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Phenylalanine & Tyrosine Metabolism/Disorders
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Phenylalanine & Tyrosine Metabolism/Disorders

Phenylalanine and Tyrosine
  • Phenylalanine is an essential amino acid.
  • Tyrosine is a nonessential amino acid but it (along with arginine, cysteine, and histidine) are all conditionally essential.
Energy Metabolites
  • Tyrosine passes through an intermediate (4-hydroxyphenylpyruvic acid) to form homogentisate.
  • Homogentisate (homogentisic acid (HGA)) metabolizes to maleylacetoacetate via homogentisate oxidase (aka homogentisate 1,2-dioxygenase).
  • Maleylacetoacetate isomerizes to fumarylacetoacetate via maleylacetoacetate isomerase.
  • Fumarylacetoacetate catabolizes into fumarate (again, a glucose glucogenic metabolite) and acetoacetate (again, a ketogenic metabolite) via fumarylacetoacetate hydrolase.
  • Phenylalanine irreversibly converts to tyrosine via phenyalanine hydroxylase.
    • Thus, tyrosine CANNOT create phenylalanine (the pathway only goes from phenylalanine to tyrosine).
  • Also, the phenomenon of the sparing action of tyrosine on the dietary requirement of phenylalanine – which refers to the fact that tyrosine ingestion makes up for the demand for phenylalanine ingestion and is especially important in phenylketonuria wherein there is toxic levels of phenylalanine due to an inability to break it down.
  • Key catabolic derivatives of tyrosine:
    • Melanin
    • The Catecholamines
    • Thyroglobulin tyrosine residues
    • Energy Metabolites: fumarate, which is glucogenic and enters the citric acid cycle and acetoacetate, which is ketogenic.
  • Phenylalanine metabolism requires…
    • Oxygen (O2)
    • & Tetrahydrobiopterin (BH4), which converts to dihydrobiopterin (BH2).
  • Tyrosine converts to DOPA via tyrosine hydroxylase.
    • This reaction involves the addition of a hydroxyl, just as the conversion of phenylalanine to tyrosine did.
  • Just like phenylalanine hydroxylase, tyrosine hydroxylase requires:
    • Oxygen (O2)
    • & Tetrahydrobiopterin (BH4) conversion to dihydrobiopterin (BH2)
Melanin
  • In a section of skin – melanocytes lie deep within the epidermis (between the stratum basal and stratum spinosum of the epidermis); they produce melanin from tyrosine – the dark brown to black pigment gives the skin its dark hue.
  • For DOPA to further metabolize to melanin it requires additional tyrosinase, which is another name for tyrosine hydroxylase but indicate it requires copper as a cofactor in both steps in the transformation of tyrosine to melanin.
  • Thus, we can remember that albinism, which is a hypopigmentation syndrome, results from tyrosinase deficiency – a failure to produce melanin.
    • Patients have white hair, pale eyes and skin (with increased risk of skin cancer from lack of protection against UV-light).
  • We can also relate this hypopigmentation to the lack of melanin in phenylketonuria patients and we can relate this dark pigment product to the hyperpigmented nature of pheochromocytoma – the adrenal medullary tumor, which we learn about later.
Thyroid gland along the trachea.
  • Iodination of thyroglobulin tyrosine residues in the thyroid gland produces Thyroxine (T4) and Triiodothyronine (T3), which we learn about in detail, elsewhere.
    • We can immediately understand the physiologic function of these hormones if we think of them as having similar but longer-acting effects as the catecholamines.
Catecholamines
  • Metabolic formation as follows:
    • Dopamine -> Norepinephrine -> Epinephrine.
  • Dopamine, most notably, is formed in the substantia nigra (pars compacta) of the midbrain.
  • Parkinson's disease, which results from degeneration of this pool of motor neurons, and thus manifests, most prominently with motor stiffness and impairment of movement.
  • Norepinephrine and epinephrine form, most notably, in the adrenal medulla (aka the suprarenal gland because it sits on top of the kidney).
  • Pheochromocytomas are catecholamine-secreting tumors of the adrenal medulla (the chromaffin cells), which produce catecholamine crisis.
  • DOPA decarboxylase (removal of a carboxyl group), converts DOPA to Dopamine.
    • It requires the cofactor pyridoxal phosphate (PLP, activated Vitamin B6).
  • DOPA beta-hydroxylase adds a hydroxyl group to Dopamine to form norepinephrine.
    • In neuroscience, we learn that the locus coeruleus (in the pons) sits beneath the substantia nigra (in the midbrain) and is the site of norepinephrine production – thus we can make a connection, now, between the anatomical production of Dopamine (in the midbrain) and norepinephrine (in the pons) and the biochemical production of Dopamine as a chemical precursor to that of norepinephrine!).
  • 2 key cofactors are:
    • Copper (which gains electrons) from Vitamin C (the electron donor), which reduces (transfers electrons to the copper). - Remember: OIL RIG – Oxidation is loss (of electrons), Reduction is Gain (of electrons)
    • Norepinephrine is produced in the adrenal medulla (the chromaffin cells) along with epinephrine.
  • Norepinephrine is methylated to epinephrine by N-Methyl transferase (full name: phenylethanolamine N-methyl transferase) (which involves a conversion of SAM to SAH, which we learn about in detail elsewhere).
Catecholamine metabolism, which is the inactivation of Dopamine, norepinephrine, and epinephrine via COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase).
  • The end products are homovanillic acid (HVA) and vanillylmandelic acid (VMA).
  • First, Dopamine metabolizes to 3-methoxytyramine (3-MT) via COMT and that it further metabolizes to homovanillic acid via MAO.
  • Next, alternatively, Dopamine metabolizes to dihydroxyphenylacetic acid (DOPAC) via MAO and that it further metabolizes to homovanillic acid via COMT.
  • Now, norepinephrine metabolizes to normetanephrine via COMT and that it further metabolizes to vanillylmandelic acid via MAO.
  • Then, in an entirely parallel process epinephrine metabolizes to metanephrine via COMT and that it further metabolizes to vanillylmandelic acid via MAO.
  • Next,alternatively they both metabolize to dihydroxymandelic acid via MAO and then on to vanillylmandelic acid via COMT.
Metabolic Disorders of Phenylalanine & Tyrosine
Phenylketonuria
  • Pathophysiology: Toxic Metabolites of Phenylalanine
    • When phenylalanine accumulates at toxic levels, it transaminates into:
    • - Phenylpyruvate (aka phenyl ketone); hence, "phenylketonuria" describes the presence of phenylpyruvate, phenylalanine, and two key other derivatives in the urine and blood:
Phenylacetate which has a distinct "must/mousy odor" and Phenyllactate.
  • Phenylalanine Excess / Tyrosine Deficiency
    • Excess of phenylalanine
    • Deficiency of tyrosine
So the goal of therapy is to reduce phenylalanine intake and to supplement tyrosine deficiency via the diet. Remember the sparing action of tyrosine on the requirements of phenylalanine
  • Clinical Presentation of PKU
    • Hypopigmentation (of the skin and iris) is a finding in this disorder (remember: melanin is a derivative of tyrosine and tyrosine is deficient in PKU).
    • Neuropsychiatric disorder: this disorder causes tremor, psychosis, seizures, and cognitive dysfunction.
Pheochromocytoma
  • Symptoms
    • Spontaneous severe anxiety: palpitations, sweating, panic
  • Physical Exam Signs
    • Tachycardia (Rapid heart rate)
    • Hypertension (High blood pressure) .
  • Biochemical Pathophysiology
    • We can attribute the agitation and possible psychosis to the surge in Dopamine.
    • The sympathetic nervous system "fight or flight" symptoms relate to the surge in norepinephrine and epinephrine.
Hyperthyroidism
  • Hypermetabolic state that manifests with:
    • Weight loss, sweats, fevers, rapid heart rate.
  • Skin and hair thinning
  • Grave's Ophthalmopathy
    • Ocular protrusion and reddening

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