Lecture 3-synthesis Of Amino Acid Derivative Hormones Flashcards
How are Catecholamines signaling mechanisms derived?
Via tyrosine
- Phenylalanine
- tyrosine
- L-Dopa
Dopaamine
Norepinephrine
Epinephrine
How is tyrosine obtained by the body?
• Tyrosine is either formed during degradation of phenylalanine, or tyrosine may be consumed in the diet
• Phenylalanine is dietary essential
• As long as phenylalanine is consumed in the diet, tyrosine
is dietary non-essential
• Tyrosine is really just hydroxylated PHE
• L-DOPA is really just PHE that has been hydroxylated twice
What is the function of dopamine?
Primary role as a neurotransmitter in the brain
-Also has signaling roles in the body
What is the role of Norepinephrine?
Primary role as a neurotransmitter for sympathetic nervous system
-Minor role as a hormone, released from adrenal glands
What is the role of epinephrine?
Primary role as a fight or flight hormone
- Sympathetic response
- Released from adrenal gland
What are the types of dopamine receptors in the brain?
Many sub-types of dopamine receptors in the
brain (all are G-proteins)
• Some work through the adenylate cyclase—>cAMP —>PKA pathway
• Might activate or inhibit
• And some…
• Work through the IP3—>DAG—>Ca2+—>PKC pathway
• Depends on the G-protein coupled receptor
how are G receptors structured?
The extracellular domain contains the binding site for a ligand (a hormone or neurotransmitter)
The intracellular domain interacts with G proteins
There are 7 transmembrane a helices
Outline the reactions to convert phenylalanine to epinephrine
Phenylalanine —> tyrosine (phenylalanine hydroxylase+ Tetrahydrobiopterin BH4)
Tyrosine—> DOPA(tyrosine hydroxylase + tetrahydrobiopterin BH4)
DOPA(L-DOPA)—> dopamine (DOPA decarboxylase+ PLP (Vit B6) )
Dopamine—>Norepinephrine (dopamine B-hydroxylase+ Vit. C)
Norepinephrine—> Epinephrine (phenylethanolamine N methyltransferase + S-Adenosyl methionine (SAM)
What is the importance of BH4 in hydroxylation?
BH4 is a cofactors
What is done in decarboxylation in DOPA decarboxylation?
The alpha carboxyl group comes off as carbon dioxide
What is the significance of PNMT in converting norepinephrine to epinephrine?
PNMT-catalyzes a methylation reaction (SAM is the methyl donor)
What is Parkinson disease?
-Neurodegenerative disorder
 Loss of dopamine producing cells in the
basal ganglia
• Characterized by movement disorders: spasticity, tremors, loss of memory, mood disturbances, postural instability
Parkinson disease resulting from not enough formation of a catecholamine molecule (in this case the catecholamine is dopamine, a neurotransmitter)
What is the significance of MAO and COMT?
The catecholamine molecules are degraded by monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) to form VMA.
Urinary VMA levels may be measured to estimate levels of epinephrine & norepinephrine produced
24-hour test
Whaat does the degradation 9f dopamine form?
HVA- Homovanillic acid (HVA)
What is phaeochromocytoma?
Pheochromocytoma is a tumor found in the adrenal gland
• A 35-year-old husband and father of three children has headaches and palpitations of increasing frequency and severity over the past 6 months.
• Also intense anxiety and panic attacks. His face is often pale and he sweats more.
• Examination reveals he is hypertensive.
• Headache, Sweating, Tachycardia predominant symptoms
Give clinical features used to diagnose pheochromocytoma
- Episodic symptoms
- Characterized by overproduction of epinephrine as a consequence of the tumor
- Adrenal medulla tumor
- Predominant Symptoms include:
- Headache, Sweating, Tachycardia
- Patients have hypertension
- Must use 24-hour urinary measurement • During a symptom episode
All Catecholamines are…
degraded by MAO and COMT
• Norepinephrine and epinephrine are degraded and eventually form VMA
• Urinary VMA levels may be measured to estimate levels of epinephrine & norepinephrine produced
• 24 hour test
• Dopamine is degraded to form homovanillic acid (HVA)
What can tryptophan be used to do?
The amino acid tryptophan can be modified to form serotonin and melatonin
• Serotonin works through G- protein coupled receptors or ligand gated ion channels
• Melatonin works through G- protein coupled receptors
• Serotonin and melatonin have functions in the body as well as in neurons
Summarize serotonin synthesis
Serotonin is synthesized in the gut, platelets & CNS
• Synthesized from tryptophan
• Serotonin is metabolized to 5-hydroxyindole acetic acid (5-HIAA) by MAO
Outline melatonin formation
Tryptophan—>( 5 hydroxy tryptophan) via tryptophan hydroxylase+ BH4/tetrahydrobiopterin
5 hydroxy tryptophan —> 5 hydroxy tryptamine (serotonin) via amino ac8d decarboxylase + pyridoxal phosphate
Some modifications converts serotonin to melatonin
Monoamine oxidase converts serotonin to 5-HIAA excretion
What is Carcinoid syndrome ?
- Tumor of serotonin producing cells in GIT (APUD cells)
- Cutaneous flushing, sometimes accompanied by sweating
- Gastrointestinal hypermotility causing diarrhea
- Bronchospasm
Increased 5-HIAA excretion in urine
Highlight a serotonin overproduction scenario
Mrs.L began to experience diarrhea and flushing
symptoms, which at first she attributed to menopause.
• Mrs.L went to doctors and specialists, none of whom accurately diagnosed the problem. The symptoms continued in varying degrees until a few months ago
• She soon felt very sick, and a few days later she was admitted to the hospital. That evening, she underwent an emergency bowel resection.
• During 24 hours she had lost four units of blood and woke up to the diagnosis of carcinoid cancer that had metastasized to the liver.”
What does MAO do to serotonin ?
Serotonin is degraded to 5-hydroxyindole acetic acid (5- HIAA) by Monoamine Oxidase (MAO)
How do MAO inhibitors affect Serotonin levels, how does this differ from SSRIs?
- MAO inhibitors have been used to increase serotonin in the CNS
- An important class of antidepressant drugs that works via serotonin
- Slows down degradation of serotonin
Do not confuse MAO inhibitors with selective serotonin reuptake inhibitors (SSRI) • A different class of drug that also functions via serotonin • SSRI increase time that serotonin is in synapse
When is melatonin release from the darkness maximized?
During darkness
Serotonin is derived from
Tryptophan
Melatonin is derived from
Serotonin
Maximum sleepiness correlates with maximal
Melatonin production
Whaat is Seasonal affecting disorder?
Circadian rhythm- Light/dark cycle- sleep disorders
What is the impact of tetrahydrobiopterin?
Coenzyme required for many amino acid hydroxylation reactions
- Reactions requiring tetrahydrobiopterin:
1. Phenylalanine hydroxylase (converts Phe to Tyr)
2. Tyrosine hydroxylase (converts Tyr to DOPA)
3. Tryptophan hydroxylase(converts Trp to 5-hydroxy tryptophan)
What are the consequences of tetrahydrobiopterin deficiency?
- Deficiency of dihydrobiopterin synthesis or dihydrobiopterin reductase results in hyperphenylalaninemia & decreased synthesis of neurotransmitters (catecholamines, serotonin).
- Results in severe mental impairment and seizures
- Management includes addition of dietary tetrahydrobiopterin • Attempt to provide neurotransmitter precursors in the diet
- Dietary Phe restriction
A deficiency in dihydrobiopterin reductase or any of the enzymes of BH4 synthesis leads to hyperphenylalanemia, and decreased synthesis of Catecholamines and serotonin
Where are thyroid hormones formed?
Formed on the thyroglobulin protein in the thyroid gland
• An example of post-translational modification
What must occur in order to synthesis a thyroid hormone?
Tyrosine amino acids are iodinated
• Means iodine is substituted on the ring
• Occurs on the protein
• Then, thyroid hormone is released
Outline the steps in control of thyroid hormone production
- TRH (Thyrotropin-releasing hormone) from hypothalamus
- TSH (Thyroid stimulating hormone) from pituitary (note TSH is also sometimes called thyrotropin)
- Thyroid hormone formation in thyroid gland; iodination and coupling by thyroperoxidase (TPO)
- 90% is released as the less active T4 version
- Local conversion to the more active T3 version
- Regulation of gene expression via the thyroid hormone receptor
Hat are the steps in formation of thyroid hormone?
- Trapping iodine in the thyroid cell
- Iodination of the thyroglobulin protein
- Coupling of the iodinated tyrosine side chains
- Release of thyroid hormone
- De-iodination: T4 may be converted to the active T3 form by the enzyme 5` Deiodinase (note the prime)
- This is called “five prime deiodinase”
- May be done in thyroid gland, or in peripheral tissues
- Deactivation :T4 may be inactivated by conversion to the reverse T3 form.
- Enzyme is 5 Deiodinase (note that this is a different enzyme than the five-prime deiodinase enzyme)
How Does the thyroid trap iodine?
Iodine enters the thyroid cell by secondary active transport powered by sodium gradient
Iodine crosses into the colloid by a different transport system
Iodination: iodine is attached to Tyr residues: post-translational modification
What are the functions of TPO (thyroperoxidase)?
First TPO fixes iodine to thyroglobulin
• Occurs on specific tyrosine side chains
• Diiodotyrosine (DIT) may form (two iodines)
• Monoiodotyrosine (MIT) may form (one iodine)
Next TPO acts as a peroxidase
• Objective is to link two iodo- tyrosine side chains together
What is the role of TPO in forming T4 and T3?
• TPO forms Iodinated tyrosine side chains that are linked together on the thyroglobulin protein
• Two molecules of diiodotyrosine (DIT) couple to form T4
• One monoiodotyrosine (MIT) and one DIT molecules will couple
to form T3
What is the function of colloid material that contains thyroglobulin
They form vesicles
- These vesicles enter back into the thyroid cell • Pinocytosis
- Vesicles fuse with lysozome
- T3 and T4 are released
- Iodotyrosine and free iodine that is released is scavenged to conserve iodine
- Some tissues may convert T4 (inactive) to T3 (active) form • Enzyme is 5′-deiodinase (activates T4 to T3 )
How does T3 act?
Via gene regulation
Thyroid hormone enters cell
T3 interacts with receptor since receptor is in the thyroid/steroid hormone family
Regulated gene expression in the nucleus
Summarize iodine deficiency
- Nutritional iodine deficiency may result in hypothyroidism and enlarged thyroid gland (goiter) due to increased TSH secretion.
- Severe thyroid hormone deficiency may present as fatigue, weight gain, cold intolerance and decreased metabolic rate (features of hypothyroidism
What are the consequences of maternal iodine deficiency ?
• Maternal iodine deficiency during fetal development can cause Congenital hypothyroidism:
- during fetal and infant development this can cause irreversible intellectual disability, hearing loss, seizure, and short stature.
What is Graves’ disease?
Graves disease is a form of hyperthyroidism (over production of thyroid hormone).
Graves disease is a form of hyperthyroidism caused by an antibody that mimics TSH.
Results in unregulated overproduction of thyroid hormone
exophthalmos
Causes weight loss, increased perspiration, elevated heart rate, protruding eyes
Hyperthyroidism may also be caused by overconsumption of iodine
What are the clinical correlations of phenylalanine?
PKU: PKU I, PKU II, Maternal PKU, the BH4 cofactor, and the reductase enzyme for BH2 (discussed in metabolism, next block)
Catecholamines – function, disorders associated with overproduction / underproduction, and degradation products
Melanin – deficiency leads to the disorder albinism –d
Anabolic protein synthesis
Catabolism –Several
disorders associated with a metabolic block in the pathway
Thyroid hormone
