Biochemistry of hormones derived from amino acids and proteins
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Biochemistry of hormones derived from amino acids and proteins. Alice Skoumalová. Content Definition of peptide hormones Common features: synthesis, interactions with receptors at the cell surface Groups of peptide hormones

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Biochemistry of hormones derived from amino acids and proteins

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Biochemistry of hormones derived from amino acids and proteins

Biochemistry of hormones derived from amino acids and proteins

Alice Skoumalová


Biochemistry of hormones derived from amino acids and proteins

Content

  • Definition of peptide hormones

  • Common features: synthesis, interactions with receptors at the cell surface

  • Groups of peptide hormones

  • Hypothalamus-hypophysis hormonal cascade (signal amplification, negative feedback system)

  • Genes and formation of polypeptide hormones (gene superfamilies)

  • Hormones of the hypothalamus and the hypophysis

  • Synthesis and degradation of catecholamines

  • Biochemistry of parathyroid hormone and insulin

  • Degradation of peptide hormones


Biochemistry of hormones derived from amino acids and proteins

Definition of peptide hormones

  • secreted into the blood stream; endocrine functions

  • synthesized from amino acids according to an mRNA template,

    which is itself synthesized from a DNA template

  • precursors (pre-prohormones) - posttranslational modification (endoplasmatic reticulum) - removal of the pre-sequence, sometimes glycosylation - resulting in prohormones

  • the prohormones - packaged into membrane-bound secretory vesicles - secreted from the cell by exocytosis in response to specific stimuli

  • mature peptide hormones diffuse through the blood to all of the cells of the body, where they interact with specific receptors on the surface of their target cells


Biochemistry of hormones derived from amino acids and proteins

Peptide hormones interact with specific receptors on the cell surface


Biochemistry of hormones derived from amino acids and proteins

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)


Biochemistry of hormones derived from amino acids and proteins

Hormones

1. Amine-derived hormones

Catecholamines and thyroxine

2. Peptide 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)

3. Steroid hormones


Biochemistry of hormones derived from amino acids and proteins

Peptide 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)


Biochemistry of hormones derived from amino acids and proteins

Hormonal cascade Signal amplification

CNS

Environmental or internal signal

Electrical-chemical signal

Limbic system

Electrical-chemical signal

Hypothalamus

Releasing hormones (ng)

Anterior pituitary

Anterior pituitary hormone (μg)

Target „gland“

The gonads, the thyroid gland, the adrenal cortex

Ultimate hormone (mg)

Systemic effects


Biochemistry of hormones derived from amino acids and proteins

CRH-ACTH-Cortisol

Environmental stress

A single stressor (change in temperature, noise, trauma)

CNS

Electrical-chemical signal

Limbic system

Electrical-chemical signal

Hypothalamus

Corticotropin releasing hormone (CRH) in ng, t1/2 minutes

Portal system

The corticotrophic cells

Anterior pituitary

Adrenocorticotropic hormone (ACTH) in µg, increased t1/2

Adrenal gland

Cortisol in mg, t1/2 hours

The glucocorticoid receptors in different cells

Systemic effects


Biochemistry of hormones derived from amino acids and proteins

Hormonal cascade Negative feedback system

CNS

Limbic system

Hypothalamus

Long feedback loop

Releasing hormones

Short feedback loop

Anterior pituitary

Anterior pituitary hormones

Target „gland“

Ultimate hormone

Systemic effects


Biochemistry of hormones derived from amino acids and proteins

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

  • 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

  • No response

  • The anterior pituitary is nonfunctional


Hypothalamic releasing hormones rh

Hypothalamic releasing hormones (RH)


Biochemistry of hormones derived from amino acids and proteins

Hypothalamus

GRH

TRH

CRH

Dopamine

PRF, PIF

GnRH

Anterior pituitary

β-Endorphin

GH

TSH

ACTH

LPH

MSH

PRL

FSH

LH

Ovary

Ovary

Liver

Adrenal cortex

Mammary gland

Testis

Testis

Thyroid

Skin darkening

β-Endorphin

Ovulation, corpus luteum, progesterone

Cell development, lactation

Corticosteroids

Hyperglycemic effects

Analgesia

Thyroid hormones

Interstitial cell development, testosterone

Development of follicles, estradiol

Growth of bone, body tissues; carbohydrate and protein metabolism; production of IGFs

Growth of seminal tubules and spermatogenesis

GH-Growth hormone, TSH-Thyrotropin, ACTH-Adrenocorticotropic hormone, LPH-Lipotropin,

MSH-Melanocyte stimulating hormone, PRL-Prolactin, FSH-Follicle stimulating hormone, LH-Luteinizing hormone


Biochemistry of hormones derived from amino acids and proteins

Hypothalamus

Oxytocin

Axonal transport

Vasopressin (ADH)

Neurohypophysis

Oxytocin

Vasopressin (ADH)

Uterine contraction, lactation

Water balance


Biochemistry of hormones derived from amino acids and proteins

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

Vasopressin: increases water reabsorption from distal kidney tubule


Biochemistry of hormones derived from amino acids and proteins

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)


Biochemistry of hormones derived from amino acids and proteins

Genes and formation of polypeptide hormones

Genes for polypeptide 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


Biochemistry of hormones derived from amino acids and proteins

Proopiomelanocortin (a single gen product) is a precursor peptide for eight hormones

  • ACTH, β-lipotropin, γ-lipotropin, γ-MSH, α-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


Biochemistry of hormones derived from amino acids and proteins

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; excessive formation-Cushing‘s syndrome

β-lipotropin: induces lypolysis, 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)


Biochemistry of hormones derived from amino acids and proteins

  • 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)


Biochemistry of hormones derived from amino acids and proteins

  • 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

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


Biochemistry of hormones derived from amino acids and proteins

Prolactin (PRL)

  • is secreted in the adenohypophysis

    Biochemical actions: the initiation and maintenance of lactation

    Pathophysiology: tumors of prolactin-secreting cells cause amenorrhea and galactorrhea in women, gynecomastia and impotence in men


Biochemistry of hormones derived from amino acids and proteins

The pituitary and placental glycoproteins:

Thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) a chorionic gonadotropin (CG)

  • structural similarities (common ancestral gene): 2 subunits-α (identical for all of these hormones) and β (determines the specific biologic activity)

  • synthesized as preprohormones and are subject to posttranslational processing (glycosylation)

  • LH and FSH are responsible for gametogenesis and steroidogenesis in the gonads

hCG is synthesized in the syncytiotrophoblast cells of the placenta; increases in blood and urine shortly after implantation; its detection is the basis of many pregnancy tests

hCG- β subunit


Biochemistry of hormones derived from amino acids and proteins

Biosynthesis of catecholamines in the adrenal medulla

1

2

3

4

  • Tyrosine hydroxylase: oxidoreductase, cofactor tetrahydropteridine; inhibition by the catecholamines, tyrosine derivates, and by chelating iron

  • Dopa decarboxylase: cofactor pyridoxal phosphate; inhibitors α-methyldopa

  • Dopamine β-hydroxylase: mixed function oxidase, ascorbate as an electron donor, copper at the active site

  • Phenylethanolamine-N-methyltransferase: the synthesis is induced by glucocorticoid hormones


Biochemistry of hormones derived from amino acids and proteins

Catecholamines are rapidly metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO)

Different metabolites are formed; two classes have diagnostic significance: metanephrines and 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid); measurable in urine; elevation in pheochromocytoma


Biochemistry of hormones derived from amino acids and proteins

Parathyroid hormone (PTH)

Pre

Pro

PTH

31

6

1

84

  • PTH affects calcium homeostasis

  • Increases the rate of dissolution of bone, reduces the renal excretion of Ca2+, increases the efficienty of calcium absorption from the intestine by promoting the synthesis of calcitriol

Endoplasmic reticulum

Parathyroid gland

Golgi apparatus

Blood (biological active)

Liver


Biochemistry of hormones derived from amino acids and proteins

Insulin

  • polypeptide consisting of 2 chains linked by 2 disulfide bridges


Biochemistry of hormones derived from amino acids and proteins

  • Synthesis and posttranslational modification of insulin

  • 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 E

  • Heterodimer and C-peptide are formed


Biochemistry of hormones derived from amino acids and proteins

The human insulin gene has been isolated

The synthesis of human insulin in bacterial expression systems, using recombinant DNA technology, affords an excellent source of this hormone for diabetic patients

Diagrammatic structure of the human insulin gene

Areas with diagonal stripes correspond to untranslated regions, open regions correspond to intervening sequences, and stippled regions correspond to coding sequences


Biochemistry of hormones derived from amino acids and proteins

  • Inactivation and degradation of peptide hormones

  • Most polypeptide hormones are degraded to amino acids by hydrolysis in the lysosome

  • Certain hormones contain modified amino acids

The hypothalamic releasing hormones

Pyroglutamic acid (pGlu)

C-terminal amino acid amide (Gly-NH2, Ala-NH2, Leu-NH2)

pGlu

C---Peptide

O

NH

O

Breakage of the pGlu or cleavage of the C-terminal amide can lead to inactivation of these hormones (this probably accounts for the short half-life of many of these hormones)


Biochemistry of hormones derived from amino acids and proteins

Some hormones contain a ring structure joined by a disulfide bridge (oxytocin, vasopressin, somatostatin)

2. Glutathione transhydrogenase

Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH2

Oxytocin

1. Cystine aminopeptidase

Step 1: Breakage of the ring structure

Step 2: Cleavage of cystine

Octapeptidefurther degradation amino acids


Biochemistry of hormones derived from amino acids and proteins

Summary

  • Peptide hormones are synthetized in the transcription and translation process (DNA-mRNA-peptid) and further modified (posttranslational modification)

  • Peptide hormones interact with specific receptors on the cell surface and trigger a cascade of secondary effects within the cytoplasm (cAMP, second messengers)

  • Peptide hormones form gene families that originate from a common ancestral gene

  • Several important peptide hormones are secreted from the hypothalamus-pituitary cascade (signal amplification, negative feedback interaction)

  • Peptide hormones are produced by many different organs and tissues


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