Transcript Synthesis of protein and peptide hormones

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
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
Protein/peptide secreting cell
Steroid secreting cells
Hormone synthesis
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 prohormone; can also include folding of polypeptide
chain and addition of carbohydrates (glycosylation)
Transcription
Post-transcriptional
modifications - removal
of introns, 5’ & 3’
modifications
Translation of mature
RNA
Post-translational
processing - cleavage
of pro-hormone, folding
of protein molecule,
glycosylation
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
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
Membrane traffic in
hormone-secreting cells
Synthesis
active hormone
signal
redundant sequence
hormone
Signal sequence + prohormone =
pre-prohormone
Active hormone + redundant sequence
prohormone
Synthesis of
insulin
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
Homologous hormones
Growth Hormone
Prolactin
Ancestral gene
Growth hormone
Prolactin
Human
placental lactogen
Also oxytocin and vasopressin
Homologous families of hormones
Homologous glycoprotein hormones
LH(hCG)
FSH
TSH
 and  sub-units.  unit common,
 unit biological activity
Ancestral gene
gonadotrophin
LH (hCG) FSH
TSH
One gene, two hormones - post transcriptional
modifications
One gene several hormones - post
translational modificatioons
Steroid synthesis
•
•
•
•
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
STEROID SYNTHESIS SIMPLIFIED
Cholesterol
Pregnenolone
Progesterone
17OH Progesterone
Aldosterone
Cortisol
Androgens
Oestrogens
Steroids highly conserved
Outline of steroid synthesis
in the adrenal cortex and
gonads
Steroid synthesis in the adrenal cortex
Genes coding for the
P450 enzymes are
abbreviated to CYP
Most steps in steroid
synthesis require
cytochrome P450 hemecontaining enzymes
Pregnenolone
Progesterone
3-HSD
Conversion of androgens
to oestrogens by
aromatase
17-hydroxyprogesterone
17 hydroxylase
Androstenedione
Testosterone
17-HSD type 5
Aromatase
Aromatase
17-HSD type 1
Oestrone (E1)
Oestradiol (E2)
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
• 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
Peripheral conversion of thyroid and
steroid hormones
•
•
•
•
T4  T3
Testosterone  dihydrotestosterone
Testosterone  oestradiol
Vitamin D (synthesised in skin) 
dihydroxy vitamin D.
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