Lec 1/2 Thyroid Medchem

Question 1

Iodine

Answer 1

• 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

Question 2

Goiter

Answer 2

Enlargement of thyroid gland (in effort to obtain more iodine)

typically caused by IODINE DEFICIENCY

Question 3

L-Tyrosine

Answer 3

T3 & T4 are biosynthesized from L-Tyrosine

All natural thyroid hormones are the L isomer

Question 4

Phenolic Acid of Thyroid Hormone

pKa

Answer 4

• 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

Question 5

Deiodinase

Answer 5

Converts T4 –> T3

kidney / liver / target cells

Question 6

Thyroxine

T4

Answer 6

• Prohormone
  
  • ​Deionated (by deiodinase) into T3 at peripheral tissue
• Preferred drug for hypothyroidism
• T3 is 5x more potent than T4

Question 7

How long of storage do we have of iodine?

Answer 7

3-6 months

• Highly bound to protein
  
  • constantly circulating the blood
  • and is stored in other parts of body

Question 8

Iodide

Answer 8

I-

I NEGATIVE

Iodine if mainly found in this form

• Trace element in many foods
  
  • Cereal / Fish / Eggs
  • SALT
    
    • in salt as KI

Question 9

NIS

Na+ / I- Symporter

Answer 9

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

Question 10

Na+ / K+ Pump

Answer 10

Creates a NET NEGATIVE - charge INSIDE thyroid cell

so that NIS can bring Iodine in with Sodium

2 K+ IN / 3 Na+ out

Question 11

Perchlorate (ClO4-)

Thiocyanate (SCN-)

Answer 11

Competitive inhibitors of NIS

Contaminated water with these large anions

–> cause GOITER, lack of iodine

Question 12

Thyroid Peroxidase

TPO

Answer 12

Oxidizes Iodide (I-) @ apical plasma membrane

Catalyzes the Coupling RXN

occurs @ ortho position

Question 13

Coupling Reaction

Answer 13

• Intramolecular coupling between:
  
  • 2 DIT residues or 1 DIT / 1 MIT
  • with a Thyroglobulin Protein
• ​Catalyzed by TPO (thyroid peroxidase)

Question 14

Proteins that Transport Thyroid Hormones

Answer 14

Thyroxine-Binding Globulin

Transtheretin

(thyroxin-binding prealbumen)

Albumin

binds T4 w/ low affinity

Question 15

Propylthiouracil

PTU

Answer 15

Inhibits Iodothyronine Deiodinases

T4 –/–> T3 or rT3 –/–> T2

Question 16

Iodothyronine Deiodinases

5-D

Answer 16

Converts T4 –> rT3 or T3

T3/rT3 –> T2

Contains SELENIUM in the form of SELENOCYSTEINE

in the active site

Question 17

Type 1 Deiodinase

5’-D

Answer 17

Thyroid, Kidney, Liver

Generates T3 for CIRCULATION

inhibited by PTU (propylthiouracil)

Question 18

Type 2 Deiodinase

5’-D

Answer 18

Target Cells

Generates T3 for LOCAL USE

NOT inhibited by PTU

Question 19

Type 3 Deiodinase

5-D

Answer 19

Present in almost all tissues

INACTIVATES T4 –> rT3

rT3 is a anti-skewed formation that is NOT ACTIVE

Question 20

Type 2 5’-deiodinase Regulation

5’-D

Answer 20

Regulated by UBIQUINATION

–> lysine residues are exposed

–> Ubiquitin inactivates Type 2 5’-D

–> degradation in the proteasome

Deubiquination can restore its activity

Question 21

Thyrotropin Releasing Hormone

TRH

Answer 21

• 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

Question 22

Thyrotropin Releasing Hormone Receptor

TRHR

Answer 22

• 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

Question 23

Thyroid Stimulating Hormone

TSH SUBUNITS

Answer 23

• 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

Question 24

TSH

Answer 24

• Pulsatile Secretion & Circadian pattern (highest at night)
• Down-Regulated by thryroid hormones
• Half life ~ 1hour
  
  • metabolized by kidney/liver
• TSHReceptor = GPCR
  
  • generation of cAMP

Question 25

**Thyroid Hormone Receptor** **Binding**

Answer 25

**_IONIC BINDING_** **to Arg** **_H-BONDING_** **to His**

Question 26

**Thyroid Hormone Receptors**

Answer 26

* Part of a super family of **Nuclear Receptors** * **Alpha & Beta** forms distingushed by: * Sequence / Chromosomal location * transcriptional heterogeneity * **Homo & Hetero**dimerization * can occur amoung superfamily members * Bind Specific response elements: * **TRE's**

Question 27

**Thyroid Hormone Receptor Alpha-2** **TR-a2**

Answer 27

***Does NOT transduce signals*** _Way for the cell to control transcription_

Question 28

**Thyroid Response Elements** **TRE**

Answer 28

* **Palindrome** * **​**reverse recognition (opposite directions) * **Direct Repeat** * **​**4 bases in-between, same direction * **Inverted Repeat** * **​**mix of both

Question 29

**Controling gene expression by the Thyroid Receptor**

Answer 29

**Acetylated Histones** **ACTIVATE TRANSCRIPTION**

Question 30

**Hypothyroidism Causes**

Answer 30

**Hashimoto's Autoimmune Thyroiditis** **Iodine DEFICIENCY** (gives rise to goiter + cretinism) **Primary Thyroid Disease**

Question 31

**Hypothyroidism Treatment**

Answer 31

**Thyroid Extract** **Synthetic T4** levothyroxine L-thryroxine

Question 32

**HYPERthyroidism Therapeutic Strategies**

Answer 32

* **Destruction of thyroid Tissue** * ​Surgery * Radioactive Iodine * **Block thyroid hormone production** * ​High dose iodine * Complex anions * **Thioamides:** * **​PTU / Methimizole**

Question 33

**Graves Disease**

Answer 33

* **Autoimmune Disease --\> HYPERthyroidism** * Stimulates Auto-Antibodies * --\> Stimulates TSH receptor * Overproduction of thryroid hormone * *no negative feedback control*

Question 34

**Blocking Thyroid Hormone Production with** **Iodine**

Answer 34

* 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

Question 35

Blocking Thyroid Hormone Production with ## Footnote **Complex Anions**

Answer 35

**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

Question 36

**Thioamides** **PTU / MMI**

Answer 36

* 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) * 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*

Question 37

**Propylthiouracil** **PTU**

Answer 37

* ***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

Question 38

**Methimazole** **MMI**

Answer 38

* Thioamide imidazole for **HYPERthyroidism** * ***INHIBITS Thyroid Peroxidase (TPO)*** * ​10x more potent than PTU * *does not inhibit Type 1 5'Deiodinase*

Question 39

**Carbimazole**

Answer 39

* Thioamide imidazole for **HYPER**thyroidism * Improve taste & *decreased rate of release* * vs **MMI** * converted to MMI in vivo