Should We Put a Title Here?

Synthesis and Function of Vitamin D and Vitamin D

Receptor
Jeffrey Lee, John Noh, and Jonathan Yu

And our names?

Introduction
Despite the cancerous nature of sunlight due to UV radiation, we are dependent
on sunlight as a natural means of obtaining vitamin D, a crucial compound that plays an
important role in maintaining bone health. However, most people do not realize that new
research has even shown a positive correlation between low vitamin D levels and risk of
cancer. (1). We can also consume vitamin D through supplements, which provide the same
Supplemental sources of vitamin D are also sold. benefits as the synthesis of vitamin D
through UV radiation. Once consumed or absorbed into the body, vitamin D goes through
a complex series of chemical reactions in the liver and kidney to form the physiologically
active 1,25-dihydroxyvitamin D [ 1,25(OH)2D], also known as calcitriol. Active vitamin
D is functionallyvery dynamic; it can induce genomic response by altering transcription
via vitamin D receptors, but it can also facilitate absorption of phosphate and magnesium
ions (among other capabilities). These aspects of vitamin D metabolism are explored in
the paper, along withas well as future implications of this powerful vitamin and hormone,
are explored in this paper.

Subcutaneous Synthesis of Vitamin D

Vitamin D comes in twohas two forms: chlolecalciferol (vitamin D3) and

Ergocalciterol ergocalciferol (vitamin D2). While vitamin D3 increases serum [25(OH)D]
levels, vitamin D2 does not achieve the same resultsBoth are precursors to 1,25(OH)2D,
which is the active form utilized by the human body as a hormone, but vitamin D3 is
significantly preferred. (2). For this reason, vitamin D3 is the form of vitamin D that will
be discussed. The major source of vitamin D3 for people comes from the exposure of the
skin to ultraviolet B (UVB) radiation (280320 nm). The synthesis of Vitamin D3 begins
when light energy (UVB rays) strikes the precursor molecule 7-dehydrocholesterol.3 The
effectiveness of UVB on formation of previtamin D3 in the skin is influenced by UVBabsorbing molecules such as chromophores in the skin, consisting of melanin,
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, and 7Dehydrocholesterol (7-DHC). 7-DHC absorbs UV radiation between 290 nm and
315 nm, causing it to isomerize, resulting in a bond cleavage between carbons 9 and 10 to
form the 9,10-seco-sterol previtamin D3.4

Dependent on temperature and timeP, previtamin D3 undergoes nonenzymatic

isomerization, which is
dependent on temperature and
time, to form vitamin D3
(cholecalcioferol) as seen in
Figure 1. In contrast to 7-DHC,
which is a 5,7-diene, vitamin D3
Figure1:ThesubcutaneoussynthesisofvitaminD3withthe
helpofUVBandthermalenergy.Alsoshowsalternatepaths
availableforthecompoundsusedinthesynthesisthatmay

is a 5,7,19-triene with three

conjugated double bonds typical

for vitamin D molecules.3 Around 50% of the previtamin D3 can isomerize to vitamin D3
within 2.5 hours in the skin. Within 1224 hours after UVB exposure, the circulating
concentrations of vitamin D3 are at their maximum levels.3 If previtamin D3 is formed in
the skin, it can also undergo either photoisomerization to lumisterol, tachysterol, and
toxisterols, or it can be retransformed to 7-DHC.3 A broad overview of this process can be
seen in Figure 1.

Figure 1: The subcutaneous synthesis of vitamin D3 with the help of UVB and thermal
energy. Also shows alternate paths available for the compounds used in the synthesis that
may occur in the dermal layer.

Activation of Vitamin D3 in Hepatocyte (Liver) and Kidneys

A At this point, the vitamin D is biologically inactive and must be activated in the
liver and the kidneys. This is also the form vitamin D comes in through consuming
supplements.The vitamin D found in vitamin supplements is also in this inactive form.
(consumption). After the inactive vitamin D binds to the carrier proteins, vitamin Dbinding protein (DBP), itInactive vitamin D is transported to the liver where it is
enzymatically hydroxylated to 25-hydroxyvitamin D [25(OH)D].5 The hydroxylation into
25-hydroxyvitamin D [25(OH)D] is catalyzed by microsomal cytochrome P450
enzyme CYP2R1 and/or the mitochondrial cytochrome P450 CYP27A1 (see Figure 2),;
both of which are constitutively expressed.3,6 Cytochromes are hemoproteins that supply
ATP via electron transport to the molecules. Besides the CYP2R1 and CYP27A1, there
are also several other cytochrome P450 mixed function oxidases
(CYP2C11,, CYP3A4,, CYP2D25, and CYP2J3) that exhibit vitamin D 25-hydroxylase

activities.3 The normal circulating levels of 25(OH)D in the blood are between 25 nmol/L
and 200 nmol/L.3 Currently, vitamin D levels of about 30 ng/mL
(75 nmol/L) are considered to be optimal for health.
(homeostasis).
25-hydroxyvitamin D [25(OH)D] , bound
to DBP, is then transported to the kidneys and is
finally hydroxylated by CYP27B1 (25hydroxyvitamin D-1-hydroxylase or; 1OHase) at the
C1 position to hormonally active 1,25dihydroxyvitamin D [1,25(OH)2D].3 The overall activation
of vitamin D3 can be seen in Figure 2 where there are two
separate pathways 25(OH)D can take to form two
Figure 2: Pathway from vitamin D to
the active form (calcitriol, bottom) and
/inactive form (right) through the use
ofprocessing by various cytochromes.
Also shows where the cytochromes

different active forms of vitamin D or return to the

inactive form as 24,25-(OH)2D.5 Calcitriol has
biological effects oin the kidneys but is usually

sent into the bloodstream to be used by other parts of the body.

Figure2:PathwayfromvitaminDtotheactiveform/inactiveformthroughtheuseofvarious
cytochromes.Alsoshowswherethecytochromestakeaction(liver,kidney)andshowsthechemical
compositionoftheproductofthechemicalpathway.

Distribution of Vitamin D to the Rest of the Body

Once in the bloodstream, vitamin D in the form of active 1,25(OH)2D 1,25-OHD3

(1,25D) or 25(-OH)D3 (25D) often binds to a protein called gc-globulin (group-specific
component of serum), also known as vitamin D binding
protein (DBP) (see Figure 31).71 This protein can be found
in plasma and cerebrospinal fluid, where it binds to vitamin
D metabolites and transports them to target organs. DBP
Figure 31: Ribbon diagram
of vitamin D binding

belongs to the family of albumin proteins and is encoded by

the GC gene residing on chromosome 4.1 DBP consists of 458 amino acids, including
numerous cysteine residues, which form multiple disulfide bridges within the protein.
The three domains of the protein have many -helices; six of them on the first domain
form the binding site for vitamin D ligands.7
DBP plays an important role in maintaining stable supplies of
vitamin D for the body. When researchers knocked out the gene coding for
DBP in mice, the knockout mice did not seem to have any physiological
defects. However, when fed a vitamin D deficient diet, the knockout mice
showed signs of bone disease (a common symptom of vitamin D deficiency)
sooner than the wild-type mice, suggesting that they were less able to cope
with vitamin D depletion.1 Another study showed that the kidneys recover vitamin-D
bound DBP from urine, demonstrating the mechanism by which DBP aids retention of
vitamin D.1 7
Cells in the body have several ways of accessing the bodys supply of vitamin D
Figure 42: Binding of 1,25D to CYP24A1 located in the
inner mitochondrial membrane. The heme group (red dotted
sphere) reduces oxygen to hydroxylate 1,25D

[(1,25(OH)2D 1,25D and 25(OH)D]).

One way is by simple diffusion of free

vitamin D across the cell membrane. The level of free vitamin D in the body is governed
by the levels and affinity of DBP. Vitamin D can also enter the cell while still bound to
DBP through active-receptor-mediated uptake. The DBP-vitamin D complex binds to a
cell surface receptor called megalin (LRP2) and is internalized in a vesicle, where
vitamin D is released and DBP is denatured.71 Once inside cells, 1,25(OH)2D1,25D
directs vitamin D-dependent gene regulation through the vitamin D receptor (VDR),
while 25(OH)D is first converted into active 1,25(OH)2D 1,25D through hydroxylation of
the 1- carbon by cytochrome p450 27B1 (CYP27B1, also known as 1- hydroxylase),
usually located in the inner mitochondrial membrane.1,27,8 This oxidation reaction of
25(OH)D occurs when NADPH-CYP reductase captures an electron pair from the
conversion of NADPH to NADP and transfers it to CYP27B1, which has high specificity
for 25-hydroxylated steroids (i.e. 25(OH)D) and reduces oxygen via the heme group in its
active site to hydroxylate 25(OH)D (see Figure 2).2,36,8 The mechanism is likely similar to
the reduction of oxygen to water,
which involves heme D, the site of
oxygen reduction in many types of
bacteria.20 Another cytochrome,
CYP24A1, operates in a similar
fashion to catalyze the hydroxylation of
Figure 42: Binding of 1,25D to CYP24A1 located in the
inner mitochondrial membrane. The heme group (red dotted
sphere) reduces oxygen to hydroxylate 1,25D.22

the 24 carbon of 1,25(OH)2D (see

Figure 4) 1,25D to form inactive

24,25(OH)2D24,25-OHD, which is later excreted in urine.6

Vitamin D in the Brain

About 50 years after the discovery of vitamin D, researchers began to find
evidence of vitamin D in the brain. One crucial discovery was that of the expression of
CYP27B1 in human and rat brains. Immunohistochemistry revealed the distribution of
CYP27B1 and VDR in the brain. Researchers found that microglial cells (macrophages in
the brain), glial cells, and Purkinje cells (located in the cerebral cortex) in the brain)
actively produced 1,25(OH)2D1,25D, the active form of vitamin D. This was done via
CYP27B1, which seemed to be restricted to just the cytoplasm of those cells.5 9 In
addition, VDR was also shown to be expressed extensively throughout the human and rat
brain of both neurons and glial cells. Unlike CYP27B1, VDR was found solely in the
nucleus of brain cells.6 10 The supraoptic and paraventricular nuclei of the hypothalamus
and the substantia nigra, which is located in the midbrain and important to the bodys
reward system, showed the most substantial expression of CYP27B1 and VDR; this same
pattern of distribution is seen with other neurosteroids.5,69,10 Most locations in the brain
that had CYP27B1 also had VDR. Interestingly, the distribution of VDR in the brain was
strikingly similar in both humans and rodents.6 10 CYP24A1 was also found in glial cells
hydroxylating and inactivating 1,25D.5 9 The presence of both CYP27B1 and CYP24A1
in brain cells reveals that the brain is capable of regulating the amount of active vitamin
D in the brain. Another study has shown that vitamin D metabolites are able to cross the
blood brain barrier. However, the mechanism by which it they does so areis still
unknown.711

This growing body of evidence demonstrates the presence of vitamin D in the

brain; however, the effects of vitamin D are still being discovered. In recent years, the list
of supposed benefits of vitamin D has grown many studies claim that it can lower blood
pressure, boost the immune system, or even help prevent cancer so has the list of
vitamin Ds effects on the brain. Looking through the literature, there are studies showing
that vitamin D can alter dopamine, acetylcholine, and noradrenaline neurotransmission;
helps prevent onset of Parkinsons, schizophrenia, depression, and other mental illnesses;
and plays a multifaceted role in brain development.5,79,11

Function of VDR: Vitamin D Receptor

Like all molecules in the body, vitamin D needs other cofactors and receptors in
order to function properly. In 1969, more than forty years after vitamin D was discovered,
the nuclear vitamin D receptor (VDR) was also found. VDR proved to play an incredible
role in the bodyin the body, as it was discovered in more than thirty tissues and organs.
of the human body. As a result of this flurry of research, it appears that there are two
main categories of action carried out by the so-called VDS-VDR conformational
ensemble model. Not only can the vitamin D receptor carry out important genomic
functions, as evidenced by the presence of VDR in the immune system, bone marrow,
adipose cells, etc., but it can also carry out rapid responses (RR) that could occur within
minutes to an hour. This This source of rapid responses comes fromis derived from the
knowledge that VDR regulates gene transcription. Once again, structure can yield
insights into function; the structural and stereospecific aspects of the VDS-VDR model

can explain how vitamin D regulates both nongenomic and genomic response via specific
ligand-binding pockets.
VDR fits into the nuclear receptor superfamily, which isare a class of
transcriptional regulators in animals. Nuclear receptors are ligand-activated; in the case of
VDR, vitamin D would be the ligand that activates transcription. Tissues that contain
VDR (over 37) define specific locations where vitamin D can initiate biological
responses. Some of these responses include
the classic calcium homeostasis system,

Figure 4: Shapes of the optimal ligands for VDRmediated responses and for RR, as well as for vitamin D
binding protein (DBP). There is a characteristic ligand
shape for each type of response.

along with five other systems, including the brain, whichh we will be focused on later.
Thee ligand-receptor complex is what produces the biological reactions.

VDR Structure and Function:

Furthermore, Vitamin D is considered a
conformationally flexible molecule; the side chain that
contains five single carbon-carbon bonds is
the source of this flexibility (see figure 54 A).812. Furthermore, the cyclohexane ring has
the ability to interchange rapidly between
alpha and beta chair conformations (B).
Probably the most practical observation is that
the three different ligand shapes that appear in
nuclear localized VDR, membrane-caveloae
localized VDR, and plasma DBP (F).

Ultimately, the conformational flexibility enables vitamin D to carry out a of variety

functions via VDR. The two major classes are the rapid cytoplasmic or membrane
responses (kinetically favored) and
the slow genomic responses
(thermodynamically favored).
The first class of response that
can be induced isare the traditional
genomic responses. VDR is a DNAbinding transcription factor consisting
of a heterodimer (two different
molecules bound together, usually
macromolecules in this case, the
VDR with the vitamin D ligand, as
well as an unoccupied retinoid X
receptor (RXR see figure 65)8.13

Figure 54: Shapes of the optimal ligands for VDR-mediated

responses and for RR, as well as for vitamin D binding protein
(DBP). There is a characteristic ligand shape for each type of
response.

After the ligand binds to the VDR genomic pocket (GP), there is a conformational change
to allow it to serve as a platform for coactivator binding. The coactivator allosterically
stabilizes the VDR-RXR heterodimer, then allowing it to be phosphorylated by serine
protein kinases. This new complex can positively and negatively regulate gene
transcription by recognizing vitamin D response elements (VDREs) in DNA. The VDRRXR then recruits additional comodulators to help initiate transcription. There are many
hypotheses concerning how exactly thisof how exactly happensthis happens; Dr.
Hausslers team proposes that there is a simultaneous binding of multiple factors in a

supercomplex at the promoter, based on the

model RANKL gene promoter. Activated
VDR can also interact with transcriptional
coregulators to control gene expression.
VDR consists of 427 amino acids with two
main functional groups: a zinc finger DNA
binding domain near the N-terminus, and a
vitamin D ligand binding domain near the
C-terminus. A structure consisting of 12 helices allows VDR to heterodimerize with
the retinoid X receptor.13
The practical implications come

Figure 65: Structure-function relationships and

proposed mechanism of gene induction and repression
by VDR.

from finding the genes that are directly regulated by this VDR complex. So far, at least
eleven genes that encode bone and mineral homeostasis (the traditional target of VDR)
have been found, including gene products that facilitate intestinal calcium intake. Another
network that has been found to be regulated by VDR is theare encoding factors that
impact cell life/cancer, the immune system, and metabolism. These come from inducing
and repressing various genes involved in diseases such as type I diabetes, multiple
sclerosis, and arthritis. It has even been found to blunt various genes involved in
inflammatory responses, thus reducing the risk of heart disease and Alzheimers. It is
clear that there are many areas regulated by VDR, and there will certainly be more to
come.

Vitamin D also plays a role in a second category of responses: rapid responses.

This cannot be explained by VDR-mediated gene transcription, as was shown in the
classical genomic responses. This is a relatively new area of research; the first rapid
responses were discovered in the 1980s from the rapid hormonal simulation of intestinal
calcium absorption in chicks. The transfer of calcium to the intestine was noticed only
after 4-5 minutes after transfer of vitamin D to the celiac artery. The main difference that
separates genomic and rapid responses is the time delay; genomic responses often take
days while the rapid response pathway takes mere minutes. However, rapid responses are
also often induced through a different mechanistic pathway. The first clue came after it
was noticed that only the 6-s-cis locked and not the 6-s-trans locked analog was capable
of producing rapid responses in the chick model. This also means that the VDR also can
adopt different
conformers the
so called VDRGP for genomic
responses, the
membrane
caveolae localized VDR-AP for alternative binding, and the plasma vitamin D-binding
protein (DBP).
In particular, it has been found that the caveolae is the source of many rapidly
responding signal transduction pathways. Caveolae are located in the plasma membrane
and are enriched in sphingolipids and cholesterol. It was demonstrated both that vitamin

D showed the same binding affinities to VDR in the caveolae as observed with nuclear
VDR, and that vitamin D localized in vivo in the plasma membrane caveolae9.14
Finally, the VDR AP site was proposed to resolve the VDR paradox (see Figure
7).23 Traditionally, only a
single ligand binding

Figure 6: Different mechanisms by which vitamin D and VDR can induce chemical
responses in the body. On the left, the caveolae-related pathway leads to activation of the
secondary messenger system to elicit short term responses. On the right, 1,25D can
interact with VDR localized in the cell nucleus to produce genomic responses through
gene transcription.

domain has been

recognized the one that
binds only the 6-s-trans shape. However, the
rapid response
conformer is not able
to dock to this specific

Figure 7: The proposed VDS-VDR conformational ensemble model. The left panel
shows the conformational flexibility of VDS, the middle panel shows the different
Figure 7: The proposed VDS-VDR conformational ensemble model. The left panel shows the
binding sites on VDR, with the yellow oval showing overlap between the two regions.
conformational flexibility of VDS, the middle panel shows the different binding sites on VDR,
The right panel shows specific conformational dynamics of VDR AF2 domain; the
with the yellow oval showing overlap between the two regions. The right panel shows specific
Boltzmann distribution is altered depending on the nature of the ligand, changing the
conformational dynamics of VDR AF2 domain; the Boltzmann distribution is altered depending
energy landscape of VDR ensemble members to bias a specific downstream event.
on the nature of the ligand, changing the energy landscape of VDR ensemble members to bias a
specific downstream event.

binding site. Computational work showed that there is an alternative binding site
available. This conformational model was proposed by Dr. Haussler and his team,
whereby the VDR could accommodate differently shaped ligands to initiate both genomic
and rapid responses. The steroid hormone would essentially test the waters and form a
receptor-hormone complex with the receptor species that provided the highest affinity
and most stability. Figure 86 shows the main differences between the genomic and rapid
response pathways.150. It seems as though the two categories are vastly different, but a
small portion of VDRs at the membrane is now believed to regulate the expression of
genes, thus regulating the activity of many kinases, phosphatases, and ion channels.
However, more research needs to be done to further elucidate the mechanisms behind this
process.

Implications of
Vitamin D/VDR

Figure 86: Different mechanisms by which vitamin D and VDR can induce chemical
responses in the body. On the left, the caveolae-related pathway leads to activation of the
secondary messenger system to elicit short term responses. On the right, 1,25(OH) 2D
1,25D can interact with VDR localized in the cell nucleus to produce genomic responses
through gene transcription.

and Sleep:
Since VDR has recently been found in the brain, some interesting new hypotheses
have emerged concerning the function of vitamin D in the brain.181. One of these concerns
the role of vitamin D in sleep. Normally, sleep is highly organized. Humans typically go
to sleep at the same time every night, going through specific phases, such as REM, slowwave, etc. Waking up from sleep is involuntary and also occurs in a fairly stable manner.
This seems to imply that sleep is not caused by a buildup of sleep-inducing hormones and
substances; rather, it is a result of a circadian rhythm type function where sleep is highly
coordinated by the time of day. This implies that one of the reasons for sleep problems
stems from brain chemistry.
Normally, many different hormones are secreted before sleep, leading to
drowsiness a warning, so to speak. Antidiuretic hormone is produced to limit urine
production, melatonin levels increase, and so on. The brain also induces paralysis as deep
sleep arrives, activating specific neurotransmitters to turn off the signals responsible for
wakefulness. These two categories, timing and paralysis, are essential to sleep. Saper and
colleagues suggest an on-off switch mechanism, which is responsible for sleep; one part
of the brainstem is active while the other is suppressed.162 Specifically, the hypothalamus
is thought to be involved because the stimulation of the posterior hypothalamus induces
arousal, while stimulation of the anterior hypothalamus and adjacent basal forebrain
region causes sleep.1317. Now, how does this tie in with vitamin D? Vitamin D targeted

neurons have been discovered in specific brain and spinal cord locations in multiple
animals. This suggests a possible role of vitamin D in regulating sleep. A 2-year
uncontrolled trial of vitamin D supplementation in 1500 patients with neurological
complaints and sleep problems saw improvements in both these functions.14 18 Further
research needs to be done in this area, as sleep is also influenced by sociological and
psychological factors. For example, pain has been shown to influence the quality of sleep,
but pain has also been linked to vitamin D.195 Therefore, vitamin D may ameliorate the
quality of sleep through a multitude of factors not only through chemical pathways in
the brain, but also through alleviating pain. There is a delicate balance between these
factors; vitamin D could directly impact sleep, which could then improve feelings of
pain. Vitamin D could also improve a multitude of variables, including mood, quality of
life, etc. which could also improve pain (a subjective feeling that could be influenced by
psychology). Further research needs to be done to elucidate the function of vitamin D in
these processes.
Vitamin D has clearly grown in importance over the last half century. The
involvement of vitamin D in vital bodily processes, from bone health to even regulating
gene expression, reveals how potent this single hormone is to human health. New models
to elucidate the nature of vitamin D and VDR binding will further this cause and may
even reveal new routes for drug development and helping curethe curing of diseases, one
of the most fundamental concerns for the human race.

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