Synthesis of protein and peptide hormones

1

• Endo 3 Genes and enzymes hormone synthesis
• Synthesis of protein and peptide hormones by
  gene transcription
• Post transcriptional and post translational
  modifications, packaging of hormones
• Hormone diversity
• Synthesis of steroid hormones from small
  molecular weight presursors
• Steroidogenic enzymes
• Transport and peripheral conversion of steroid
  hormones

2
Hormone synthesis

• Peptides and proteins
• Water soluble, made from large precursor
  molecules - prohormones.
• Steroids and iodinated tyrosines
• Lipid soluble, made from low molecular weight
  precursors
• Morphology
• Peptides - secretory granules, RER. Steroids
  - lipid droplets

3
Protein/peptide secreting cell
Steroid secreting cells
4
Hormone synthesis
5
Synthesis of protein and peptide hormones

• Gene transcription (controlled by transcription
  factors)
• Processing of the initial mRNA transcript to
  mature mRNA excision of introns and
  modifications of the 3 and 5 ends
• Translation of mRNA Bound to the polyribosomes
  of RER, the mRNA acts as a template for
  assembling amino acids by way of tRNA
• Post translation processing Cleavage of large
  pro-hormone can also include folding of
  polypeptide chain and addition of carbohydrates
  (glycosylation)

6
Transcription Post-transcriptional modifications
- removal of introns, 5 3 modifications Trans
lation of mature RNA Post-translational
processing - cleavage of pro-hormone, folding of
protein molecule, glycosylation
7
Packaging of hormones

• Signal sequence docking protein on RER
• As amino acids are assembled they are
  internalized into the RER
• RER Golgi apparatus
• Formation of secretory granules storage
• Secretion by exocytosis

8
Packaging of hormones

• Signal sequence finds docking protein on RER
• As amino acids are assembled they are
  internalized into the RER
• RER Golgi apparatus
• Formation of secretory granules
  storage
• Secretion by exocytosis

9
Membrane traffic in hormone-secreting cells
10
Synthesis active hormone

• Signal sequence prohormone
• pre-prohormone
• Active hormone redundant sequence
• prohormone

signal
hormone
redundant sequence
11
Synthesis of insulin
12
Diversification of protein and peptide hormones

• Gene duplication - homologous families of
  hormones
• Processing of mRNA
• One gene two hormones
• Post translational processing
• One prohormone several hormones

13
Homologous hormones

• Growth Hormone Prolactin Ancestral
  gene
• Growth hormone Prolactin
• Human placental lactogen
• Also oxytocin and vasopressin

14
Homologous families of hormones
15
Homologous glycoprotein hormones

• LH(hCG) FSH TSH
• ? and ? sub-units. ? unit common,
• ? unit biological activity
• Ancestral gene
• gonadotrophin TSH
• LH (hCG) FSH

16
One gene, two hormones - post transcriptional
modifications
17
One gene several hormones - post translational
modificatioons
18
Steroid synthesis
19

• Steroid hormone synthesis
• Cholesterol bound to sterol transfer protein -
  transported to mitochondria
• StAR protein transports cholesterol to inner
  mitochondrial membrane
• Cholesterol to pregnenolone by side chain
  cleavage enzyme, P450scc
• Between mitochondria and SER steroids synthesised
  by hydroxylase enzymes

20
STEROID SYNTHESIS SIMPLIFIED

• Cholesterol Pregnenolone
• Progesterone 17?OH Progesterone
• Aldosterone Cortisol
  Androgens
• Oestrogens
• Steroids highly conserved

21
Outline of steroid synthesis in the adrenal
cortex and gonads
22
Steroid synthesis in the adrenal cortex
Genes coding for the P450 enzymes are abbreviated
to CYP Most steps in steroid synthesis require
cytochrome P450 heme-containing enzymes
23
Conversion of androgens to oestrogens by aromatase
Pregnenolone
Progesterone
3?-HSD
17?-hydroxyprogesterone
17? hydroxylase
Androstenedione
Testosterone
17?-HSD type 5
Aromatase
Aromatase
17?-HSD type 1
Oestrone (E1)
Oestradiol (E2)
24
Synthesis of thyroid hormones

• Active uptake of iodine into follicular cell
• Oxidation of iodide to iodine
• Iodination of tyrosine residues of thyroglobulin
  and apical-colloid interface
• Storage in colloid
• Uptake of thyroglobulin droplets into follicle
  cell
• Release and secretion of T3 and T4

25

• Active uptake of iodine
• Oxidation of iodide to iodine
• Iodination of tyrosine residues at
  apical/colloid interface to form MIT and DIT
• Uptake of thyroglobulin into the lumen of the
  follicle

26
Peripheral conversion of thyroid and steroid
hormones

• T4 ? T3
• Testosterone ? dihydrotestosterone
• Testosterone ? oestradiol
• Vitamin D (synthesised in skin) ? dihydroxy
  vitamin D.

27
Transport of steroid and thyroid hormones

• An equilbrium exists between bound and free
  hormone.
• H BG H.BG
• Keq H.BG (H bound)
• H BG (H free)
• H H.BG x 1
• Keq BG
• e.g. transcortin, sex hormone binding globulin,
  transthyretin