Lec 1/2 Thyroid Medchem Flashcards Preview

PDAT2 > Lec 1/2 Thyroid Medchem > Flashcards

Flashcards in Lec 1/2 Thyroid Medchem Deck (39):
1

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

2

Goiter

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

typically caused by IODINE DEFICIENCY

 

3

L-Tyrosine

T3 & T4 are biosynthesized from L-Tyrosine

All natural thyroid hormones are the L isomer

4

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 

5

Deiodinase

Converts T4 --> T3

 

kidney / liver / target cells

6

Thyroxine

T4

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

7

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

8

Iodide

I-

I NEGATIVE

Iodine if mainly found in this form

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

9

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

10

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

11

Perchlorate (ClO4-)

Thiocyanate (SCN-)

Competitive inhibitors of NIS

 

Contaminated water with these large anions

--> cause GOITER, lack of iodine 

12

Thyroid Peroxidase

TPO

Oxidizes Iodide (I-) @ apical plasma membrane

 

Catalyzes the Coupling RXN

occurs @ ortho position

 

 

13

Coupling Reaction

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

14

Proteins that Transport Thyroid Hormones

Thyroxine-Binding Globulin

 

Transtheretin

(thyroxin-binding prealbumen)

Albumin

binds T4 w/ low affinity

15

Propylthiouracil

PTU

Inhibits Iodothyronine Deiodinases

 

T4 --/--> T3 or rT3 --/--> T2

 

16

Iodothyronine Deiodinases

5-D

Converts T4 --> rT3 or T3

T3/rT3 --> T2

 

Contains SELENIUM in the form of SELENOCYSTEINE

in the active site

17

Type 1 Deiodinase

5'-D

Thyroid, Kidney, Liver

Generates T3 for CIRCULATION

inhibited by PTU (propylthiouracil)

18

Type 2 Deiodinase

5'-D

Target Cells

Generates T3 for LOCAL USE

NOT inhibited by PTU

 

19

Type 3 Deiodinase

5-D

Present in almost all tissues

INACTIVATES T4 --> rT3

rT3 is a anti-skewed formation that is NOT ACTIVE

20

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

21

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

22

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

23

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

24

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

25

Thyroid Hormone Receptor

Binding

IONIC BINDING

to Arg

H-BONDING

to His

26

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

27

Thyroid Hormone Receptor Alpha-2

TR-a2

Does NOT transduce signals

Way for the cell to control transcription

28

Thyroid Response Elements

TRE

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

29

Controling gene expression by the Thyroid Receptor

Acetylated Histones

ACTIVATE TRANSCRIPTION

30

Hypothyroidism Causes

Hashimoto's Autoimmune Thyroiditis

Iodine DEFICIENCY

(gives rise to goiter + cretinism)

Primary Thyroid Disease

31

Hypothyroidism Treatment

Thyroid Extract

Synthetic T4

levothyroxine

L-thryroxine

32

HYPERthyroidism Therapeutic Strategies

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

33

Graves Disease

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

34

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

35

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

36

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)
  • 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

37

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

38

Methimazole

MMI

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

39

Carbimazole

 

  • Thioamide imidazole for HYPERthyroidism
    • Improve taste & decreased rate of release 
      • vs MMI
      • converted to MMI in vivo