- PAH is encoded by the PAH gene located in Chromosome 12 and consist of 13 exons
- Tetrameters with each monomer consisting of the catalytic site, regulator site, and subunit binding domain
- Phenylalanine hydroxylase is tetrahydrobiopterin (BH4) requiring enzyme
- Dihydrobioteridine reductase catalyzes the conversion of dihydrobiopteridine to tetrahydrobiopterin
- Deficiency of enzyme caused phenylketonuria
- PAH is encoded by the PAH gene located in Chromosome 12 and consist of 13 exons
- Tetrameters with each monomer consisting of the catalytic site, regulator site, and subunit binding domain
- Phenylalanine hydroxylase is tetrahydrobiopterin (BH4) requiring enzyme
- Dihydrobioteridine reductase catalyzes the conversion of dihydrobiopteridine to tetrahydrobiopterin
- Deficiency of enzyme caused phenylketonuria
Figure- Overview of Phenylalanine and Tyrosine Metabolism
Transamination of Tyrosine
- Tyrosine aminotransferase catalyzes the conversion to tyrosine to p-hydroxyphenylpyruvate
- Tyrosine aminotransferase is a Pyridoxal-5-phosphate requiring enzyme
- In the process, alpha-ketoglutarate is converted into glutamate
- Deficiency of the enzyme causes neonatal tyrosinemia (Type III)
Hydroxylation of p-hydroxyphenylpyruvate to homogentisate
- The reaction is catalyzed by an enzyme p-hydroxyphenylpyruvate hydroxylase (dioxygenase)
- Requires Vit C (ascorbate) for its activity
- Deficiency of the enzyme causes Tyrosinemia Type II
Oxidation of Homogentisate to 4-maleylacetoacetate
- Catalyzed by an enzyme homogentisate oxidase
Deficiency of the enzyme causes Alkaptonuria
Conversion of Maleylacetoacetase to 4-fumarylacetoacetate
- Catalyzed of by an enzyme isomerase
- Conversion of 4-fumarlyacetoacetate to acetoacetate and fumarate
- Catalyzed of by an enzyme 4-fumarlyacetoacetate hydrolase
- Deficiency of the enzyme causes Tyrosinemia Type-I
Inborn Errors of Phenylalanine and Tyrosine Pathway
Phenylketonuria: PAH DeficiencyPrevalence
- Rare Genetic Disorder of Phenylalanine Metabolism
- The most common form of amino acid disorders with US prevalence of 1 in 10,000 to 1 in 15,000
- Rare Genetic Disorder of Phenylalanine Metabolism
- The most common form of amino acid disorders with US prevalence of 1 in 10,000 to 1 in 15,000
Biochemical Basis
- Deficiency of enzyme that converts phenylalanine to tyrosine
- Mutation of gene encoding phenylalanine hydroxylase (PAH) or dihydrobiopteridine reductase.
- Mutations include missense (62%) and the remainder of insertion or deletions, nonsense, splicing defects, etc.
- Increased Blood Phenylalanine (>1200 µM) & Urine Phenylketones
- Deficiency of enzyme that converts phenylalanine to tyrosine
- Mutation of gene encoding phenylalanine hydroxylase (PAH) or dihydrobiopteridine reductase.
- Mutations include missense (62%) and the remainder of insertion or deletions, nonsense, splicing defects, etc.
- Increased Blood Phenylalanine (>1200 µM) & Urine Phenylketones
Pathological Manifestation
-In uncontrolled PKU, the Phenylalanine (Phe) level is >1200 µM in blood
-Impairment caused by the accumulation of toxic by-products of Phe.
-Clinical manifestation includes growth failure, microcephaly, seizures, and intellectual impairment.
- Two possible mechanisms of clinical manifestation including neurological disorders.
-In uncontrolled PKU, the Phenylalanine (Phe) level is >1200 µM in blood
-Impairment caused by the accumulation of toxic by-products of Phe.
-Clinical manifestation includes growth failure, microcephaly, seizures, and intellectual impairment.
- Two possible mechanisms of clinical manifestation including neurological disorders.
a) Decreased or absent PAH activity can lead to a deficiency of Tyr and its downstream products, including melanin, l-thyroxine, and the catecholamines neurotransmitters.
b) Elevated Phe competes for large neutral amino acid Transporter blocking transport Tyr and Trp, thereby reducing serotonin and catecholamines
-Decreased melanin synthesis leads to hyperpigmentation
-Decreased melanin synthesis leads to hyperpigmentation
Diagnosis
Screening test:
Screening test:
Blood phenylalanine (normal- <120 µM) and tyrosine (high phenylalanine & Low tyrosine)- Chromatographic techniques
Guthrie Test: B. substilis Inhibition test- use of bacteria to measure the presence of high Phe in a sample
Confirmed by Mutation analysis of the PAH gene using southern blot, Restriction analysis, Sequencing analysis
Guthrie Test: B. substilis Inhibition test- use of bacteria to measure the presence of high Phe in a sample
Confirmed by Mutation analysis of the PAH gene using southern blot, Restriction analysis, Sequencing analysis
Treatment
Diet
Diet
- A low Phe diet is used for treatment
-Regimen intake of low protein diets and exclusion of high protein diets such as eggs, milk, cheese, meat, poultry, fish, dried beans, and legumes
Monitoring Phe (Target <600 µM)
Kuvan (BH4) in BH4 responsive individuals
Palynziq- FDA approved enzyme substitution therapy that degrades and clear Phe from circulations.
Type I Tyrosinemia: Fumaryl-Acetoacetate Hydrolase (FAH) Deficiency
Prevalence:
- 1 in 100,000 to 120,000
Inheritance Pattern
- Autosomal Recessive
Biochemical Basis
- Defective FAH gene (15q25.1), leading to accumulation of fumarylacetoacetate, succinylacetoacetate, and succinylacetone
Pathological Manifestation
- Accumulation of fumarylacetoacetate causes cellular damage and apoptosis in liver
- Succinylacetone interferes hepatic enzyme including para hydroxyphenyl pyruvic acid hydroxylase and ALA-dehydratase
Diagnosis (Newborn screening)-
- Elevated blood tyrosine
- Increased succinylacetone in blood and urine -Low delta-ALA dehydratase enzyme activity
Molecular diagnosis
-Sequence analysis of the FAH gene
-Regimen intake of low protein diets and exclusion of high protein diets such as eggs, milk, cheese, meat, poultry, fish, dried beans, and legumes
Monitoring Phe (Target <600 µM)
Kuvan (BH4) in BH4 responsive individuals
Palynziq- FDA approved enzyme substitution therapy that degrades and clear Phe from circulations.
Type I Tyrosinemia: Fumaryl-Acetoacetate Hydrolase (FAH) Deficiency
Prevalence:
- 1 in 100,000 to 120,000
Inheritance Pattern
- Autosomal Recessive
Biochemical Basis
- Defective FAH gene (15q25.1), leading to accumulation of fumarylacetoacetate, succinylacetoacetate, and succinylacetone
Pathological Manifestation
- Accumulation of fumarylacetoacetate causes cellular damage and apoptosis in liver
- Succinylacetone interferes hepatic enzyme including para hydroxyphenyl pyruvic acid hydroxylase and ALA-dehydratase
Diagnosis (Newborn screening)-
- Elevated blood tyrosine
- Increased succinylacetone in blood and urine -Low delta-ALA dehydratase enzyme activity
Molecular diagnosis
-Sequence analysis of the FAH gene
Treatment
- Nitisinone (Orfadin), 22-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC), which blocks para hydroxyphenyl pyruvic acid dioxygenase (p-HPPD), and prevents the accumulation of fumarylacetoacetate with dietary management
Type II Tyrosinemia: Tyrosine Aminotransferase (TAT) Deficiency (Richner Hanhart syndrome)
- Nitisinone (Orfadin), 22-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC), which blocks para hydroxyphenyl pyruvic acid dioxygenase (p-HPPD), and prevents the accumulation of fumarylacetoacetate with dietary management
Type II Tyrosinemia: Tyrosine Aminotransferase (TAT) Deficiency (Richner Hanhart syndrome)
Prevalence
Rare less than 1 in 1,000,000
Rare less than 1 in 1,000,000
Inheritance Pattern
- Autosomal Recessive
Biochemical Basis
- Defective TAT gene (16q22.2), leading to accumulation of tyrosine
- Increased formation and excretion of p-hydroxyphenypyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate in urine
Pathological Manifestation
- Ophthalmic manifestation- recalcitrant pseudodendritic keratitis
Diagnosis (Newborn screening)
- Elevated blood tyrosine (usually > 500 µM)
- Presence of p-hydroxyphenypyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate in urine
Molecular diagnosis
-Sequence analysis of the TAT gene
- Autosomal Recessive
Biochemical Basis
- Defective TAT gene (16q22.2), leading to accumulation of tyrosine
- Increased formation and excretion of p-hydroxyphenypyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate in urine
Pathological Manifestation
- Ophthalmic manifestation- recalcitrant pseudodendritic keratitis
Diagnosis (Newborn screening)
- Elevated blood tyrosine (usually > 500 µM)
- Presence of p-hydroxyphenypyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate in urine
Molecular diagnosis
-Sequence analysis of the TAT gene
Treatment
- Dietary management
Tyrosinemia III (Neonatal ): Hydroxy-phenylalanine Pyruvate Hydroxylase Deficiency
Prevalence:
- Rarest less than 1 in 1,000,000
Inheritance Pattern
- Autosomal Recessive
Biochemical Basis
- Defective HPD gene (16q22.2), leading to accumulation of tyrosine
- Increased formation and excretion of p-hydroxyphenypyruvate, p-hydroxyphenyllactate and p-hydroxyphenylacetate in urine
Pathological Manifestation
-Neurological manifestation with intellectual disability or ataxia
- No liver involvement
Diagnosis (Newborn screening)-
- Elevated blood tyrosine (usually > 350 to 650 µM)
- Presence of p-hydroxyphenypyruvate, p-hydroxyphenyllactate and p-hydroxyphenylacetate in urine
Molecular diagnosis
-Sequence analysis of the HPD gene
Treatment
- Dietary management
Alkaptonuria: Homogentisate Oxidase Deficiency
Prevalence:
- In US, 1 in 250,000 to 1,000,000
Inheritance Pattern
- Autosomal Recessive
Biochemical Basis
- Defective HGD gene (3q13.33), leading to accumulation of homogentisate in blood and urine,
- Urine to turn dark on standing
Pathological Manifestation
- Accumulation of HGA and its oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis
- Brown pigmentation of the sclera is observed
- Ear cartilage pigmentation is seen in the concha and antihelix
- Ochronotic arthritis
Diagnosis (New born screening)
-Urinary HGA > 1 gm/day (Normal- 30mg/day)
Molecular diagnosis
-Sequence analysis of HGD gene
- Dietary management
Tyrosinemia III (Neonatal ): Hydroxy-phenylalanine Pyruvate Hydroxylase Deficiency
Prevalence:
- Rarest less than 1 in 1,000,000
Inheritance Pattern
- Autosomal Recessive
Biochemical Basis
- Defective HPD gene (16q22.2), leading to accumulation of tyrosine
- Increased formation and excretion of p-hydroxyphenypyruvate, p-hydroxyphenyllactate and p-hydroxyphenylacetate in urine
Pathological Manifestation
-Neurological manifestation with intellectual disability or ataxia
- No liver involvement
Diagnosis (Newborn screening)-
- Elevated blood tyrosine (usually > 350 to 650 µM)
- Presence of p-hydroxyphenypyruvate, p-hydroxyphenyllactate and p-hydroxyphenylacetate in urine
Molecular diagnosis
-Sequence analysis of the HPD gene
Treatment
- Dietary management
Alkaptonuria: Homogentisate Oxidase Deficiency
Prevalence:
- In US, 1 in 250,000 to 1,000,000
Inheritance Pattern
- Autosomal Recessive
Biochemical Basis
- Defective HGD gene (3q13.33), leading to accumulation of homogentisate in blood and urine,
- Urine to turn dark on standing
Pathological Manifestation
- Accumulation of HGA and its oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis
- Brown pigmentation of the sclera is observed
- Ear cartilage pigmentation is seen in the concha and antihelix
- Ochronotic arthritis
Diagnosis (New born screening)
-Urinary HGA > 1 gm/day (Normal- 30mg/day)
Molecular diagnosis
-Sequence analysis of HGD gene
Treatment
- Dietary management
- Dietary management
(For MCQ Practice click here)
Lecture Video on Phenylalanine and Tyrosine Metabolism
Phenylketonuria: Biochemical Basis, Diagnosis, and Treatment
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