Notes
Phenylalanine & Tyrosine Metabolism
Sections
Full-Length Text
- Here, we'll learn about the biochemistry, pathological disorders, and key pharmacotherapeutics of phenylalanine and tyrosine in two parts.
- In Part 1, we'll review the key biochemistry.
- In Part 2, we'll add-in the key pharmacotherapeutics and pathophysiologies.
- To begin, start a table.
- Denote phenylalanine (Phe, F)
- Show that attached to its central carbon is a carboxylic acid and an amino group.
- For the "R group," attached at the beta carbon is a benzene ring (a hexagonal ring with three double bonds) – phenylalanine is the simplest of the aromatic amino acids.
- Consider that we omit drawing the hydrogen in this type of diagram.
Next, tyrosine (Tyr, Y).
- Redraw phenylalanine and add an alcohol group attached at position 4 on the benzene ring.
- Show we synthesize tyrosine from phenylalanine via phenylalanine hydroxylase.
- Indicate phenylketonuria, which classically occurs when there is a deficiency of or a defect in phenylalanine hydroxylase.
Before we delve into the derivatives of phenylalanine and tyrosine, let's contextualize them within the pool of 20 amino acids.
- First, review the essential amino acids with the acronym…
- My – Methionine
- Tall – Threonine
- (Handsome – Histidine)
- Vegan – Valine
- Friend – Phenylalanine
- Is – Isoleucine
- Watering – Tryptophan
- Kale – Lysine
- Leaves – Leucine
Next, the nonessential amino acids...alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine.
- Show that phenylalanine is an essential amino acid.
- Show that tyrosine is a nonessential amino acid but indicate that it (along with arginine, cysteine, and histidine) are all conditionally essential.
And as an important reminder, signify the branched chain amino acids: valine, isoleucine, and leucine, which build-up pathologically in the condition – Maple Syrup Urine disease, which results from branched-chain alpha-keto acid dehydrogenase complex deficiency. We signify this here with our branched chain symbol and the acronym: BCKDH for Branched-chain alpha-Keto acid DeHydrogenase.
Next, let's review the catabolic pathways for each of the amino acids, so we can see why tyrosine's is so interesting:
- The two L's – Lysine and Leucine are ketogenic
- Then, the following do NOT "FITTT"… (they are both glucogenic and ketogenic).
- Phenylalanine, Isoleucine, Tryptophan, Threonine, Tyrosine.
- The rest are purely glucogenic.
Now, start our diagram:
- Show that phenylalanine irreversibly converts to tyrosine via phenyalanine hydroxylase.
- Thus, tyrosine CANNOT create phenylalanine (the pathway only goes from phenylalanine to tyrosine).
- Also, denote 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.
- Now, let's introduce the 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.
- Importantly, we could intuit that the citric acid cycle and ketogenesis would both be energy pathways of tyrosine breakdown because at the beginning we reviewed that tyrosine is one of the amino acids that falls into the category that do NOT "FITTT" – it is both glucogenic and ketogenic.
- Next, indicate that phenylalanine metabolism requires…
- Oxygen (O2)
- & Tetrahydrobiopterin (BH4), which converts to dihydrobiopterin (BH2).
- Now, let's divide phenylketonuria into classic PKU – indicate that here there is a defect in phenylalanine hydroxylase.
- Then, indicate that in malignant PKU there is a defect in dihydrobiopterin reductase, which is an enzyme, which requires NADPH to convert dihydrobiopterin back to tetrahydrobiopterin.
- To begin our walk through tyrosine metabolism, show that tyrosine converts to DOPA via tyrosine hydroxylase.
- This reaction involves the addition of an hydroxyl, just as the conversion of phenylalanine to tyrosine did.
- Show that (just like phenylalanine hydroxylase), tyrosine hydroxylase requires:
- Oxygen (O2)
- & Tetrahydrobiopterin (BH4) conversion to dihydrobiopterin (BH2)
- Importantly, show that the addition of the second hydroxyl to tyrosine forms a phenyl ring with two adjacent –OH groups, called a "catechol"
- Draw this ring structure in our table.
- Hence the derivatives of DOPA are called "catecholamines".
- If we remember that DOPA refers to "DihydrOxyPhenylAlanine," we can remember that it comes from phenylalanine with two hydroxyl groups (the first from the formation of tyrosine, the second from the formation of the catechol – DOPA).
Before we address the catecholamines, let's address melanin.
- Draw 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.
- Indicate that 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 → 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.
Next, let's show learn about the catecholamines.
- Show their metabolic formation as follows:
- Dopamine → Norepinephrine → Epinephrine.
- Show that Dopamine, most notably, is formed in the substantia nigra (pars compacta) of the midbrain.
- Indicate 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.
- Then, show that norepinephrine and epinephrine form, most notably, in the adrenal medulla (aka the suprarenal gland) because it sits on top of the kidney.
- Indicate that pheochromocytomas are catecholamine-secreting tumors of the adrenal medulla (the chromaffin cells), which produce catecholamine crisis (we address them in detail later).
- Next, show that DOPA decarboxylase (removal of a carboxyl group), converts DOPA to Dopamine.
- Indicate that it requires the cofactor pyridoxal phosphate (PLP, activated Vitamin B6).
- Now, show that 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!).
- Indicate that two 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.
- Show that 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).
Next, let's move on to thyroglobulins.
- Draw the thyroid gland along the trachea.
- Show that 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.
Now, let's transition to the energy metabolites.
- Show that tyrosine passes through an intermediate (4-hydroxyphenylpyruvic acid) to form homogentisate.
- Indicate that homogentisate (homogentisic acid (HGA)) metabolizes to maleylacetoacetate via homogentisate oxidase (aka homogentisate 1,2-dioxygenase).
- Next, show that maleylacetoacetate isomerizes to fumarylacetoacetate via maleylacetoacetate isomerase.
- And then show that fumarylacetoacetate catabolizes into fumarate (again, a glucose glucogenic metabolite) and acetoacetate (again, a ketogenic metabolite) via fumarylacetoacetate hydrolase.
Now introduce 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).
Let's step through this metabolism, now.
- First, show that Dopamine metabolizes to 3-methoxytyramine (3-MT) via COMT and that it further metabolizes to homovanillic acid via MAO.
- Next, show that, alternatively, Dopamine metabolizes to dihydroxyphenylacetic acid (DOPAC) via MAO and that it further metabolizes to homovanillic acid via COMT.
- Now, show that norepinephrine metabolizes to normetanephrine via COMT and that it further metabolizes to vanillylmandelic acid via MAO.
- Then, show that in an entirely parallel process epinephrine metabolizes to metanephrine via COMT and that it further metabolizes to vanillylmandelic acid via MAO.
- Notice the only difference is that NOREPInpephrine metabolizes to NORMETAnephrine and whereas EPInephrine metabolizes to METAnephrine.
- Next, show that alternatively they both metabolize to dihydroxymandelic acid via MAO and then on to vanillylmandelic acid via COMT.