Biochem-Thyroid

7/23/2019 Biochem-Thyroid

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Biochemical aspects of

thyroid hormonemetabolism

Mahmoud A. Alfaqih BDS

PhDJordan University of

Science and Technoloy

material " #linical #hemistry. Principles techniques and corre#hapter $%


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&vervie'

The thyroid gland, locatedimmediately below the larynx oneach side of and anterior to thetrachea

Thyroid gland is one of thelargest of the endocrine glands,normally weighing 15 to 20grams in adults

The thyroid secretes two major

hormones, thyroxine andtriiodothyronine, commonlycalled T4 and T3, respectiely

!alcitonin is secreted by para"follicular cells #$noled in

calcium metabolism


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&vervie'

%bout &3' of the metabolically actiehormones secreted by the thyroid gland isthyroxine #T4()

*' is triiodothyronine)

%lmost all the thyroxine is eentuallyconerted to triiodothyronine in the

tissues)


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Di(erences bet'een T)and T%

They di+er in rapidity and intensity ofaction) ow-

Triiodothyronine is about four timesas potent as thyroxine)

Triiodothyronine is present in theblood in much smaller .uantities

T3 has a shorter half life than T4


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*ote

$n tissues, most of the e+ect of T4 resultsfrom its conersion to T3)

This reaction is cataly/ed by selenium"containing en/yme iodothyroninedeiodinases)

eiodination can also produce reersetriiodothyronine #rT3( #physiologicallyinactie(


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#onenital+ypothyroidism

Thyroid hormone is critical to neurologic deelopment of thefetus)

!ongenital hypothyroidism occurs in 1 of 4,000 lie births)

$f the mother has normal thyroid function, the fetus is protectedduring deelopment by maternal thyroid hormone crossing theplacenta)

ostpartum, newborns re.uire initiation of appropriate doses ofthyroid hormone or neurologic deelopment will be impaired

creening tests are performed on all newborns to diagnosecongenital hypothyroidism and preent complications


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#retinism


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hysiologic anatomy of the thyroid

gland

The thyroid gland is composed ofclosed follicles lled with colloid)

ollicles are lined with cuboidal

epithelial cells that secrete colloid

!olloid is mainly made fromthyroglobulin #large glycoprotein(

Thyroid hormones are foundwithin thyroglobulin)


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Ma,or Actions of thyroidhormones

Thyroid hormones are essential fornormal ro'th and development andhae many e+ects on metabolic processes

They stimulate the synthesis of a numberof hormones and en/ymes)

ne of the 6ey en/ymes stimulated iscytochrome oxidase


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Their oerall e+ect on metabolism is tostimulate the basal metabolic rate,o-yen consumptionand heat

production)

Thyroid hormones increase net catabolism)

7eight loss, muscle wasting and heatintolerance are features of excessiesecretion of thyroid hormones)


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Thyroid hormones increase thesensitiity of the cardioascular andnerous systems to catecholamines)

This leads to an increases in heartrate, cardiac output, and to increased

arousal)


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Synthesis of thyroidhormones

Thyroid hormone synthesis inoles anumber of specic en/yme"catalysedreactions)

ynthesis begins with the upta6e ofiodide by the gland and ends in the

iodination of tyrosine residues in theprotein thyroglobulin)

%ll of these reactions are stimulated


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Synthesis Detailed reactions/. 0odide trappin

The rst stage in the formation of thyroid hormones, istransport of iodides from the blood into the thyroid gland)

The basal membrane of the thyroid cell has the specicability to pump the iodide actiely to the interior of the cell)

The iodide pump concentrates the iodide to about 30 timesits concentration in the blood)

The rate of iodide trapping by the thyroid is in8uenced bythe concentration of TS+)


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!adioactive iodine upta1e 2!A0U3can help dianose thyroid disease


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Thiocyanate

0ons Decrease0odide Trappin


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A note aboutthyrolobulin

9ach molecule of thyroglobulin contains about *0tyrosine amino acid residues)

These tyrosine residues are the substrates that bind

with iodine to form the thyroid hormones)

Thyroid hormones form within the thyroglobulinmolecule)

Thyroid hormones remain part of thyroglobulin duringsynthesis and later on during storage of the colloid)


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Synthesis Detailed reactions$. &-idation of iodide ion.

This is conersion of the iodide ions to an oxidi/edform of iodine

$odide ion is conerted to $2that is capable of

combining directly with tyrosine)

xidation of iodine is cataly/ed by peroxidase and

its accompanying hydrogen peroxide, which proidea potent system capable of oxidi/ing iodides)

7hen the peroxidase system is bloc6ed rate of

synthesis falls down to /ero)


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Synthesis" Detailed reactions%. &rani4cation and couplin

The binding of iodine with the thyroglobulin molecule is calledorganication of the thyroglobulin)

This process is cataly/ed by the en/yme iodinase

Tyrosine is rst iodi/ed to monoiodotyrosine #:$T( and then todiiodotyrosine #$T(

$odotyrosine residues become coupled with one another and the

coupling reactions result in the formation of thyroid hormones T4 andT3

;nder normal condition *0' of tyrosine residues of thyreoglobulin arein the form :$T and $T and 30' as thyroxine #with minor part of T 3(


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&rani4cation and couplin


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&rani4cation and couplin


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Propylthiouracil inhibitpero-idase en5yme as'ell as couplin of

iodinated tyrosineresidues


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Storae of thyrolobulin

Thyroid gland can store large amounts of hormone #unli6eother endocrine glands()

9ach thyroglobulin molecule contains up to 30 thyroxine

molecules and a few triiodothyronine molecules)

The thyroid hormones stored in the follicles are su


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!elease and Secretion ofthyroid hormones

Thyroglobulin itself is not releasedinto the circulating blood)

Thyroxine and Triiodothyronine arecleaed from the thyroglobulin andthen released)


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!elease and secretion of thyroidhormones

1) Thyroid cells sends out pseudopod extensions thatclose around portions of the colloid to form pinocyticesicles)

2) =ysosomes in the cell cytoplasm immediately fuse withthese esicles)

3) :ultiple proteases digest the thyroglobulin moleculesand release thyroxine and triiodothyronine in free form)

4) T4 and T3 then di+use through the base of the thyroidcell into the surrounding capillaries)


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Textboo6 of >iochemistry with !linical !orrelations, *e edited by Thomas :) elin ? 2011 @ohn 7iley A ons, $nc.

6iure $$./) #ellular mechanisms for T%and T)release into bloodstream.Bedrawn from >erne, B) :), and =ey, :) =)#9ds)() hysiology, 2d ed) Cew Dor6E :osby, 1&&0, &3F.


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!ecyclin of iodine

uring the digestion of the thyroglobulinmolecule to release thyroxine andtriiodothyronine, :$T and $T released fromthyroglobulin

:$T and $T are not secreted into the blood inlarge amounts)

$nstead, their iodine is cleaed by deiodinaseen/yme that ma6es iodine aailable for ma6ingthyroid hormones)


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!eulation of thyroid hormonesecretion

/. TS+ T #thyrotropin( an anterior pituitary hormone is chemically a

glycoprotein)

This hormone, increases the secretion of thyroxine andtriiodothyronine by the thyroid gland)

pecic e+ects on thyroid glandE

1) $ncreased proteolysis of the stored thyroglobulin)

2) $ncreased actiity of the iodide pump)

3) $ncreased iodination of tyrosine to form the

thyroid hormones)

4) $ncreased si/e and increased secretory actiity of

the thyroid cells #hypertrophy()

5) $ncreased number of thyroid cell #hyperplasia()


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Cote

The most important early e+ect afteradministration of T is to initiateproteolysis of thyroglobulin)

Thyroxine and triiodothyronine will getreleased into the blood within 30 minutes)

:ost of the e+ects of T are mediated byc%: second messenger system)


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!eulation of thyroid hormonesecretion

2) Thyrotropin"Beleasing ormone #TB(

%nterior pituitary secretion of T is controlled by ahypothalamic hormone, thyrotropin"releasinghormone #TB()

TB is secreted by nere endings in the medianeminence of hypothalamus)

TB is transported to the anterior pituitary by

hypothalamic hypophysial portal blood)

TB causes an increase in the output of T byanterior pituitary)


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!eulation of thyroid hormone secretion3) !old and %nxiety

!old is a stimuli for increasing therate of TB secretion by thehypothalamus and therefore T

secretion by the anterior pituitarygland)

9xcitement and anxiety cause anacute decrease in the rate ofsecretion of T)

db 6 + f h id


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eedbac6 9+ect of Thyroid ormoneto ecrease %nterior ituitary

ecretion of T


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Transport of thyroidhormones

7hen released into the circulation, only 0)04' of T4 and 0)4' of T3

are unbound by proteins #physiologically actie(

The three major binding proteins, in order of signicance, arethyro-ine7bindin lobulin 2TB839 thyro-ine7bindin

prealbumin9 and albumin

The .uantity of T4 and T3 in the circulation can be a+ected by theamount of binding protein aailable for carrying these hormones

igh T>G leels result in higher leels of bound thyroid hormones,

leading to high leels of total T3 and total T4

:easurement of free T) and free T% may be necessary toeliminate any confusion caused by abnormal binding protein leels


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Mechanism of action of thyroidhormones


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Mechanism of action of thyroidhormones

ree thyroid hormone receptor #TB( without boundhormone is bound to hormone response elementof C% #+!:( and corepressor#!oB(

>inding T3to its receptor liberates co"repressor

and recruits coactiator and BC% polymerasewhich dries mBC% transcription


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Thyroid autoantibodies

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