Thyroid chemistry

what is this?

thyroxine/ T4

what is this?

Triiodothyronine/ T3

how is T3 formed from T4?

deiodinase= removal of iodine

which is more potent T3 or T4?

T3 is more potent (by 5x)

which amino acid is the thyroid hormone synthesized from?

L-tyrosine

what is the function of the 2 inner iodine molecules?

Creates a skewed conformation needed for activity

what effect does Iodine have on the phenyl ether bond?

restricts its movement

what is the necessary bond angle for the phenyl ether bond?

120^o so the inner and outer ring are perpendicular to each other

what is the role of the O-bridge on the phenyl ether bond?

to maintain orientation of the phenyl rings (120^o), the oxygen atom has nothing to do with it

can the oxygen on the phenyl ether bond be replaced/substituted? or is it an essential molecule

it can be replaced! by -S or -CH₂ as long as the bond angle remains 120^o

which part of the thyroid hormone is responsible for a majority of the mass?

Iodine

in which peripheral tissues is the prohormone Thyroxine (T4) deiodinated?

liver and kidneys

what is the predominate circulating form of the thyroid hormone? and why

Thyroxine (T4)

more ionized = able to form ionic bonds with protein carriers

where is thyroxine (T4) formed?

thyroid gland ONLY

where is Triiodothyronine (T3) formed?

T4 conversion= 80%

thyroid gland= 20%

what isomer are ALL natural thyroid hormones?

L

does Iodine act as an EWG or a EDG?

EWG

makes phenolic -OH more acidic

what happens to most of the phenolic -OH located on T4?

ionized to -O (80% of the time)

due to more ionic binding

what happens to most of the phenolic -OH located on T3?

remains unionized (only 10% ionized at body pH)

due to more hydrogen bonding

which thyroid hormone is usually more ionized at body pH? and why

T4

iodine increase electronegativity —> increases molecule’s acidity —> more deprotonated/ionized at lower pHs

which thyroid hormone is the active form? and why

T3

not ionized at body pH —> better able to transport into nucleus —> can hydrogen bind to thyroid hormone receptor

is T3 preferred by receptors or by transport proteins?

receptors (hydrogen binding)

is T4 preferred by receptors or by transport proteins?

transport proteins (ionic binding)

what is the first step of thyroid hormone synthesis?

iodine taken into thyroid follicular cell by N/I symporter

what does the Na/I symporter do?

taken iodine from the blood up into the thyroid follicular cell

what drives the Na/I symporter? does it require energy?

sodium gradient

doesn’t require energy

what is the role of the thyroid peroxidase (TPO)? where is this located?

oxidizes iodine in the apical membrane (for MIT/DIT production)

after TPO, where does the now oxidized iodine bind to?

thyroglobulin

what is the role of thyroglobulin? after binding the oxidized iodine

forms MIT (monoiodotyrosine) and DIT (diiodotyrosine)

what catalyzes the coupling reaction?

TPO

which reaction is a target for some antithyroid drugs/ high-dose iodine treatments to treat hyperthyroidism?

coupling reaction

what is endocytosis? what is it facilitated by?

MIT/DIT/T3/T4 bound to thyroglobulin goes back into follicular cell

facilitated by TSH

what is proteolysis?

T4 and T3 released from the follicular cell into the bloodstream

the basal membrane is located between the follicular cell and the ______?

blood

the apical membrane is located between the follicular cell and the ______?

follicular colloid

where is thyroglobulin synthesized?

endoplasmic reticulum

where is thyroglobulin stored?

follicular colloid

are thyroid hormones soluble in water?

NO!

where is T4 deiodinated?

liver/kidney peripheral tissues and target cells

what does T3 play an important role in? (think: why is it important that pregnant mothers get enough iodine)

regulating metabolism

growth/development

maintaining homeostasis

where is Thyroid Stimulating Hormone TSH produced?

hypothalamus

what are the 3 carrier proteins?

thyroxine binding globulin (75%)

transthyretin (10-15%)

albumin (least)

why are thyroid hormones bound to carriers during transportation?

protect from thyroxine metabolism and secretion

which carrier binds most of the thyroid hormones?

thyroxine binding globulin

is there lots of free thyroid hormone is circulation? or is most of it bound

very little free thyroid hormone

almost 99% are bound

T3 vs. rT3 —> which is the active/inactive form?

T3= active

rT3= inactive (rings turn freely)

what does the thioamide propylthiouracil (PTU) do?

inhibits type I 5’D enzymes

catalyzes T4 —> T3

what is the ubiquitination mechanism?

inhibits type 2 5’D enzymes

type I 5’D generates T3 for _______? where are the enzymes located?

circulation in the thyroid, kidney, and the liver

type 2 5’D generates T3 for _______? where are the enzymes located?

local use in target tissues

what do type 1 & 2 5’Deiodinases generate?

T3

what does type 3 5’D do? where are the enzymes located?

INACTIVATES T3 (results in rT3) in all tissues

which enzyme converts T4 to T3 in peripheral tissue?

iodothyronine deiodinases (D)

aka: 5’D

thyroid hormone release pathway from hypothalamus ——→ target cells

hypothalamus releases TRH

TRH moves through hypophyseal portal system to pituitary glan, which stimulates release of TSH

TSH travels through bloodstream to the thyroid, which stimulates release of thyroid hormone

do thyroid hormones give a positive or negative feedback loop to the hypothalamus/pituitary gland?

NEGATIVE

too much T3/T4 leads to less TRH/TSH released

where is the Thyroid Releasing Hormone (TRH) located?

anterior pituitary gland

where is the Thyroid Stimulating Hormone (TSH) located?

basal membrane of thyroid

what type of receptors are TRH and TSH?

G-coupled Protein Receptors (GPCRs)

what 3 amino acids make up TRH?

histidine, proline, glutamate

which TSH subunit give specificity to the hormone?

beta

what types of bonds are present between the thyroid hormones and their receptors?

IONIC (carboxylate/arginine)

H-BOND (phenol/histidine)

where is the Thyroid Receptor located? what superfamily do they belong to?

nucleus of target cells in the nuclear superfamily

what are Thyroid Response Elements (TREs)?

what the Thyroid Receptors bind to