Download steroid hormone-97

Phosphoglycerides
Steroid hormone action
Fat-soluble vitamins
+ N PO 4
Membrane composition
•
•
•
•
•
•
- PC, PE, PS form bulk of membrane
bilayers
glycerol
Membrane proteins
oleic acid
lenoleic acid
Biological membranes
about 50% lipids: 50% proteins
- amphipathic lipids form bi-layer
Lipid component
Cholesterol esters
PC, PE, PS
Sphingomyelin
- globular proteins are intersperced
in bi-layer
% by wt.
35
40
10
• Glycolipids
5
Membrane structure
membrane protein
phospholipids
polar head
hydrophobic
tails
alpha helix
of protein
- lipid components are represented:
polar
+
head
-
hydrophobic tails
Membrane Proteins
Hormone receptor proteins
- membrane proteins which
bind specific hormones
insulin receptor
glucagon receptor
epinephrine receptor
Membrane Proteins
• Transport proteins are found in
the membranes of all cells
•
• Na+/K+ pump protein pumps
sodium out and potassium in
•
• Glucose transport proteins are in
all cell membranes
Membrane proteins
• many membrane proteins allow
cells to recognize foreign cells
and foreign proteins
•
• viruses bind to some of these
recognition proteins to gain
entrance into the cell
Hormone receptor proteins
in membranes
Steroid Hormones
Steroid hormones do NOT act
through a second messenger.
Hormones bind receptor proteins to
stimulate activity of neighboring
proteins to produce 2nd mess.
Steroid hormones bind to
nuclear receptor proteins and
alter transcription of specific
genes.
Insulin binds -irs-1 is formed.
Glucagon binds -cAMP is formed.
Mechanism of Action of
Steroid hormones
• 1. steroid hormone enters target
cells
• 2. steroid binds to receptor protein
in the nucleus
• 3. steroid + protein bind to specific
DNA site
• 4. binding alters gene transcription
Steroid hormones
testosterone
OH
cholesterol
HO
CH3
C=O
progesterone
HO
O
OH
estradiol
HO
Testosterone and Estrogen
• - same mechanism of action as
•
other steroid hormones
•
• - very similar to mechanism by
which cholesterol regulates its
own synthesis
Differentiation of sex
characteristics
• depends on:
• i) level of sex hormones in blood
• ii) presence of hormone receptor
protein in target cell
•
•
Androgen insensitivity
- an inherited condition in mammals
where XY individual fails to
develop male sex characteristics
- due to: Tfm syndrome- lack of
testosterone receptor protein
genotype is: Tfm
X
Y
Androgen insensitivity
In humans:
affected individuals are XY and
have higher than normal levels of
testosterone but no functional
receptor proteins in target cells
Phenotype of Tfm -male (XY) is that of
a sexually undifferentiated adult.
Androgen insensitivity
Androgen insensitivity
• Affected individuals are
classified as females at birth due
to absense of male sex organs
(penis and testes)
• Condition becomes apparent with
failure to menstruate by age 13-15
• Affected individuals are XY
genotype but believe they are
female
• Physcian explains condition as
due to abnormal mass in abdomen
which must be surgically removed.
(mass = rudimentary testes)
Compare molecular defects
Fat-soluble vitamins
• in the hereditary diseases:
• hypercholesterolemia
All fat-soluble vitamins are formed
from intermediates in the
cholesterol synthetic pathway.
• androgen insensitivity
Fat soluble vitamins
• vitamin A and its derivatives
- retinol, retinal ,retinoic acids
• vitamin D and its derivatives
- cholecalciferols
• vitamin E and its derivatives
- tocopherols
Chemistry of vision
Rhodopsin is a membrane lipoprotein
found in rod cells of the retina.
retinal + opsin
rhodopsin
Visible light strikes rhodopsin,
triggering cascade that causes
perception of light
Vitamin A - retinal
- carotene (C40)
2 retinol (C20)
retinol (alcohol) is oxidized to retinal
C=O
H
- complexes with the protein, opsin
in the cells of the retina
Chemistry of vision
11-cis retinal + opsin
rhodopsin
light
rhodopsin
11-cis retinal-opsin
11-trans retinal
opsin
isomerase
11-cis retinal
light starts cascade
• light striking rhodopsin in
retina of eye starts “cascade”
which causes drop in [cGMP],
a 2nd messenger
• a drop in [cGMP] in a specific
cell stimulates a nerve fiber in
optic nerve
Rhodopsin
• is membrane lipoprotein* which
has domains both inside and
outside of retinal cell membrane
• *lipoprotein is protein with lipid
covalently bound to it
Retinitis pigmentosum
• genetic defect where the opsin
protein is not folded correctly
in retinal cell membrane
• problems with sight develop in
mid 20’s
• blindness often results by age 60
Retinoic acid - RA
• Retinoic acid is form of vitamin A
•
• RA binds to retinoic acid receptor
protein in nucleus
•
• Retinoic acid and receptor bind to
specific regions in DNA
Retinoic acid - RA
Vitamin D - cholecalciferols
• - stimulates transcription of genes
which code for cell division
proteins
•
• - formed in skin cells from light
striking cholesterol
•
• - cholecalciferol is steroid hormone
•
which stimulates transcription
•
of gene for Ca ++ transport
protein
•
• - Vit. D deficiency causes rickets
• - retinoic acids stimulate cell
division and increase probability
of tumor formation
Mechanism of action of vit D
(cholecalciferol)
Hormone receptor proteins
N
C
• 1. vit. D enters through cell membrane
•
cortisone
estrogen
• 2. vit. D enters nucleus and binds to its
receptor protein
•
testosterone
vitamin D
hormone
binding
region
retinoic acid
• 3. together they bind to DNA and
stimulate transcription of gene for Ca++
transport protein
rat liver cell
DNA
binding
region
hormone
HRE
p
Ca++ transport
protein gene
CAATTACGATACCGCGGCCACTATACGCGTACAATCCATGAGCCGATTACGGCAT
mitochondrion
GTTAATGCTATGGCGCCGGTGATATGCGCATGTTAGGTACTCGGCTAATGCCGTA
endoplasmic
reticulum
RNA polymerase
enzyme (pol)
hormone
receptor
protein
nucleus
chromosome
(DNA)
p
Ca++ transport
protein gene
Mechanism of action of
cholecalciferol
p
Ca++ transport
protein gene
CAATTACGATACCGCGGCCACTATACGCGTACAATCCATGAGCCGATTACGGCAT
CAATTACGATACCGCGGCCACTATACGCGTACAATCCATGAGCCGATTACGGCAT
GTTAATGCTATGGCGCCGGTGATATGCGCATGTTAGGTACTCGGCTAATGCCGTA
GTTAATGCTATGGCGCCGGTGATATGCGCATGTTAGGTACTCGGCTAATGCCGTA
vit. D
hormone
receptor
protein
pol
vit. D binds to its
receptor in nucleus
pol
cholecalciferol + receptor
bind to DNA at Hormone Response
Element
p
p
CAATTACGATACCGCGGCCACTATACGCGTACAATCCATGAGCCGATTACGGCAT
CAATTACGATACCGCGGCCACTATACGCGTACAATCCATGAGCCGATTACGGCAT
GTTAATGCTATGGCGCCGGTGATAT
GTTAATGCTATGGCGCCGGTGATAT
GCGCATGTTAGGTACTCGGCTAATGCCGTA
GCGCAUGUUAGGUA
GCGCATGTTAGGTACTCGGCTAATGCCGTA
mRNA
Binding to response element in DNA
stimulates pol enzyme to bind to
Promoter region next to Ca++ tpt. gene.
p
pol transcribes the gene forming
mRNA for Ca++ transport protein.
Ca++ transport
protein gene
Translation of mRNA
on ribosomes in ER
CAATTACGATACCGCGGCCACTATACGCGTACAATCCATGAGCCGATTACGGCAT
GTTAATGCTATGGCGCCGGTGATATGCGCATGTTAGGTACTCGGCTAATGCCGTA
pol
enzyme
mGGCGCAUGGUACUCGCGUAAAAA
mRNA leaves nucleus,
moves to ER,
binds to small
ribosome subunit
cap
tail
mG-GCCGCAUGUUAGGUA-AAAA
mRNA is capped and tailed in nucleus
mRNA is translated into
Ca++ transport protein
mRNA is translated into
Ca++ transport protein
mGGCGCAUGGCUUCAGCGUAAAAA
UAC CGA
met ala
anticodon
-
tRNA
mG
GCGCAUGGCUUCAGCGUAAAAA
UAC CGA
met
ala
anticodon
-
tRNA
peptide bond forming
Translation of mRNA
into Ca++ tpt. protein
-GCAUGGCUUCAGCGUAAAAA
CGA AGU
ala
Translation of mRNA
Ca++ tpt. protein
is formed and moves
to cytoplasmic
membrane.
ser
met-ala-ser-phe-asp-gln-
met
Vitamin E - tocopherol
• effective anti-oxidant
• formed from isopentenyl PP
• may be effective in reducing
cardiovascular disease
Review questions
1. Describe the mode of action of
the following hormones:
Vitamin K - menadione
• essential for blood clotting
• cofactor in formation of
prothrombin , a clotting factor
in human blood
• formed by intestinal bacteria in
humans
Review questions
2. Describe the molecular basis for the
inherited human diseases below.
a. glucagon
a. hypercholesterolemia
b. testosterone
b. androgen insensitivity
Review questions
3. a. Diagram the carbon skeleton of
metabolism showing location of
pathways in the cell. No
structures are required.
Review questions
4. Describe how the cholesterol
pathway is regulated. (Include
both regulation of enzyme
activity and enzyme synthesis .)
b. Show how each of the pathways
for lipid synthesis is connected to
the carbon skeleton.
Review questions
Review questions
5. Give the main function(s) of each
of the following metabolic
pathways in human cells.
6. Match letters corresponding to cellular
locations for each pathway below.
A. endoplasmic
reticulum
B. cytoplasm
____ TCA cycle
a. pentose shunt
C. mitochondrion
____ cholesterol
synthesis
____ glycogen syn.
b. glycolysis
c. cholesterol synthesis
Review questions
Describe the pentose shunt pathway
using the following headings:
Main function:
Location in cell:
Substrate:
Sndproduct(s):
Regulation:
Structures to know
cholesterol
acetyl
palmitate
Know the components of:
triglycerides
phosphoglycerides
sphingomyelin