endo 3: genes and enzymes: hormone synthesis synthesis of protein and peptide hormones by gene...
TRANSCRIPT
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 tyrosinesLipid soluble, made from low molecular weight precursors
Morphology:
Peptides - secretory granules, RER. Steroids - lipid droplets
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)
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
Synthesis active hormone
Signal sequence + prohormone =
pre-prohormoneActive hormone + redundant sequence
prohormone
signal hormone redundant sequence
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 glycoprotein hormones
LH(hCG) FSH TSH
and sub-units. unit common, unit biological activity
Ancestral gene
gonadotrophin TSH
LH (hCG) FSH
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 17OH Progesterone
Aldosterone Cortisol Androgens
OestrogensSteroids highly conserved
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
Oestrone (E1) Oestradiol (E2)
Androstenedione Testosterone
Pregnenolone Progesterone
17-hydroxyprogesterone
17-HSD type 5
17-HSD type 1
3-HSD
Aromatase Aromatase
17 hydroxylase
Conversion of androgens to oestrogens by
aromatase
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.