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

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 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

Membrane traffic in hormone-secreting cells

Synthesis active hormone

Signal sequence + prohormone =

pre-prohormoneActive hormone + redundant sequence

prohormone

signal hormone redundant sequence

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 TSH

LH (hCG) FSH

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 17OH Progesterone

Aldosterone Cortisol Androgens

OestrogensSteroids 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 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.

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