Hormone Chemistry and Mode of Action

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Hormone Chemistry and Mode of Action

Chapter 17

Hormone Chemistry

and Mode of Action


• Three Chemical Classes

– steroids

• derived from cholesterol

• secreted by gonads and adrenal

glands

• estrogens, progesterone,

testosterone, cortisol, corticosterone,

aldosterone, DHEA, and calcitriol

– peptides (and glycoproteins)

• created from chains of amino acids

• secreted by pituitary and

hypothalamus

• oxytocin, antidiuretic hormone,

releasing and inhibiting hormones,

and anterior pituitary hormones

– monoamines (biogenic amines)

• derived from amino acids

• secreted by adrenal, pineal, and

thyroid glands

• epinephrine, norepinephrine,

melatonin, and thyroid hormone

• Note: all hormones are made from either

cholesterol or amino acids with carbohydrate

added to make glycoproteins.

O

HO

(a) Steroids

(c) Peptides

Hormone

Chemistry

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CH 3

Angiotensin II

Testosterone

Estradiol

Insulin

CH 3

OH

H 2 N

OH

CH 3

I

I

OH

Thyroxine

OH

HO

CH CH 2

HO

(b) Monoamines

I

H

C

CH 2

O

Epinephrine

S

S

S

COOH

Pro Thr Tyr Asn

Phe Cys Tyr Asn Glu

Lys

Phe

Leu

S

Gln

Thr

Gly

Gly

Tyr

Arg

Leu

lle

Glu

S

Ser

Val

Gly

Cys

Glu

Cys

Gln

Val

lle

Cys

Ser

Thr Cys

Leu

Tyr

Arg Val Tyr

Leu

Asp

lle

Ala

His

Glu

Val

Pro Phe

Leu His Ser Gly Cys Leu

His

Gln

Asn

Val

Phe

S

I

NH

CH 2


Hormone Synthesis: Steroid Hormones

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CH 3

CH 3

HO

Cholesterol

CH 3

CH 3

CH 3

C O

CH 3

CH 3

C

O

Progesterone

CH 2 OH

OH

C O

CH 3

HO

CH 3 OH

HO

CH

O 2 OH

O

HC

CH 3

CH 3

CH 3

CH 3

O

Testosterone

O

Cortisol (hydrocortisone)

O

Aldosterone

OH

HO

Estradiol

• synthesized from cholesterol – differs in functional

groups attached to 4-ringed steroid backbone


Peptides

• synthesized in same way as any

protein

• at first is an inactive pre-prohormone

• first several amino acids is a signal

peptide that guides it into cisterna of

rough endoplasmic reticulum

• signal peptide removed to form

prohormone

• Golgi does final transformation to

hormone packaged for secretion


Hormone Synthesis: Insulin

• begins as preproinsulin,

then

becomes proinsulin

• when connecting

peptide is removed,

two polypeptide chains

are formed that make

up insulin

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C peptide

Proinsulin

Insulin


Monoamines

• Synthesized from amino acid

• melatonin is synthesized from

amino acid tryptophan

• thyroid hormone is composed

of 2 tyrosines


Thyroid Hormone Synthesis

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Thyroid follicle

Blood capillary

Transport

proteins

I −

Iodide

1 Iodide absorption and oxidation

5

1

Follicle cell

2 Thyroglobulin synthesis and secretion

T 3

T 4

3 Iodine added to tyrosines of thyroglobulin

4

Thyroglobulin uptake and hydrolysis

Lysosome

4

I –

2

Thyroglobulin

5 Release of T 4 and a small amount of T 3 into

the blood

I *

Iodine

Stored

thyroglobulin

3


T 3 and T 4 Synthesis

• follicular cells

– absorb iodide (I - ) ions from blood and store in

lumen as a reactive form of iodine

– synthesize thyroglobulin and store in lumen

• forms colloid

• contains lots of tyrosine

– tyrosine and iodine combine to form thyroxine (T 4 )

bound to thyroglobulin

– stored in follicle

• TSH

– stimulates follicular cells to remove T 4 from

thyroglobulin for release into plasma

– most T 3 is produced in liver or by target cells

removing an iodine from circulating T 4

– 95% T 4 and 5% T 3


Chemistry of Thyroid Hormone

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Thyroglobulin

CH 2

CH 2

Tyrosine

OH

DIT

l

l

OH

+

1

Addition of iodine to

tyrosine to form MIT

DIT

l

l

OH

3 Two DITs

combine to

form thyroxine (T4)

CH 2

MIT

CH 2

I

OH

l

l

O

OH

l

l

2

Addition of another

iodine to form DIT

H 2 N

H

C

4

CH 2

Thyroxine

released from

thyroglobulin

COOH

CH 2

DIT

Figure 17.19

l

l

OH

MIT contains one iodine atom, DIT has two

T 3 - combination of MIT plus DIT

T 4 - combination of two DITs

l

l

O

l

l

OH


Hormone Transport

• most monoamines and peptides are hydrophilic

– mix easily with blood plasma

• steroids and thyroid hormone are hydrophobic

– bind to transport proteins (albumins and globulins synthesized

by the liver)

– these hormones are “bound hormones”

– have longer half-life

– protected from liver enzymes and kidney filtration

– transport proteins protect circulating hormones

– being broken down by enzymes in the plasma and liver

– being filtered out of the blood by the kidneys

– only unbound hormone leaves capillaries to reach target cell

• thyroid hormone binds to three transport proteins in the

plasma

– albumin, thyretin and TGB (thyroxine-binding globulin)

– more than 99% of circulating TH is protein bound

• steroid hormones bind to globulins

– transcortin – the transport protein for cortisol

• aldosterone - short half-life; 85% unbound, 15% binds

weakly to albumin and others


Hormone Receptors

• hormones stimulate only those cells that have

receptors for them

• receptors are protein or glycoprotein molecules:

– on plasma membrane, in the cytoplasm, or in the

nucleus

• receptors act like switches turning on metabolic

pathways when hormone binds to them

• usually each target cell has a few thousand

receptors for a given hormone

• receptor-hormone interactions exhibit specificity

and saturation

– specific receptor for each hormone

– saturated when all receptor molecules are occupied by

hormone molecules


Hormone Mode of Action

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Transport

protein

Free

hormones

Bound

hormone

Blood

Hydrophilic

hormone

Receptor in

plasma

membrane

Secondmessenger

activation

Hydrophobic

hormone

Receptor in

Tissue fluid

nucleus

Target

cell

• hydrophobic hormones

– penetrate plasma

membrane and enter

nucleus

– act directly on the genes

changing target cell

physiology

– estrogen, progesterone,

thyroid hormone act on

nuclear receptors

– take several hours to days

to show effect due to lag

for protein synthesis

• hydrophilic hormones

– cannot penetrate into

target cell

– must stimulate

physiology indirectly


Thyroid Hormone

TBG

• thyroid hormone enters target

cell by diffusion – mostly as T 4

with little metabolic effect

Various

metabolic effects

• within target cell, T 4

is

converted to more potent T 3

Protein

synthesis

mRNA

• T 3

enters target cells and binds

to receptors in chromatin

T 3

T 4

T 4

T 3

I

DNA

• activates genes

– make a muscle protein

(myosin) enhancing cardiac

muscle response to

sympathetic stimulation

– strengthening heartbeat

Blood

Tissue fluid

Target cell


Peptides and Catecholamines: Hydrophilic

1

Receptor

G

GTP

ACTH

FSH

LH

PTH

TSH

Glucagon

Calcitonin

Catecholamines

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Hormone

G protein

GDP

+

P

i

2

Adenylate

cyclase

G

ATP cAMP + PP

3 i

4

Inactive protein

kinase

Inactive

enzymes

Activated protein

kinase

5

6

Enzyme

substrates

Activated

enzymes

Enzyme

products

Various

metabolic

effects

1

2 G protein activates adenylate cyclase.

3 Adenylate cyclase produces cAMP.

4 cAMP activates protein kinases.

5

6

Hormone–receptor binding

activates a G protein.

Protein kinases phosphorylate enzymes.

This activates some enzymes and

deactivates others.

Activated enzymes catalyze metabolic

reactions with a wide range of possible

effects on the cell.

• hormone binds to cell-surface

receptor

• receptor linked to second

messenger system on other

side of the membrane

• activates G protein which

• activates adenylate cyclase

• produces cAMP

• activates or inhibits enzymes

• possible metabolic reactions:

– synthesis

– secretion

– change membrane potentials


Other Second Messengers

Diacylglycerol (DAG) pathway

Inositol triphosphate (IP 3 ) pathway

1

Hormone

Ca 2+ -gated

ion channel

Ca 2+

IP 3 -gated Ca 2+ channeI

Hormone

1

Receptor

Phospholipase

Phospholipase

Receptor

3

DAG

G

IP G

3

G

4 6

2 2

Inactive Activated

8

5

PK

PK

G

Various

metabolic

effects

Enzyme

Activated

PK

9

10

Calmodulin

Ca 2+

IP 3

IP 3

7

Hormones

ADH

TRH

OT

LHRH

Catecholamines

Key

DAG

G

IP 3

PK

Diacylglycerol

G protein

Inositol triphosphate

Protein kinase

Inactive

PK

Smooth

ER

• diacylglycerol (diglyceride) second-messenger system

• inositol triphosphate second-messenger system

• act on cell metabolism in a variety of ways


Enzyme Amplification

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Small stimulus

Hormone

cAMP and

protein kinase

Activated enzymes

Metabolic product

Great effect

Reaction cascade (time)

• hormones are

extraordinarily potent

chemicals

• one hormone

molecule can trigger

the synthesis of many

enzyme molecules.

• very small stimulus

can produce very

large effect

• circulating

concentrations very

low


Modulation of Target Cell Sensitivity

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Hormone

Receptor

Low receptor density

Weak response

(a ) Up-regulation

High receptor density

Strong response

(b ) Down-regulation

Increased receptor density

Increased sensitivity

Reduced receptor density

Reduced sensitivity

Response

Stronger response

Response

Diminished response

• target cell sensitivity

adjusted by changing the

number of receptors

• up-regulation means

number of receptors is

increased

– sensitivity is increased

• down-regulation reduces

number of receptors

– cell less sensitive to hormone

– happens with long-term

exposure to high hormone

concentrations

• bind to other receptors

• converted to different hormone


Hormone Interactions

• most cells sensitive to more than one

hormone and exhibit interactive effects

• synergistic effects

– multiple hormones act together for greater effect

• synergism between FSH and testosterone on sperm

production

• permissive effects

– one hormone enhances the target organ’s

response to a second later hormone

• estrogen prepares uterus for action of progesterone

• antagonistic effects

– one hormone opposes the action of another

• insulin lowers blood glucose and glycogen raises it


Hormone Clearance

• hormone signals must be turned off

when they have served their purpose

• most hormones are taken up and

degraded by liver and kidney

– excreted in bile or urine

• metabolic clearance rate (MCR)

– rate of hormone removal from the blood

– half-life - time required to clear 50% of

hormone from the blood

– faster the MCF, the shorter is the half-life

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