Sunteți pe pagina 1din 62

BIOCHIMIA HORMONILOR

CURS 1

A hormone (from Greek , "impetus") is


a chemical released by a cell, a gland, or an
organ in one part of the body that affects
cells in other parts of the organism. Only a
small amount of hormone is required to
alter cell metabolism. In essence, it is a
chemical messenger that transports a signal
from one cell to another.

Hypothyroidism

Hyperthyroidism

Addison disease

Cushing disease

Acromegaly

Growth hormone deficiency


and gigantism

Pheochromocytoma
(tumorof themedullaof the adrenal glands)

Cytostatic - Tamoxifenis anantagonistof theestrogen receptor

Method of measuring hormones

Catecholamines
(Adrenalin, Noradrenalin, Dopamine)

Catecholamines
Biologically-active water-soluble amines derived
from tyrosine that serve as neurotransmitters in the
CNS and as hormones in circulation in response to
psychological stress (fight or flight response) or
hypoglycemia:
Epinephrine (adrenaline)
Norepinephrine (noradrenlaine)
Dopamine
All three and are produced in chromaffin cells of
the adrenal medula of the sympathetic nervous
system and and post-ganglionic fibers of the
sympathetic division of the autonomic nervous
system.
Dopamine also acts as a neurotransmitter in the
CNS and is synthesized by neuronal cell bodies of
the substantia nigra and ventral tegmental area in
the midbrain (as well as serotonin)

Biosynthesis of
Catecholamines

Synthesis of Catecholamines

Tyrosine hydroxylase is the rate-limiting


step
DOPA decarboxylase is a pyridoxal-5-phosphatedependent enzyme
Dopamine -hydroxylase is a Cu2+-containing
enzyme
Catecholamines act at - and -adrenergic receptors
Ephedrine and pseudoephedrine are C 1-diastereometric
sympathomimetic amines of lower efficacy
Vasoconstriction and hypertensive activity of ephedrine
and pseudoephedrine are through -adrenergic receptors

Degradation of
Catecholamines

One released, catecholamines have a half-life of ca. 1


min due to subsequent inactivation
Monoamine oxidase (MAO) inactivates catecholamines
by oxidative deamination to yield the corresponding
aldehyde
Catechol-O-methyltransferase (COMT) also inactivates
catecholamines by methylation using Sadenosylmethionine (SAM) as the one-carbon donor
MAO inhibitors and methamphetamine block
catecholamine degradation, allowing their accumulation
in the presynaptic neuron and subsequent leakage into
circulation, providing an antidepressant action.

Important fetures of catecholamine


biosynthesis, uptake and signaling
1. Biosynthesis
2. Release
3. Uptake
(transporter)
4. Receptormediated
signaling
5. Catabolism

Tyrosine hydrogenase: rate-limiting


enzyme
1. TH is a homotetramer, each subunit has
m.w. of 60,000
2. Catalyzes OH group to meta position of
tyrosine
3. Km = M range; saturation under
normal condition
4. Cofactor: biopterin; competitive
inhibitor: -methyl-p-tyrosine
5. Sequence homology: phenylalanine
hydroxylase and tryptophan
hydroxylase
6. Phosphorylation at N-terminal sites:

Dopa decarboxylase
1. Cofactor: pyridoxine; low Km but high Vmax
2. Also decarboxylate 5-HTP and other aromatic a.a.:
aromatic amino acid decarboxylase (AAAD)
3. Inhibitor: -methyldopa

Dopamine -hydroxylase
1. Cofactor: ascorbate; substrate: dopamine
2. Inhibitor: diethyldithiocarbamate (copper chelator)
3. DBH is a tetrameric glycoprotein (77kDa and 73kDa)
4. Store in the synaptic vesicle and releasable

Phenylethanolamine N-methyltransferase
(PNMT) regulated by
Substrate: S-adenosylmethionine;
corticosteroids

Metabolism of dopamine

Major acidic
metabolites:
A. 3,4-dihydroxy
phenylacetic acid
(DOPAC)
B. Homovallic acid

Inactivation of Norepinephrine

Monoamine oxidase (MAO)


1. Cofactor: flavin; located on the outer membrane of
mitochondria
2. Convert amine into aldehyde (followed by aldehyde
dehydrogenase to acids or aldehyde reductase to glycol)
3. MAO-A: NE and 5-HT (inhibitor: clorgyline); MAO-B:
phenylethylamines (DA) (inhibitor: deprenyl)
4. Patient treated for depression or hypertension with
MAO inhibitors: severe hypertension after food taken
with high amounts of tyramine (cheese effect)

Catechol-O-methyltransferase
1. (COMT)
Enzyme can metabolize both intra- or extracellularly
2. Requires Mg2+ and substrate of S-adenosylmethionine

2-D structure of dopamine D2


receptor

Classification of Adrenergic receptors

1.

Features of Adrenergic
receptors
Both NE and epinephrine bind to and receptors

1 locates mainly in the heart and cortex; 2


predominate in the lung and cerebellum; 3 in the
adipose tissue (significance in obesity)
-receptor stimulates AC; in turn, inactivates receptor
via ARK and -arrestin
1 is a post-synaptic receptor (three subtypes: 1A, 1B
and 1D); while 2 is both post- and pre-synaptic
receptor (three subtypes: 2A, 2B and 2C)
5. Representative ligands: propranolol ( antagonist),
yohimbine ( agonist)

propanolol

yohimbine

Dynamics of catecholamine
receptors
agonist
antagonist

(up-regulation and downregulation)

catecholamine receptor