Download STEROIDS, BILE ACIDS, STEROID HORMONES

2012-10-02
STEROIDS, BILE ACIDS,
STEROID HORMONES
Vitamins D
Conformation
• Steroids form an important
group of compounds based on
the
fundamental
saturated
tetracyclic hydrocarbon : cyclopentanoperhydrophenanthrene
(sterane).
• The prefix „perhydro” refers to
the fact that all the necessary
hydrogen atoms have been
added to the compound to make
it fully saturated
For two-ring system, the structures of cis - and
trans-fused rings look like this:
• There are four rings in
a steroid skeleton and
hence there are three
fusion points. A/B, B/C
and C/D rings share two
carbons each (fusion).
•When there are directed on the same side, it is called cis.
•When the tow hydrogens are oriented opposite to each other with the
ring system thought to as forming a plane, the ring fusion is called
trans.
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The methyl groups are attached at
points of ring junction and are called
angular methyl groups.
• Natural steroids have two
methyl groups
• Two
methyl
groups
attached to C-10 and C-13
lie above the plane of the
molecule
and
are
customarily the points of
reference for the describing
the spatial orientation of
other substituents in the
steroid nucleus.
Other groups on the same side of the
steroid plane as the angular methyl
groups are said to be β substitutents
Groups below the plane of the steroid
ring system are said to be α
substituents
The main sterol found in the membranes of eukaryotic cells is cholesterol.
The polar head in this lipids is the hydroxyl in carbon C3.
CHOLESTEROL FACTS
synthesized from acetyl CoA and eliminated as bile acids
precursor of all other steroids in the body
product of animal metabolism - in foods of animal origin
amphipathic lipid (hydrophobic and hydrophilic portions)
storage form is cholesterol ester found in most tissues.
O
||
R-C-O
hydrophilic
Cholesterol ester (1st ring only)
R = fatty acid hydrocarbon chain
HO
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Biosynthesis of Cholesterol
Cholesterol
One of the most widely occuring steroids, was first isolated in 1770.
Contains 8 chiral C atoms, this means that 28 or 256 stereoisomers are
possible, but only one of them is cholesterol.
Contains 27 carbons
The process has five major steps:
• 1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutarylCoA (HMG-CoA)
• 2. HMG-CoA is converted to mevalonate
• 3. Mevalonate is converted to the isoprene based
molecule, isopentenyl pyrophosphate (IPP), with
the concomitant loss of CO2
• 4. IPP is converted to squalene
• 5. Squalene is converted to cholesterol.
Overview of cholesterol synthesis
Bile Acids Synthesis and Utilization
• The end products of cholesterol utilization are the bile
acids, synthesized in the liver.
• Synthesis of bile acids is one of the predominant
mechanisms for the excretion of excess cholesterol.
• However, the excretion of cholesterol in the form of
bile acids is insufficient to compensate for an excess
dietary intake of cholesterol.
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SYNTHESIS OF BILE ACIDS
Bile
•
Bile is a complex solution of salts
and protein, containing micelles
composed of cholesterol,
phospholipids and bile salts.
• The composition of
these
micelles
is
critical , as imbalance
may lead to crystallization of cholesterol
in the gallbladder,
leading to the formation of gallstones.
•
•
•
Bile acids are synthesized from
cholesterol in the liver, stored in the
gallbladder, and secreted through
the common bile duct.
alpha-Hydroxylation of 7-carbon is
the key step in bile-acid synthesis.
This hydroxylation destines the
product to become a bile-acid.
Lose 3 carbons of the alpha-side:
This is also common to all bile acids.
Then the terminal carbon is
oxidized to an acid (hence bile acid).
Bile acid synthesis
Synthesis of bile salts
Reaction is catalyzed by 7ahydroxylase.
An α –hydoxyl group is formed
at position 7 of cholesterol.
This reaction is inhibited by bile
salts, and is the rate-limiting step
in bile salt synthesis.
7α
α-hydroxylase
Cholesterol + NADPH + O2
7-hydroxycholesterol + NADP+
The initial reaction, 7α
α-hydroxylase, in the
conversion of cholesterol to bile acids.
Rate-determining step
Repressed (decreased synthesis) by bile salts
Induced (increased synthesis) by cholesterol
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Bile acids
Bile acids
• CHOLATE: The major bile
acid.
• It has three OH-groups in
the rings, and a carboxyl
group at the end of the side
chain.
• DEOXYCHOLATE: The
minor bile acid.
• It is missing one of the OHgroups (at the 12 carbon)
Grups –OH localized at:
C-3
C-7
C-12
Primary bile acids:
cholic acid
OH
OH
OH
chenodeoxycholic acid
OH
OH
H
deoxycholic acid
OH
H
OH
lithocholic acid
OH
H
H
Secondary bile acids:
Primary bile acids.
• The most abundant bile acids in human bile are
chenodeoxycholic acid (45%) and cholic acid
(31%).
• These are referred to as the primary bile acids.
Primary
bile acids
Secondary
bile acids
•Within the intestines the primary bile acids are converted by bacteria into the
secondary bile acids, identified as deoxycholate (from cholate) and lithocholate
(from chenodeoxycholate).
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Bile acids are excreted in conjugated form, as taurocholic
acid and glycocholic acid
Clinical Significance of Bile Acid Synthesis
• Bile acids perform four physiologically significant functions:
• 1. Their synthesis and subsequent excretion in the feces
represent the only significant mechanism for the elimination of
excess cholesterol.
• 2. Bile acids and phospholipids solubilize cholesterol in the
bile, thereby preventing the precipitation of cholesterol in the
gallbladder.
• 3. They facilitate the digestion of dietary triacylglycerols by
acting as emulsifying agents that render fats accessible to
pancreatic lipases.
• 4. They facilitate the intestinal absorption of fat-soluble
vitamins.
Bile acids are conjugated with glycine or taurine before being secreted into
bile, where the ratio of glycine to taurine-conjugated acid is about 3:1
Action of bile salts in emulsifying fats in the
intestine
BILE-ACID FUNCTIONS
•
• Emulsification of triacylglycerols ( Emulsification is
a physical, not a chemical process).
• Promote absorption of fat-soluble vitamins.
• Maintain cholesterol homeostasis by promoting
excretion of cholesterol
•
The hydrophobic surface of the
bile salt molecule associates
with triacylglycerol, and a
number of these complex
aggregate to form a micelle,
with the polar surface of the bile
salt facing outward.
This allows association with
pancreatic lipase, whose action
liberates free fatty acids in a
much smaller micelle, which
can be absorbed through the
intestinal mucosa
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Circulation of bile acids
• Bile acids are carried from the liver through these ducts to the
gallbladder, where they are stored for future use.
• The ultimate fate of bile acids is secretion into the intestine,
where they aid in the emulsification of dietary lipids.
• In the gut the glycine and taurine residues are removed and the
bile acids are either excreted (only a small percentage) or
reabsorbed by the gut and returned to the liver.
• This process of secretion from the liver to the gallbladder, to
the intestines and finally reabsorbtion is termed the
enterohepatic circulation.
• Steroid hormone production takes up a tiny
fraction of the total body cholesterol, but is
important because of the physiological
function of the hormones.
Steroid hormones
Steroid hormones are grouped into five categories:
- progestins,
- glucocorticoids,
- mineralocorticoids,
- androgens,
- estrogens.
All contain the four-ring structure of the steroid nucleus and are
remarkably similar in structure, considering the enormous differences
in their physiological effects.
They mediate a wide variety of vital physiological functions.
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Groups of steroid hormones
SYNTHESIS OF STEROID HORMONES
1. Progestins – regulate events during pregnancy, progesterone is the major
hormone involved in sustaining pregnancy
CHOLESTEROL ------> PREGNENOLONE
• Removal of 6 of the side-chain
carbons.
This step is common to all steroid
hormone synthesis.
2. Glucocorticoids –affect basal metabolism, host defense mechanisms, blood
pressure, response to stress, promote gluconeogenesis and supress
inflammation reactions (cortisol, corticosterone)
•
3. Mineralocorticoids – affect electrolyte balance and ion transport, regulate
ion balance by promoting reabsorption in the kidney of Na+ , Cl-, HCO3(aldosterone)
•
4. Androgens – promote male sexual differentiation, spermatogenesis, and
maintain male characteristics (androstenedione, testosterone),
CHOLESTEROL ------>
PREGNENOLONE
This step occurs on the mitochondrial
membrane.
This leaves a C21 compound,
pregnenolone, which may accurately be
described as the mother of all steroids
(the C21 steroid carbon skeleton is given
the name pregnane).
5. Estrogens – female sex hormones, stimulate the development of tissues
involved in reproduction, support femal characteristics (estrone, estradiol)
activated to turn
on pathways
Cholesterol
Progesterone
Pregnenolone
11-Deoxycortisone
Progesterone
Aldosterone
21-hydroxylase
Progesterone
21-hydroxylase
11-Deoxycortisol
Cortisol
General pathways for the synthesis of aldosterone and
cortisol in the adrenal cortex
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Functions of Hormones
Derived from Cholesterol
Functions of Hormones
Derived from Cholesterol cont.
Product
Functions
Androgens (strongest = testosterone)
(produced in testes primarily but weak
androgens in adrenal cortex) (anabolic
steroid)
development of male
secondary sex
characteristics; prevents
bone resorption
Estrogen
development of female
(produced in ovaries primarily but also secondary sex
in adipose cells of males and females) characteristics; prevents
bone resorption
Vitamin D (not a steroid hormone)
(produced in the skin in response to
UV light and processed to active form
in kidney)
intestinal calcium
absorption; promotes
bone formation; prevents
phosphate loss by
kidneys
Product
Functions
Progesterone
prepares uterus lining for
implantation of ovum
Glucocorticoids (cortisol)
(produced in adrenal cortex)
(catabolic steroid)
promote gluconeogenesis;
favor breakdown of fat and
protein (fuel mobilization);
anti-inflammatory
Mineralocorticoids
(aldosterone) (produced in
adrenal glands)
maintains blood volume and
blood pressure by increasing
sodium reabsorption by kidney
Vitamin D
Vitamin D is a steroid prohormone, by various metabolic changes in the
body it gives rise to a hormone known as calcitriol, which play a central
role in calcium and phosphate metabolism.
D Vitamins are generated from the provitamins ergosterol and
7-dehydrocholesterol by the action of sunlight.
Ergosterol occurs in plants and 7-dehydrocholesterol in animals.
UV light from sunlight cleaves the B ring of both compounds.
Ergocalciferol (vitamin D2) is formed in plants.
Cholecalciferol (vitamin D3) is formed in exposed skin.
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Formation of provitamin D (7-dehydrocholesterol)
A specific transport protein called the vitamin D-binding protein binds
vitamin D3 and moves its from the skin or intestine to the liver, where it
undergoes 25-hydroxylation
Photobiosynthesis of vitamin D3 and its
metabolism
The product (1α,25-dihydroxyD3) is the most potent vitamin D
metabolite. Its production is regulated by its own concentration,
parathyroid hormone, and serum phosphate.
25-HydroxyD3 can also be hydroxylated at the 24 position. The
level of the product 24,25-dihydroxyD3 is reciprocally related to
the level of 1,25-dihydroxyD3 in serum.
Deficiency of vitamin D causes rickets and osteomalacia.
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