peptide hormones

Section 1: Aims of the Lecture (Page 1)

By the end of this lecture, students will be able to:

• Gain an introduction to key peptide hormones.

• Understand the overview of structure and function of peptide hormones.

• Consider key chemical alterations used to improve duration of action of peptide hormones.

Section 2: Hormones – An Overview (Page 2)

Hormones are chemical messengers that can be classified into different types based on their chemical structure:

PART 2: THYROID HORMONES

Section 3: Thyroid Hormones – Overview (Page 3)

• Key Hormones: Thyroxine (T₄) and Tri-iodothyronine (T₃) .

• Production: T₃ is primarily produced by de-iodination of T₄ outside the thyroid (in peripheral tissues).

• Potency: T₃ is 3-5 times more active than T₄.

• Physiological Functions:

  • Necessary for development and function of cells throughout the body.

  • Increase protein synthesis.

  • Increase oxygen consumption (regulate metabolic rate).

  • Essential for cell differentiation during early life (especially brain development).

• Clinical Relevance: Imbalances of thyroxine cause muscular and developmental problems (e.g., hypothyroidism leads to fatigue, weight gain; hyperthyroidism leads to weight loss, tachycardia).

Section 4: Thyroxine Biosynthesis (Pages 4-5)

4.1. Amino Acid Origin (Page 4):

• T₃ and T₄ are derivatives of the amino acid tyrosine.

• They are released from a protein (thyroglobulin) rather than being produced as free small molecules.

4.2. Biosynthetic Steps (Page 4):

1. Iodination: Two tyrosine residues within the large protein thyroglobulin have iodine atoms added (catalysed by thyroid peroxidase).

2. Oxidative Coupling: The iodinated tyrosine residues are linked via an ether group through an oxidative (radical) coupling reaction.

3. Detachment: Re-instatement of the aromaticity of one of the rings causes detachment of the final T₃ or T₄ molecule from the thyroglobulin protein.

Image Description (Page 5): A detailed chemical diagram showing two iodinated tyrosine residues within thyroglobulin undergoing oxidative coupling to form thyroxine (T₄), with the subsequent release of the hormone.

PART 3: CALCITONIN

Section 5: Calcitonin (Page 6)

• Structure: A 39 amino-acid peptide produced in the thyroid gland.

• Function: Works with parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D₃ to regulate calcium balance and bone turnover.

• Mechanism: Can suppress Ca²⁺ loss from bone (inhibits osteoclast activity).

• Therapeutic Use: Used to treat bone-weakening conditions (e.g., osteoporosis, Paget's disease).

• Key Note: The analogous peptide from salmon is more potent and longer-lasting than human calcitonin, and is used therapeutically.

PART 4: HORMONES FROM THE HYPOTHALAMUS

Section 6: Hypothalamic-Pituitary Axis (Page 7)

• The hypothalamus releases releasing hormones that travel via the hypothalamic-pituitary portal system to the anterior pituitary.

• These stimulate the pituitary to release trophic hormones, which then act on peripheral endocrine glands.

Example:

• Thyrotropin-releasing hormone (TRH) (hypothalamus) → stimulates anterior pituitary to release thyroid-stimulating hormone (TSH) .

• TSH is a glycoprotein which causes the thyroid to secrete thyroxines (T₃ and T₄) .

Section 7: Thyrotropin-Releasing Hormone (TRH) – Structure and Modification (Page 8)

7.1. Structure:

• TRH is a tri-peptide (three amino acids): pyroGlu – His – ProNH₂.

7.2. Key Chemical Modifications:
TRH has modified N and C termini. These modifications are common in peptides as they protect against peptidases which act by removing end residues (exopeptidases).

Section 8: Luteinizing Hormone-Releasing Hormone (LHRH) / Gonadotropin-Releasing Hormone (GnRH) (Page 9)

• Structure: A decapeptide (10 amino acids).

• Alternative Name: Gonadotropin-releasing hormone (GnRH).

• Site of Action: Acts on the anterior pituitary to release two gonadotropins:

  • Luteinizing hormone (LH)

  • Follicle-stimulating hormone (FSH)

• Gonadotropins: LH and FSH are glycoproteins.

• Physiological Role: They control male and female reproduction and influence steroidal sex hormone production (e.g., estrogen, testosterone).

Section 9: LHRH Analogues – Improving Duration of Action (Page 10)

9.1. Production:

• LHRH is available via synthetic production (solid phase peptide synthesis).

• Analogues are also manufactured using similar techniques.

9.2. Modifications to Enhance Activity and Duration:

9.3. Comparison of Half-Lives and Activity:

• LHRH (native): Half-life = 4 minutes.

• Leuprorelin (synthetic analogue): Half-life = 4 hours; 50 times the activity of native LHRH.

9.4. Types of Analogues:

• Agonists: e.g., Leuprorelin, Goserelin. Initially stimulate, then downregulate receptors (leading to suppression of LH/FSH).

• Antagonists: e.g., Degarelix. Immediately block the receptor, causing rapid suppression.

9.5. Clinical Use:
Both agonist and antagonist analogues can be used to treat hormone-dependent cancers (e.g., prostate cancer, breast cancer) by suppressing sex hormone production.

Section 10: Solid Phase Peptide Synthesis (Page 11)

• Method: Peptides are produced using solid phase chemical synthesis.

• Components:

  • Solid support or resin (e.g., polystyrene beads).

  • A linker to attach the amino acid to the resin.

  • Suitable protecting groups to direct the reaction and prevent unwanted side reactions.

• Process: Amino acids are added stepwise from the C-terminus to the N-terminus.

Problem (Page 11): Draw the solid phase synthesis for a given peptide (exercise for students).

Section 11: Growth Hormone-Releasing Hormone (GHRH) (Page 12)

• Structure: A 44 amino acid peptide.

• Alternative Name: Growth hormone-releasing factor (GHRF).

• Source: Released from the hypothalamus and acts on the pituitary gland.

• Active Fragment: The first 29 amino acids retain full biological activity. This sequence is produced synthetically and is called sermorelin.

• Action: Releases human growth hormone (HGH, somatotrophin) from the anterior pituitary.

Section 12: Growth Hormone-Release Inhibiting Factor (Somatostatin) (Pages 13-14)

12.1. Structure and Source (Page 13):

• Structure: A 14 amino-acid peptide (cyclic due to disulfide bridge).

• Alternative Names: Growth hormone-release inhibiting hormone (GHRIH), somatostatin.

• Distribution: As well as the hypothalamus, it is also found in the pancreas and gastrointestinal (GI) tract.

12.2. Functions (Page 13):
It inhibits the release of several hormones:

• Human growth hormone (HGH)

• Thyrotropin (TSH)

• Insulin

• Glucagon

12.3. Therapeutic Analogues (Page 14):

• Native somatostatin has a very short duration of action (half-life minutes).

• Synthetic analogues have been developed to improve duration, e.g., lanreotide, octreotide.

• Clinical Use: These analogues are used to treat acromegaly (excess HGH) and neuroendocrine tumours.

PART 5: ANTERIOR PITUITARY HORMONES

Section 13: Human Growth Hormone (HGH) / Somatotrophin (Page 15)

• Structure: A 191 amino-acid protein.

• Historical Production: Previously recovered from human cadavers or animals, but this carried risks (e.g., prion diseases).

• Current Production: Now produced by recombinant DNA technology (identical to human HGH).

• Abuse: HGH has been abused by athletes to increase muscle mass and improve performance. Such use can give rise to abnormal bone growth (acromegaly) and other side effects.

Other Anterior Pituitary Hormones (Page 15):

• Corticotropin (ACTH): Stimulates adrenal cortex to release corticosteroids (covered in corticoid lecture).

• Prolactin: Has a similar structure to HGH; promotes mammary tissue growth and lactation in conjunction with estrogens.

PART 6: POSTERIOR PITUITARY HORMONES

Section 14: Oxytocin and Vasopressin (Page 16)

14.1. Oxytocin:

• Structure: A nine amino acid peptide with a disulfide bridge (forming a cyclic structure).

• Function: Causes uterine contractions at the end of pregnancy (labour induction/augmentation) and milk ejection (let-down reflex).

• Source: Synthetically manufactured for medicinal use.

14.2. Vasopressin (Antidiuretic Hormone, ADH):

• Structure: Closely related to oxytocin (differs by two amino acids).

• Function: Regulates reabsorption of water in the kidney (acts on collecting ducts).

• Deficiency: A deficiency leads to diabetes insipidus (due to excessive urinary output – large volumes of dilute urine).

• High Doses: High doses cause contraction of arterioles and capillaries, causing raised blood pressure (vasopressor effect).

Image Description (Page 16): A 3D molecular model of oxytocin, showing the cyclic structure formed by the disulfide bridge.

PART 7: PANCREATIC HORMONES

Section 15: Insulin and Glucagon (Page 17)

• Pancreas: Produces two key peptide hormones:

PART 8: OTHER PEPTIDES

Section 16: Other Biologically Active Peptides (Page 18)

• Interferons: Associated with the immune system; involved in antiviral and immunomodulatory responses.

• Opioid Peptides: e.g., endorphins, enkephalins. Act as natural painkillers by binding to opioid receptors in the brain.

PART 9: READING REFERENCES

Section 17: Recommended Reading (Page 19)

• Dewick, Medicinal Natural Products – for detailed peptide biosynthesis and chemistry.

• Rang and Dale's Pharmacology – for pharmacology of peptide hormones.

SUMMARY TABLE: KEY PEPTIDE HORMONES

KEY CONCEPT: PROLONGING PEPTIDE HALF-LIFE