MCP Lecture 3 Flashcards
What is the precursor of all steroid hormones?
cholesterol
What are the classes of steroid hormones?
glucocorticoids (i.e. cortisol) mineralocorticoids (i.e. aldosterone) sex hormones (androgens, estrogens, progestins)
Where is cortisol, aldosterone, and androgens secreted from?
adrenal cortex
How do steroid hormones reach their target?
carrier proteins in the blood
Describe the synthesis of steroid hormones
shortening the hydrocarbon chain of cholesterol and hydroxylating the steroid nucleus
What is the rate limiting step in steroid hormone synthesis? What is the enzyme that catalyzes this reaction?
conversion of cholesterol to the 21 carbon pregnenolone
catalyzed by CYP11A (cholesterol side-chain cleavage enzyme
What type of enzyme is CYP11A, and where is it located? What does the reaction require?
cytochrome P450 mixed function oxidase
located on inner mitochondrial membrane
requires NADPH and O2
What mediates the transfer of cholesterol from the mitochondrial outer membrane to the inner membrane?
StAR (steroidogenic acute regulatory protein)
What are congenital adrenal hyperplasias?
an enzyme deficiency in the conversion of cholesterol to a steroid hormone causing serious metabolic imbalance
Where is cortisol produced? How is its production and secretion controlled?
produced in middle layer of adrenal cortex (zona fasciculata)
controlled by hypothalamus
When and why is cortisol released?
in response to stress (infection) - corticotropin releasing hormone (CRH) produced by hypothalamus travels to anterior pituitary where it induces the production and secretion of ACTH - the “stress hormone” - which causes the adrenal cortex to synthesize and secrete glucocorticoid cortisol
What does cortisol do?
helps the body respond to stress through effects on metabolism (stimulating gluconeogensis) and the inflammatory and immune responses
What inhibits CRH and ACTH?
cortisol - negative feedback
What are the steps of cortisol synthesis?
ACTH binding to G-protein receptor = increased cAMP = activated PKA which phosphorylates and activates the lipase which converts cholesterol ester to cholesterol and StAR protein (cholesterol to inner mitochondrial membrane)
pregnenolone is returned to the cytosol and converted to progesterone
CYP17 and CYP21 convert progesterone to 11-deoxycortisol which is returned to inner mitochondrial membrane where CYP11B1 catalyzes Beta hydoxylation at c21 to give cortisol
What causes production of aldosterone and where is it produced?
production stimulated by decrease in plasma Na+/K+ ratio and by angiotensin II (which binds Gcoupled cell surface receptor and acts through phosphatidylinositol 4,5 biphosphate pathway)
produced in outer layer of adrenal cortex (zona glomerulosa)
What is the function of aldosterone?
enhances Na+ and water uptake and K+ efflux in the kidney tubules
this increases blood pressure
Where are the sex hormones produced?
androgens produced by the inner (zona reticularis) and middle layers of adrenal cortex
they are converted to testosterone and estrogen in peripheral tissues
What causes the testes and ovaries to synthesize the sex hormones?
GRH (gonadotropin-releasing hormone) stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH)
LH and FSH both bind to g-protein linked surface receptors - increase cAMP - PKA
What effect does LH have?
stimulates testes to produce testoesterone
stimulates ovaries to produce estrogens and progesterones
What effect does FSH have?
regulates the growth of ovarian follicles and stimulates spermatogenesis within the testes
How is estrogen produced? What enzyme catalyzes?
produced from androstenedione and then testosterone
enzyme involved is aromatase
What is the hormone response element? (HRE)
found in the promoter or an enhancer element for genes that are responsive to a specific steroid hormone
How are steroid hormones converted into inactive excretion products in the liver?
reduction of unsaturated bonds and introduction of additional hydroxyl groups
How are steroid hormone excretion products made more water soluble?
conjugation with glucuronic acid or sulfate
How are the steroid hormones excreted?
first the reduction of unsaturated bonds and introduction of addition hydroxyl groups along with conjugation with glucuronic acid or sulfate (to make more water soluble) - from there 20-30% secreted into bile and secreted in poop
the remained are released in blood and filtered in the kidneys passing into urine
What is the active molecule of D vitamins and what does it do?
1,25-dihydroxycholecalciferol (1,25-diOH-D3)
aka calcitriol - interacts with DNA to enhace or repress transcription of a coordinate a set of genes
most important function: regulate plasma levels of calcium and phosphorous
What are the sources of Vitamin D?
exogenous source/diet - D2 from plants and D3 from animal tissues
endogenous source - 7-dehydrocholesterol converted to cholecalciferol in the dermis that is exposed to sunlight - cholecalciferol transported to liver bound to vitamin D binding protein
How is inactive vitamin D (D2 and D3) converted to active vitamin D
converted in vivo first in liver by the enzyme 25 hydroxylase yielding 25-hydroxycholecalciferol (25-OH-D3 or calcidiol)
in the kidney, 25-hydroxycholecalciferol 1-hydroxylase forms 1,25-diOH-D3 calcitriol
What type of enzymes are 25 hydroxylase and 25-hydroxycholecalciferol 1-hydroxylase?
cytochrome p450 proteins
How is 25-hydroxycholecalciferol 1-hydroxylase regulated?
activity is increased directly by low plasma phosphate and indirectly by low plasma calcium (low calcium triggers secretion of PTH which upregulates the enzyme)
elevated levels of 1,25-diOH-D3 (calcitriol) inhibits the enzyme in negative feedback loop
What are the effects of calcitriol?
increased calcium mobilization from bone
increased renal reabsorption of calcium
decreased renal excretion of calcium
increased calcium absorption from intestine
What is the mechanism that calcitriol stimulates intestinal absorption of calcium?
binds to a ligand binding domain within the vitamin D receptor (VDR) - enters nucleus and forms heterodimer with retinoid-X-receptor (RXR) - recognize VDRE in the promoter or regulatory element of the genes
What are the enhanced proteins within enterocytes by calcitriol?
calbindin-D9K (mediates transport of calcium across the enterocyte from the apical side)
calcium transport protein TRPV5 (allows entry of calcium into the epithelial cell
What does low plasma calcium cause?
elevation of calcitriol (1,25-DiOH-D3) and PTH which both act to increase calcium absorption and bone resportion
What does calcitonin do?
hormone that decreases blood calcium and opposes effects of PTH (which raise blood calcium)
What are the levels of vitamin d associated with deficiency? toxic level? best level?
deficiency: 50 adequate/best level
>125 adverse effects (loss of appetite, nausea, thirst, stupor - hypercalcemia (calcium deposits in organs))
What is rickets?
formation of the collagen matrix but insufficient mineralization = soft and pliable bones in children
What is osteomalacia?
demineralization of existing bones making them more susceptible to fracture
What is renal osteodystrophy?
decreased synthesis of active vitamin D and increased retention of phosphate - hypocalcemia and hyperphosphatemia
What is hyperthyroidism?
lack of PTH causes hypocalcemia and hyperphosphatemia (trated with calcium and calcitriol)
