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Catecholamines Catecholamine Biosynthesis

Made by the adrenal medulla and by the


HC O
sympathetic and parasympathetic nervous
system. HO CH 2 CH NH 2

Tyrosine hydroxylase is the rate limiting Tyrosine


step. Tyrosine hydroxylase

Glucocorticoids from the adrenal cortex HO


HC O
increase the synthesis of DBH in the adrenal
medulla. HO CH 2 CH NH 2
Dopa
Norepinephrine is converted to epinephrine
by phenylethanolamine-N-methyltransferase. Dopa decarboxylase
HO
Epinephrine is only made in the adrenal
medula.
HO CH 2 CH 2 NH 2
Degraded by catechol-O-methyltransferase Dopamine
(COMT) and monoamine oxidase
Dopamine -hydroxylase
(deaminates the catecholamine).
HO
Pheochromocytomas are tumors of the OH
adrenal medulla that overproduce
HO CH 2 CH 2 NH 2
epinephrine and norepinephrine.
Norepinephrine

PNMT
HO
OH CH 3

HO CH 2 CH 2 NH
Epinephrine

Eicosanoids
COO-
Made from arachidonic acid, a fatty acid with 20 carbons (eikosi O
= 20 in Greek) and 4 double bonds (20:4).
O C CH 3
Arachidonic acid can be converted into prostaglandin H2 by
prostaglandin synthase
Aspirin
Prostaglandin synthase has two components, a (Acetylsalicylate)
cyclooxygenase and a hydroperoxidase
+
Prostaglandin H2 (PGH2) is the precursor to prostacyclin, E Ser OH
thromboxanes and other prostaglandins.
The cyclooxygenase is inhibited by aspirin (acetylsalicylate) Salicylate
due to acetylation of a specific serine in the enzyme. Aspirin
therefore has anti-inflammatory activity. O
E Ser O C CH 3

Danielsen Inactive enxyme 9


Aspirin is also antithrombotic because it inhibits formation of PGH2 the precursor of

EICOSANOIDS

OH

COO-

CH 3 OH

Leukotriene B 4

Lipoxygenases

COO-

CH 3

Arachidonate

Aspirin irreversibly inhibits Prostaglandin synthase


cyclooxygenase activity (Cyclooxygenase, Hydroperoxidase)

COO-
O

CH 3
O

Prostacyclin synthase OH T hromboxane synthase


Prostaglandin H 2

COO-
COO-
O CH 3 O
Other prostaglandins CH 3
O

OH
OH
OH Prostacyclin (PGI 2) Thromboxane

thromboxane A2, a potent aggregator of blood platelets.

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Mode of Action

Classical Endocrine

The classic definition: hormones are chemicals secreted by specific tissues into the blood stream
that then act on target organs. Examples include:

Class of Hormone Examples


Steroid hormones glucocorticoids produced in the adrenal cortex act on the liver.
Vitamin D produced in the kidney acts on the intestine.
Protein hormones Insulin produced in the pancreas acts on adipose tissue.
Glycoprotein hormones TSH produced in the anterior pituitary acts on the thyroid.
Peptide hormones glucagon produced in the pancreas acts on the liver.
Thyroid hormones thyroxine (T4) produced in the thyroid acts on muscle.
Amino acid derivatives Norepinephrine produced in the adrenal medulla act on the heart

Paracrine

Hormones act on an adjacent cell type to the one that produced the hormone. All chemical classes of
hormone can potentially act in a paracrine manner. Examples include:

Class of Hormone Examples

Steroid hormones testosterone synthesized in the Leydig cells, acts on seminiferous


tubules
Protein hormones insulin produced in B-cells acting on A-cells

Amino acid derivatives histamine, released by mast cells, acts locally on blood vessels.
Neurotransmitters and neuromodulators
Eicosanoids prostaglandins released in inflammation

Autocrine

Hormones act on the cells that produce the hormone. This is a much rarer event than paracrine or
endocrine action. It requires that the hormone producing cells have the receptor for that hormone. It is
not thought to occur with steroid or thyroid hormones. Examples include:

Class of Hormone Examples


Proteins/peptides e.g. growth factors.
Eicosanoids e.g. prostaglandins

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Endocrine System Hormones secreted by specific tissues into the blood
stream and then act on target organs. This is the classic
definition of a hormone.
Testosterone produced by the testis acts on skin.
Paracrine System Hormones secreted by one cell type and act on an adjacent
cell type in the same tissue/organ.
Histamine, released by mast cells, acts locally on blood
vessels.
Testosterone synthesized in the Leydig cells, acts on
seminiferous tubules
Autocrine System Hormones secreted by one cell type and act on the same
cell type.
Prostaglandins, possibly some growth factors.

BIOSYNTHESIS and MODIFICATION

Secreted in Active Form. e.g. Hydrocortisone, aldosterone, T3, estradiol,


catecholamines.

e.g.
Intracellular Processing Before Secretion. Tissue specific processing of the 285 amino
acid polypeptide pro-opiomelanocortin
(POMC) to ACTH, -lipotropin, -endorphin,
MSH, MSH.
Proinsulin, Preproparathyroid hormone,
Thyroglobulin to T3 and T4.

e.g.
Activated Peripherally in Target Tissues. Thyroxine (T4) to triiodothyronine (T3).
Testosterone to dihydroxytestosterone.
Testosterone to 17-estradiol.

Activated Peripherally in Target and/ore.g. Dehydroepiandrosterone (adrenal) to


Non-Target Tissues. androstenedione (liver), to testosterone or
estradiol in fat, liver or skin.
Vitamin D3 from skin to 25-
hydroxycholecalciferol in liver, to 1,25-
dihydroxycholecalciferol in kidney.

Structural similarity, functional e.g The glycoproteins TSH, LH, FSH, and hCG
diversity are heterodimers with and subunits. The
subunits are all the same.

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Biosynthesis and Modification
Much of the specificity of hormone action is due to the way in which hormones are synthesized and
modified.

Synthesis
Steroid hormones
Derived from cholesterol and are synthesized in either the ER or mitochondria.
The types of steroids produced by specific cells is determined by their complement of enzymes.
Since they are lipid soluble, they are not stored within cells but are released immediately synthesis
The main mechanism controlling circulating levels of steroid hormones is the rate of synthesis.
Thyroid hormones
Synthesized as an inactive precursor within the colloid of the thyroid (as part of thyroglobulin)
Many weeks of thyroid hormone can be stored in the thyroid.
The main mechanism controlling circulating levels of thyroid hormones is therefore release.
Proteins/glycoproteins/peptides/amino acid derivatives
Synthesized on the RER and Golgi
Stored in secretory vesicles
Can be stored as inactive complexes
The main mechanism controlling circulating levels of these hormones is therefore release.
Eicosanoids
Synthesized in membranes
Have a very short half-life.
They are not stored.
Act locally.

Modification
Steroid Hormones
Secreted in an active form.
Can be converted into more active forms at the target tissue.
Can be converted into a hormone with a different specificity at the target tissue. For instance,
testosterone can be converted into estradiol.
Thyroid hormones
Both T4 and T4 are released from the thyroid.
T4 can be converted into the more active T3 at the target tissue.
Proteins/glycoproteins/peptides/amino acid derivatives
All protein-derived hormones are made as a precursor
The modification of the precursor to give the active hormone can be tissue specific.
One precursor can give rise to more than one hormone
Eicosanoids
All are produced from arachidonic acid.
They are not stored
Product formed depends on the compliment of enzymes present in the synthesizing cell.
Have the potential to be modified in the target cell.

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Hormone Transport
Carrier proteins act as a reservoir for hormone; they protect against degradation, and thus increase
the half-life of the hormone.
Carrier proteins act as a buffer to prevent large surges in hormone levels
Only isoprenoid derived hormones and insulin like growth factors (IGFs) bind to carrier proteins.
There are at least 6 IGF-binding proteins. These are unusual in that they bind hormone with high
affinity and that they play a role in the control of IGF activity.

HORMONE TRANSPORT

Isoprenoid derived Bound to carrier proteins in the circulation. Low affinity,


Steroid high capacity. Only free hormone has biological activity.
Vitamin D Bound form cannot be metabolized or excreted. Act as
Retinoid reservoirs of hormone. Half-lives of these hormones are
Thyroid hours to days.
Insulin-like growth factors

All others Do not bind carrier proteins, half-life seconds to minutes.

Hormone Primary Binding Protein Percent Hormone Bound

Aldosterone Albumin 50
Cortisol CBG 90
Estrogen TeBG uncertain
Testosterone TeBG/albumin 97
Vitamin D D-Binding protein Varies by type of Vit. D
Retinoic acid Albumin uncertain
Triiodothyronine (T3) TBG 99.7
Thyroxine (T4) TBG 99.97
IGF1 IGF-binding proteins Varies by BP (6 forms of BP).
CBG, Corticosteroid Binding Globulin, TeBG, testosterone binding globulin,
TBG Thyroid hormone binding globulin.
Carrier-
bound
hormone

Endocrine Free Hormone


cell hormone receptor

Hormone
degradation Biological
Danielsen effects 14
Hormone Receptors
All receptors transduce a signal, therefore at least 2 functional domains.

Hormone binding domain. Specific high affinity, reversible binding, can be determined by binding
assays (Scatchard plots).
Agonists bind and bring about a response.
Antagonists bind and inhibit agonist responses.
Antagonists are often weak agonists.

Transducing Domain. Induction of second messengers, activation of transcription.

Comparison of Binding Proteins and Receptors


Carrier proteins are not receptors they are merely binding proteins
In endocrinology, receptors are defined as proteins that bind specifically to a hormone and transduce
a response.
That is hormone binding initiates a signal cascade within the cell.
Receptors thus have at least two activities/domains; a hormone-binding domain and a transduction
domain
Hormone binding can give rise to the formation of second messengers such as cAMP or they can
bind to DNA and modulate transcription.

Feature Receptors Plasma Transport


Proteins
Concentration Very Low (thousands/cell) Very high (billions/l)
Binding affinity (Kd) Very High (10-11 to 10-9) Low (10-7 to 10-5)
Binding specificity High Low
Saturable at physiological Yes No
concentrations
Reversibility Yes Yes
Signal Transduction Yes No

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