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PDAT2 > Lec 1/2 Thyroid Medchem > Flashcards

Lec 1/2 Thyroid Medchem Flashcards

1
Q

Iodine

A
  • 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
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2
Q

Goiter

A

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

typically caused by IODINE DEFICIENCY

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3
Q

L-Tyrosine

A

T3 & T4 are biosynthesized from L-Tyrosine

All natural thyroid hormones are the L isomer

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4
Q

Phenolic Acid of Thyroid Hormone

pKa

A
  • 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
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5
Q

Deiodinase

A

Converts T4 –> T3

kidney / liver / target cells

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6
Q

Thyroxine

T4

A
  • Prohormone
    • ​Deionated (by deiodinase) into T3 at peripheral tissue
  • Preferred drug for hypothyroidism
  • T3 is 5x more potent than T4
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7
Q

How long of storage do we have of iodine?

A

3-6 months

  • Highly bound to protein
    • constantly circulating the blood
    • and is stored in other parts of body
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8
Q

Iodide

A

I-

I NEGATIVE

Iodine if mainly found in this form

  • Trace element in many foods
    • Cereal / Fish / Eggs
    • SALT
      • in salt as KI
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9
Q

NIS

Na+ / I- Symporter

A

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

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10
Q

Na+ / K+ Pump

A

Creates a NET NEGATIVE - charge INSIDE thyroid cell

so that NIS can bring Iodine in with Sodium

2 K+ IN / 3 Na+ out

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11
Q

Perchlorate (ClO4-)

Thiocyanate (SCN-)

A

Competitive inhibitors of NIS

Contaminated water with these large anions

–> cause GOITER, lack of iodine

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12
Q

Thyroid Peroxidase

TPO

A

Oxidizes Iodide (I-) @ apical plasma membrane

Catalyzes the Coupling RXN

occurs @ ortho position

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13
Q

Coupling Reaction

A
  • Intramolecular coupling between:
    • 2 DIT residues or 1 DIT / 1 MIT
    • with a Thyroglobulin Protein
  • ​Catalyzed by TPO (thyroid peroxidase)
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14
Q

Proteins that Transport Thyroid Hormones

A

Thyroxine-Binding Globulin

Transtheretin

(thyroxin-binding prealbumen)

Albumin

binds T4 w/ low affinity

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15
Q

Propylthiouracil

PTU

A

Inhibits Iodothyronine Deiodinases

T4 –/–> T3 or rT3 –/–> T2

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16
Q

Iodothyronine Deiodinases

5-D

A

Converts T4 –> rT3 or T3

T3/rT3 –> T2

Contains SELENIUM in the form of SELENOCYSTEINE

in the active site

17
Q

Type 1 Deiodinase

5’-D

A

Thyroid, Kidney, Liver

Generates T3 for CIRCULATION

inhibited by PTU (propylthiouracil)

18
Q

Type 2 Deiodinase

5’-D

A

Target Cells

Generates T3 for LOCAL USE

NOT inhibited by PTU

19
Q

Type 3 Deiodinase

5-D

A

Present in almost all tissues

INACTIVATES T4 –> rT3

rT3 is a anti-skewed formation that is NOT ACTIVE

20
Q

Type 2 5’-deiodinase Regulation

5’-D

A

Regulated by UBIQUINATION

–> lysine residues are exposed

–> Ubiquitin inactivates Type 2 5’-D

–> degradation in the proteasome

Deubiquination can restore its activity

21
Q

Thyrotropin Releasing Hormone

TRH

A
  • 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
Q

Thyrotropin Releasing Hormone Receptor

TRHR

A
  • 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
Q

Thyroid Stimulating Hormone

TSH SUBUNITS

A
  • 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
Q

TSH

A
  • 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
Q

Thyroid Hormone Receptor

Binding

A

IONIC BINDING

to Arg

H-BONDING

to His

26
Q

Thyroid Hormone Receptors

A
  • 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
Q

Thyroid Hormone Receptor Alpha-2

TR-a2

A

Does NOT transduce signals

Way for the cell to control transcription

28
Q

Thyroid Response Elements

TRE

A
  • Palindrome
    • ​reverse recognition (opposite directions)
  • Direct Repeat
    • ​4 bases in-between, same direction
  • Inverted Repeat
    • ​mix of both
29
Q

Controling gene expression by the Thyroid Receptor

A

Acetylated Histones

ACTIVATE TRANSCRIPTION

30
Q

Hypothyroidism Causes

A

Hashimoto’s Autoimmune Thyroiditis

Iodine DEFICIENCY

(gives rise to goiter + cretinism)

Primary Thyroid Disease

31
Q

Hypothyroidism Treatment

A

Thyroid Extract

Synthetic T4

levothyroxine

L-thryroxine

32
Q

HYPERthyroidism Therapeutic Strategies

A
  • Destruction of thyroid Tissue
    • ​Surgery
    • Radioactive Iodine
  • Block thyroid hormone production
    • ​High dose iodine
    • Complex anions
    • Thioamides:
      • ​PTU / Methimizole
33
Q

Graves Disease

A
  • Autoimmune Disease –> HYPERthyroidism
    • Stimulates Auto-Antibodies
      • –> Stimulates TSH receptor
      • Overproduction of thryroid hormone
        • no negative feedback control
34
Q

Blocking Thyroid Hormone Production with

Iodine

A
  • 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
Q

Blocking Thyroid Hormone Production with

Complex Anions

A

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
Q

Thioamides

PTU / MMI

A
  • 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
Q

Propylthiouracil

PTU

A
  • 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
Q

Methimazole

MMI

A
  • Thioamide imidazole for HYPERthyroidism
  • INHIBITS Thyroid Peroxidase (TPO)
    • ​10x more potent than PTU
    • does not inhibit Type 1 5’Deiodinase
39
Q

Carbimazole

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

PDAT2 (22 decks)

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