Lec 1/2 Thyroid Medchem Flashcards
Iodine
- Thyroid is the only ORGAN in mammals that incorporate IODINE into organic compounds
- *all vertebrates have thyroid tissue
-
Only known natural iodine containing molecule with biological activity
- Thyroid Hormones
Goiter
Enlargement of thyroid gland (in effort to obtain more iodine)
typically caused by IODINE DEFICIENCY
L-Tyrosine
T3 & T4 are biosynthesized from L-Tyrosine
All natural thyroid hormones are the L isomer
Phenolic Acid of Thyroid Hormone
pKa
- T4 pKa = 6.73
- More acidic, due to extra iodine
- T3 pka = 8.47
- less acidic, lacking 1 iodine
-
but is the ACTIVE FORM - when bound
- only 10% ionized at 7.4
- why there is less of it
Deiodinase
Converts T4 –> T3
kidney / liver / target cells
Thyroxine
T4
-
Prohormone
- Deionated (by deiodinase) into T3 at peripheral tissue
- Preferred drug for hypothyroidism
- T3 is 5x more potent than T4
How long of storage do we have of iodine?
3-6 months
- Highly bound to protein
- constantly circulating the blood
- and is stored in other parts of body
Iodide
I-
I NEGATIVE
Iodine if mainly found in this form
- Trace element in many foods
- Cereal / Fish / Eggs
-
SALT
- in salt as KI
NIS
Na+ / I- Symporter
Pumps Na+ & I- INSIDE the
basal membrane of follicular cell
uses ion gradient and is active transporter
Na/K pump creates a lower Na+ concentration INSIDE the thyroid cell
Regulated by TSH
Na+ / K+ Pump
Creates a NET NEGATIVE - charge INSIDE thyroid cell
so that NIS can bring Iodine in with Sodium
2 K+ IN / 3 Na+ out
Perchlorate (ClO4-)
Thiocyanate (SCN-)
Competitive inhibitors of NIS
Contaminated water with these large anions
–> cause GOITER, lack of iodine
Thyroid Peroxidase
TPO
Oxidizes Iodide (I-) @ apical plasma membrane
Catalyzes the Coupling RXN
occurs @ ortho position
Coupling Reaction
- Intramolecular coupling between:
- 2 DIT residues or 1 DIT / 1 MIT
- with a Thyroglobulin Protein
- Catalyzed by TPO (thyroid peroxidase)
Proteins that Transport Thyroid Hormones
Thyroxine-Binding Globulin
Transtheretin
(thyroxin-binding prealbumen)
Albumin
binds T4 w/ low affinity
Propylthiouracil
PTU
Inhibits Iodothyronine Deiodinases
T4 –/–> T3 or rT3 –/–> T2
Iodothyronine Deiodinases
5-D
Converts T4 –> rT3 or T3
T3/rT3 –> T2
Contains SELENIUM in the form of SELENOCYSTEINE
in the active site
Type 1 Deiodinase
5’-D
Thyroid, Kidney, Liver
Generates T3 for CIRCULATION
inhibited by PTU (propylthiouracil)
Type 2 Deiodinase
5’-D
Target Cells
Generates T3 for LOCAL USE
NOT inhibited by PTU
Type 3 Deiodinase
5-D
Present in almost all tissues
INACTIVATES T4 –> rT3
rT3 is a anti-skewed formation that is NOT ACTIVE
Type 2 5’-deiodinase Regulation
5’-D
Regulated by UBIQUINATION
–> lysine residues are exposed
–> Ubiquitin inactivates Type 2 5’-D
–> degradation in the proteasome
Deubiquination can restore its activity
Thyrotropin Releasing Hormone
TRH
- Produced by neurons in suproptic/supraventricular nuclei
- of the HYPOTHALAMUS
- __TRH –> thyrotropes in the anterior pituitary
- binds –> to TRHR
-
Stimulates RELEASE OF TSH
- –> the pituitary
Thyrotropin Releasing Hormone Receptor
TRHR
- TRH binds to this on the Anterior Pituitary
-
G-Protein receptor
-
activates Phospholipase C
- –> Ca+ release & PKC activation
- Transcription of TSH is initiated
- thyrotropes begin to SECRETE TSH
- –> Ca+ release & PKC activation
-
activates Phospholipase C
Thyroid Stimulating Hormone
TSH SUBUNITS
- Glycoprotein hormone with 2 Subunits
- Alpha subunit
- TSH/LH/FSH/CG are all coded by the same gene
- all identical subunits (collectively called glycoprotein hormones)
-
Beta subunit
- Functional specificity is conferred by this
- Alpha subunit
TSH
- Pulsatile Secretion & Circadian pattern (highest at night)
- Down-Regulated by thryroid hormones
- Half life ~ 1hour
- metabolized by kidney/liver
- TSHReceptor = GPCR
- generation of cAMP
Thyroid Hormone Receptor
Binding
IONIC BINDING
to Arg
H-BONDING
to His
Thyroid Hormone Receptors
- Part of a super family of Nuclear Receptors
-
Alpha & Beta forms distingushed by:
- Sequence / Chromosomal location
- transcriptional heterogeneity
-
Homo & Heterodimerization
- can occur amoung superfamily members
- Bind Specific response elements:
- TRE’s
Thyroid Hormone Receptor Alpha-2
TR-a2
Does NOT transduce signals
Way for the cell to control transcription
Thyroid Response Elements
TRE
-
Palindrome
- reverse recognition (opposite directions)
-
Direct Repeat
- 4 bases in-between, same direction
-
Inverted Repeat
- mix of both
Controling gene expression by the Thyroid Receptor
Acetylated Histones
ACTIVATE TRANSCRIPTION
Hypothyroidism Causes
Hashimoto’s Autoimmune Thyroiditis
Iodine DEFICIENCY
(gives rise to goiter + cretinism)
Primary Thyroid Disease
Hypothyroidism Treatment
Thyroid Extract
Synthetic T4
levothyroxine
L-thryroxine
HYPERthyroidism Therapeutic Strategies
-
Destruction of thyroid Tissue
- Surgery
- Radioactive Iodine
-
Block thyroid hormone production
- High dose iodine
- Complex anions
-
Thioamides:
- PTU / Methimizole
Graves Disease
-
Autoimmune Disease –> HYPERthyroidism
- Stimulates Auto-Antibodies
- –> Stimulates TSH receptor
- Overproduction of thryroid hormone
- no negative feedback control
- Stimulates Auto-Antibodies
Blocking Thyroid Hormone Production with
Iodine
- For HYPERthyroidism, IODINE
-
High Concentrations of Iodine
- -/-> Inhibit NIS symporter
- -/-> Inhibit TPO & Thyroid hormone release
- Preparation for surgery
-
SLOW TREATMENT
- storage of thyroid in your blood for several monts
-
High Concentrations of Iodine
Blocking Thyroid Hormone Production with
Complex Anions
Perchlorate & Pertechnetate
ClO4- / TcO4-
- Compete w/ iodide for the NIS Symporter
- inhbit uptake of IODIDE by the thyroid
- Not metabolized
- Iodide transport is the RATE LIMITING STEP
- in iodide uptake by thyroid
Thioamides
PTU / MMI
- Drug of choice for HYPERthyroidism
- Thiourelynes (5-6 membered heterocyclic derivatives of thiourea)
-
INHIBIT TPO
-
inhibit coupling rxn
- incorporation of Iodine –> tyrosine resdues of TG (MIT/DIT formation)
-
inhibit coupling rxn
- Actively trapped by thyroid gland against conc. gradient
-
Slow Onset
- inhibits synthesis but not the stored T3/T4
- no effect on NIS or hormone release
Propylthiouracil
PTU
-
ALSO inhibits Type 1 5’-deiodinase
- T4 –/–> T3
- Rapidly absorbed & 50-80% bioavailability
-
Short plasma half life (1.5hrs)
- but trapped by thyroid gland
- Glucoronide = major metabolite
Methimazole
MMI
- Thioamide imidazole for HYPERthyroidism
-
INHIBITS Thyroid Peroxidase (TPO)
- 10x more potent than PTU
- does not inhibit Type 1 5’Deiodinase
Carbimazole
- Thioamide imidazole for HYPERthyroidism
- Improve taste & decreased rate of release
- vs MMI
- converted to MMI in vivo
- Improve taste & decreased rate of release
