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Welcome, everyone,
to Chapter 17 on
this short talk series on
Nuclear Receptors as
Therapeutic Targets.
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This chapter will deal
with the first member of
the NR1I family, which is
the vitamin D receptor
abbreviated as VDR.
The next chapter will then
address the two other
members of this
subfamily, PXR and CAR, which
act as xenobiotic sensors.
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As the name says, VDR is a
receptor for vitamin D but
similar to what we have seen for
vitamin A and retinoid
acid receptor,
vitamin D first needs to be
metabolized to become
a potent VDR agonist.
Vitamin D is a group of
secosteroids from various
biological sources.
Secosteroids have similar
constitution as steroids,
but ring B of the steroid core
is opened in the secosteroids.
Vitamin D3 or cholecalciferol
shown on the left
is derived from
the cholesterol precursor,
dehydro-cholesterol,
and found, for
example, in oily fish.
But it can also be
desynthesized in the body.
Vitamin D2 or ergocalciferol
is the fungal analog and
derived from ergosterol.
Vitamin D from whatever
source must be
processed at several sites
in the body including
liver and kidney to become
a potent VDR agonist
which will see in detail
on the next slide.
The activated vitamin D
will then interact with
vitamin D receptors in
various tissues and
organs as shown here.
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Metabolic activation
of vitamin D involves
hydroxylation at two
positions. One and 25 to
become the potent
VDR agonist 1.25D
hydroxy vitamin D3 which
is also termed calcitriol.
It activates VDR which
acts as a heterodimer with
RXR like many other members
of the NR1 nuclear
receptor family.
On the bottom, you see
the biosynthesis of
vitamin D and
oxidized metabolites.
In the body, the
cholesterol precursor
7-dehydrocholesterol, also
termed pre-vitamin
D, can undergo
an electrocyclic ring
opening reaction followed by
a sigmatropic isomerization to
vitamin D3 to form
the secosteroid.
In liver, vitamin D3 is
then hydroxylated at
position 25 by the
enzyme CYP2R1,
which is also termed
vitamin D 25-hydroxylase.
Further hydroxylation at
position 1 in the kidneys by
CYP27B1 also termed
25-hydroxyvitamin D3
1-alpha-hydroxylase.
Eventually it generates
the active VDR agonist,
calcitriol, from
vitamin D. Vitamin D
receptor activation,
