biochemistry of hormones derived from amino acids and proteins
TRANSCRIPT
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Biochemistry of hormones
derived from amino acids and
proteins
Martina Srbová
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Hormones derived from amino acids and
proteins
Hydrophilic signal molecules
1. Amino acid derivatives hormones
Catecholamines
! thyroxine – lipophilic !
2. Protein hormones
Small peptide hormones (thyrotropin releasing hormone, oxytocin, vasopressin)
Protein hormones (insulin, growth hormone)
Glycoprotein hormones (luteinizing hormone, follicle-stimulating hormone and
thyroid-stimulating hormone)
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Synthesis of protein hormones
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Genes and formation of protein hormones
Genes for protein hormones contain the information for the hormone
1. More than one hormone is encoded in a gene
Proopiomelanocortin peptide family
Vasopressin and neurophysin II; oxytocin and neurophysin I
2. Multiple copies of a hormone are encoded in a gene
e.g. Enkephalins
3. Only one hormone is encoded in a gene
e.g. CRH
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1. Proopiomelanocortin (a single gen product) is a precursor peptide for nine hormones
ACTH, β-lipotropin, γ-lipotropin, γ-MSH, α-, β-MSH, CLIP, β-endorphine, enkephalins
Proopiomelanocortin occurs in both the corticotropic cells of the anterior pituitary and the pars intermedia cells, the products are different
CLIP-corticotropin-like
intermediary peptide
(under control of norepinephrine)
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Proopiomelanocortin peptide family
Contains hormones (ACTH, LPH, MSH) and neurotransmitters
Precursor molecule involves 285 amino acids
Gene expression in the anterior and intermediary pituitary, but also in other tissues
(intestine, placenta, male reproductive system)
Cleavage into peptides, further modification (glycosylation, acetylation,
phosphorylation)
ACTH: acts on cells in the adrenal gland to increase cortisol production and secretion;
β-lipotropin: induces lipolysis, precursor of β-endorphine
Endorphines: endorphines bind to the opioid receptors in CNS, analgesia
MSH: acts on skin cells to cause the dispersion of melanin (skin darkening)
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2. Multiple copies of a hormone can be encoded on a
single gene
The gene product for enkephalins (located in the adrenal medulla)
Enkephalins are pentapeptides with opioid activity
Tyr-Gly-Gly-Phe-Met (methionine-enkephalin)
Tyr-Gly-Gly-Phe-Leu (leucine-enkephalin)
Model of enkephalin precursor
encodes several met-enkephalins (M) molecules and a molecule of leu-enkephalin (L)
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Hydrophilic hormones interact with specific receptors on
the cell surface Hormone or
neurotrasmitter
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G protein-coupled receptors
Signal transduction via:
1. Protein kinase A pathway (the elevation of cAMP activates protein kinase A)
Corticotropin releasing hormone, thyrotropin, luteinizing hormone, follicle stimulating hormone, adrenocorticotropic hormone, vasopressin, opioid peptides, norepinephrine, epinephrine
2. Protein kinase C and IP3-Ca2+ (inositoltriphosphate) pathway (triggering of the hydrolysis of phosphatidylinositol-4,5-bisphosphate and stimulation of protein kinase C)
Thyrotropin releasing hormone, gonadotropic releasing hormone, thyrotropin, norepinephrine, epinephrine, angiotensin
3. Protein kinase G pathway (the elevation cGMP activates protein kinase G)
Atrionatriuretic factor
Protein kinase receptors
e.g. Tyrosin specific protein kinases (Insulin)
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Protein hormones
Hormones of the hypothalamus-hypophysis cascade
Hormones produced by other tissues
heart (atrionatriuretic factor)
pancreas (insulin, glucagon, somatostatin)
gastrointestinal tract (cholecystokinin, gastrin)
fat stores (leptin)
parathyroid glands (parathyroid hormone)
kidney (erythropoietin)
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Hypothalamus
GRH TRH CRH PRF, PIF GnRH
GH TSH ACTH LPH β-Endorphin PRL FSH LH MSH
Anterior pituitary
Growth of bone, body
tissues; carbohydrate
and protein
metabolism;
Hyperglycemic
effects
Thyroid hormones
Liver Thyroid Adrenal cortex Mammary gland Ovary
Testis
Corticosteroids
β-Endorphin
Analgesia
Skin darkening
Testis
Cell
development,
lactation
Development of
follicles, estradiol
Growth of seminal
tubules and
spermatogenesis
Ovary
Ovulation,
corpus luteum,
progesterone
Interstitial cell
development,
testosterone
GH-Growth hormone, TSH-Thyrotropin, ACTH-Adrenocorticotropic hormone, LPH-Lipotropin,
MSH-Melanocyte stimulating hormone, PRL-Prolactin, FSH-Follicle stimulating hormone, LH-Luteinizing hormone
norepinephrine
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Hypothalamic releasing hormones (RH)
Releasing hormone Number of
amino acids Anterior pituitary hormone
released or inhibited
Thyrotropin releasing hormone
(TRH)
3 Thyrotropin (TSH)
Gonadotropin releasing hormone
(GnRH)
10 Luteinizing hormone (LH), Follicle
stimulating hormone (FSH)
Corticotropin releasing hormone
(CRH)
41 Adrenocorticotropic hormone
(ACTH), β-lipotropin, β-endorphin
Growth hormone releasing
hormone (GHRH)
44 Growth hormone (GH)
Somatostatin 14 GH release inhibited
Prolactin releasing factor (PRF) Prolactin (PRL)
Prolactin release inhibiting factor
(PIF), Dopamine
PRL release inhibited
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Clinical correlation of the hormonal cascade
Testing the activity of the anterior pituitary
For example infertility: which organ is at fault in the hormonal cascade?
Step 1 The gonads must be considered
Step 2 The anterior pituitary must be tested
No response
The anterior pituitary is nonfunctional
injecting LH or FSH
if sex hormone is elicited, the gonads function properly
i.v. administration of GnRH (secretion of LH and FSH;
by RIA)
Normal response
The hypothalamus is nonfunctional
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Hypopituitarism
The deficiency of one or more hormones of the pituitary gland
The connection between the hypothalamus and anterior pituitary can be
broken by
1. Trauma (automobile accidents)
2. Tumor of the pituitary gland
Decreased generation of the pituitary hormones
A life-threatening situation
The usual therapy involves administration of the end organ hormones
(cortisol, thyroid hormone, sex hormones, progestin, growth hormone in
children)
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Vasopressin and oxytocin
Synthetized in the hypothalamus (nucleus supraopticus and paraventricularis)
Axonal transport with transport proteins (neurophysins)
Nonapeptides with disulfide bridge
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2
Arginine vasopressin
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2
Lysine vasopressin
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH2
Oxytocin
Structural similarity, overlapping functions
Oxytocin: causes milk ejection in lactating female, uterine contraction
Vasopressin: increases water reabsorption from distal kidney tubule
Hypothalamus
Axonal transport
Neurohypophysis
Oxytocin Vasopressin (ADH)
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Biochemical actions
1. GH increases protein synthesis
2. Carbohydrate metabolism: GH antagonizes the effects of insulin (hyperglycemia); decreased peripheral utilization of glucose, increased hepatic production via gluconeogenesis
3. Lipid metabolism: GH promotes the release of free fatty acids and glycerol from adipose tissue, increases circulating free fatty acids, causes increased oxidation of free fatty acids in the liver
4. Mineral metabolism: GH promotes a positive calcium, magnesium, and phosphate balance (promotes growth of long bones)
5. Prolactin-like effects
Pathophysiology: dwarfism, gigantism, acromegaly
Growth hormone (GH)
synthesized in the adenohypophysis, the
concentration in the pituitary is 5-15 mg/g
single polypeptide, two disulfide bridges
is essential for postnatal growth
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Parathyroid hormone (PTH)
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PTH
Parathyroid gland (behind thyroid)
STIMULUS: Falling blood
Ca2+ level
Homeostasis: Blood Ca2+ level
(about 10 mg/100 mL)
Blood Ca2+ level rises.
Stimulates Ca2+ uptake in kidneys
Stimulates Ca2+ release from bones
Increases Ca2+ uptake in intestines
Active vitamin D
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Insulin polypeptide consisting of 2 chains linked by 2 disulfide bridges
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Insulin Synthesis
Hydrophobic pre-sequence (signal peptide) is cleaved after transporting to ER
Proinsulin is further transported to GA and cleaved by trypsin-like enzymes and
carboxypeptidase like enzyme
Heterodimeric insulin and C-peptide are formed
Insulin combine with zinc to form hexamers
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Signal transduction
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Homeostasis: Blood glucose level
(about 90 mg/100 mL)
Glucagon
STIMULUS: Blood glucose level
falls.
Alpha cells of pancreas release glucagon.
Liver breaks down glycogen and releases glucose.
Blood glucose level rises.
STIMULUS: Blood glucose level
rises.
Beta cells of pancreas release insulin into the blood.
Liver takes up glucose and stores it as glycogen.
Blood glucose level declines.
Body cells take up more glucose.
Insulin
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• Insulin reduces blood glucose levels by
– Promoting the cellular uptake of glucose
– Slowing glycogen breakdown in the liver
– Promoting fat storage
• Glucagon increases blood glucose levels by
– Stimulating conversion of glycogen to glucose in the
liver
– Stimulating breakdown of fat and protein into glucose
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Some hormones contain a ring structure joined by a disulfide
bridge (oxytocin, vasopressin, somatostatin)
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH2 Oxytocin
1. Cystine aminopeptidase
2. Glutathione transhydrogenase
Step 1: Breakage of the ring structure
Step 2: Cleavage of cystine
Octapeptide further degradation amino acids
Inactivation and degradation of peptide hormones
Most polypeptide hormones are degraded to amino acids by hydrolysis in the lysosome
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Amino acid derived hormones
Catecholamines
• The adrenal medulla secretes epinephrine (adrenaline) and norepinephrine
(noradrenaline)
• They are secreted in response to stress-activated impulses from the
nervous system
• They mediate various fight-or-flight responses
– Trigger the release of glucose and fatty acids into the blood
– Increase oxygen delivery to body cells
– Direct blood toward heart, brain, and skeletal muscles, and away from skin, digestive system, and kidneys
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Biosynthesis of catecholamines in the adrenal medulla
1 2 3 4
1. Tyrosine hydroxylase: oxidoreductase, cofactor tetrahydropteridine; inhibition by the
catecholamines, tyrosine derivates, and by chelating iron
2. Dopa decarboxylase: cofactor pyridoxal phosphate; inhibitors α-methyldopa
3. Dopamine β-hydroxylase: mixed function oxidase, ascorbate as an electron donor,
copper at the active site
4. Phenylethanolamine-N-methyltransferase: the synthesis is induced by
glucocorticoid hormones, S-adenosyl methionin coenzyme
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• The same hormone may have different effects
on target cells that have:
• Different receptors for the hormone
• Different signal transduction pathways
• Different proteins for carrying out the response
The biological effects of catecholamines are mediated by two
classes of plasma transmembrane receptors, the alfa- and beta-
adrenergic receptors
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Glycogen deposits
βreceptor
Vessel dilates.
Epinephrine
(a) Liver cell
Glycogen breaks down and glucose is released.
(b) Skeletal muscle
blood vessel
Same receptors but different intracellular proteins (not shown)
β receptor
Different receptors
Epinephrine
α receptor
Vessel constricts.
(c) Intestinal blood
vessel
Epinephrine
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Catecholamines are rapidly metabolized by catechol-O-methyltransferase
(COMT) and monoamine oxidase (MAO)
Different metabolites are formed:
3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid);
measurable in urine; elevation in pheochromocytoma
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Literature
• Devlin, T. M. Textbook of biochemistry: with clinical correlations. 6th
edition. Wiley-Liss, 2006.
• Marks´ Basic Medical Biochemistry, A Clinical Approach, third
edition, 2009 (M. Lieberman, A.D. Marks)
• Color Atlas of Biochemistry, second edition, 2005 (J. Koolman and
K.H. Roehm)
• Harper´s Biochemistry 23rd edition1993