Vitamin D Final Draft

7/23/2019 Vitamin D Final Draft

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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. owever, most people do not reali!e that new

research has even shown a positive correlation between low vitamin D levels and ris" of

cancer . #1$. %e can also consume vitamin D through supplements, which provide the same

&upplemental sources of vitamin D are also sold. benefits as the synthesis of vitamin D

through UV radiation. 'nce consumed or absorbed into the body, vitamin D goes through

a comple( series of chemical reactions in the liver and "idney to form the physiologically

active )*,+-dihydro(yvitamin D ),+#'$+D/, also "nown as calcitr iol. 0ctive vitamin

D is functionallyvery dynamic1 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$. 2hese aspects of vitamin D metabolism are e(plored in

the paper , along withas well as future implications of this powerful vitamin and hormone,

are e(plored in this paper .

Sucutaneous Synthesis of Vitamin D



Vitamin D comes in twohas two forms3 chlolecalciferol #vitamin D4$ and

5rgocalciterol ergocalciferol #vitamin D+$. %hile vitamin D4 increases serum +#'$D/

levels, vitamin D+ does not achieve the same results6oth are precursor s to ),+#'$+D,

which is the active form utili!ed by the human body as a hormone, but vitamin D4 is

significantly preferred. #!$. 7or this reason, vitamin D4 is the form of vitamin D that will

be discussed. 2he ma8or source of vitamin D4 for people comes from the e(posure of the

s"in to ultraviolet 6 #UV6$ radiation #+9:;4+: nm$. 2he synthesis of Vitamin D4 begins

when light energy #UV6 rays$ stri"es the precursor molecule <-dehydrocholesterol.4 2he

effectiveness of UV6 on formation of previtamin D4 in the s"in is influenced by UV6-

absorbing molecules such as chromophores in the s"in, consisting of melanin,

deo(yribonucleic acid #DN0$, ribonucleic acid #=N0$, proteins, and <-

Dehydrocholesterol #<-D>$. <-D> absorbs UV radiation between +?: nm and

4) nm, causing it to isomeri!e, resulting in a bond cleavage between carbons ? and ): to

form the ?,):-seco-sterol previtamin D4.@



Dependent on temperature and timeA, previtamin D4 undergoes nonen!ymatic

isomeri!ation, which is

dependent on temperature and

time, to form vitamin D4

#cholecalcioferol$ as seen in

7igure ). Bn contrast to <-D>,

which is a ,<-diene, vitamin D4

is a ,<,)?-triene with three

con8ugated double bonds typical

for vitamin D molecules.4 0round :C of the previtamin D4 can isomeri!e to vitamin D4

within +. hours in the s"in. %ithin )+;+@ hours after UV6 e(posure, the circulating

concentrations of vitamin D4 are at their ma(imum levels.4 Bf previtamin D4 is formed in

the s"in, it can also undergo either photoisomeri!ation to lumisterol, tachysterol, and

to(isterols, or it can be retransformed to <-D>.4 0 broad overview of this process can be

seen in 7igure ).

Figure 1: The subcutaneous synthesis of vitamin D3 with the

help of UVB and thermal energy. Also shows alternate paths



7igure )3 2he subcutaneous synthesis of vitamin D4 with the help of UV6 and thermal

energy. 0lso shows alternate paths available for the compounds used in the synthesis that

may occur in the dermal layer.

Acti"ation of Vitamin D# in Hepatocyte $%i"er& and 'idneys

0 0t this point, the vitamin D is biologically inactive and must be activated in the

liver and the "idneys. 2his is also the form vitamin D comes in through consuming

supplements.2he vitamin D found in vitamin supplements is also in this inactive form.

#consumption$. 0fter the inactive vitamin D binds to the carrier proteins, vitamin D-

binding protein #D6A$, itBnactive vitamin D is transported to the liver where it is

en!ymatically hydro(ylated to +-hydro(yvitamin D +#'$D/. 2he hydro(ylation into

+-hydro(yvitamin D +#'$D/ is cataly!ed by microsomal cytochrome A@:

en!yme >YA+=) andor the mitochondrial cytochrome A@: >YA+<0) #see 7igure +$,1

both of which are constitutively e(pressed.

4,E

>ytochromes are hemoproteins that supply

02A via electron transport to the molecules. 6esides the >YA+=) and >YA+<0), there

are also several other cytochrome A@: mi(ed function o(idases

#>YA+>)), , >YA40@, , >YA+D+5, and >YA+J4$ that e(hibit vitamin D +-hydro(ylase



activities.4 2he normal circulating levels of +#'$D in the blood are between + nmolL

and ; +:: nmolL.4 >urrently, vitamin D levels of about 4: ngmL

#< nmolL$ are considered to be optimal for health.

#homeostasis$.

+-hydro(yvitamin D +#'$D/ , bound

to D6A, is then transported to the "idneys and is

finally hydro(ylated by CYP27B1 #+-

hydro(yvitamin D-)*-hydro(ylase or1 )*'ase$ at the

>)* position to hormonally active )*,+-

dihydro(yvitamin D ),+#'$+D/.4 2he overall activation

of vitamin D3 can be seen in 7igure + where there are two

separate pathways +#'$D can ta"e to form two

different active forms of vitamin D or return to the

inactive form as +@,+-#'$+D.

>alcitriol has

biological effects oin the "idneys but is usually

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

Fi(ure !3 Aathway from vitamin D tothe active form #calcitriol, bottom$ and

inacti"e form #right$ throu(h the useofprocessing by various cytochromes)



Figure 2: Pathway from vitamin D to the active form/inactive form through the use of various

cytochromes. Also shows where the cytochromes take action (liver, kidney) and shows the chemical

composition of the product of the chemical pathway.

Distriution of Vitamin D to the Rest of the *ody



'nce in the bloodstream, vitamin D in the form of active ),+#'$+D ),+-'D4

#),+D$ or +#-'$D4 #+D$ often binds to a protein called gc-globulin #group-specific

component of serum$, also "nown as vitamin D binding

protein #D6A$ #see 7igure 4)$.< ) 2his protein can be found

in plasma and cerebrospinal fluid, where it binds to vitamin

D metabolites and transports them to target organs. D6A

belongs to the family of albumin proteins and is encoded by

the F> gene residing on chromosome @.) D6A consists of @9 amino acids, including

numerous cysteine residues, which form multiple disulfide bridges within the protein.

2he three domains of the protein have many *-helices1 si( of them on the first domain

form the binding site for vitamin D ligands.<

D6A plays an important role in maintaining stable supplies of

vitamin D for the body. %hen researchers "noc"ed out the gene coding for

D6A in mice, the "noc"out mice did not seem to have any physiological

defects. owever, when fed a vitamin D deficient diet, the "noc"out 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.) 0nother study showed that the "idneys recover vitamin-D

bound D6A from urine, demonstrating the mechanism by which D6A aids retention of

vitamin D.) <

>ells in the body have several ways of accessing the bodyGs supply of vitamin D

#),+#'$+D ),+D and +#'$D/$.

'ne way is by simple diffusion of free

Fi(ure #13 =ibbon diagram

of vitamin D binding

Fi(ure +!3 6inding of ),+D to >YA+@0) located in the

inner mitochondrial membrane. 2he heme group #red dottedsphere$ reduces o(ygen to hydro(ylate ),+D



vitamin D across the cell membrane. 2he level of free vitamin D in the body is governed

by the levels and affinity of D6A. Vitamin D can also enter the cell while still bound to

D6A through active-receptor-mediated upta"e. 2he D6A-vitamin D comple( binds to a

cell surface receptor called megalin #L=A+$ and is internali!ed in a vesicle, where

vitamin D is released and D6A is denatured.< ) 'nce inside cells, ),+#'$+D),+D

directs vitamin D-dependent gene regulation through the vitamin D receptor #VD=$,

while +#'$D is first converted into active ),+#'$+D ),+D through hydro(ylation of

the )-* carbon by cytochrome p@: +<6) #>YA+<6), also "nown as )-* hydro(ylase$,

usually located in the inner mitochondrial membrane.

),+<,9

2his o(idation reaction of

+#'$D occurs when N0DA->YA reductase captures an electron pair from the

conversion of N0DA to N0DA and transfers it to >YA+<6), which has high specificity

for +-hydro(ylated steroids #i.e. +#'$D$ and reduces o(ygen via the heme group in its

active site to hydro(ylate +#'$D #see 7igure +$.+,4E,9 2he mechanism is li"ely similar to

the reduction of o(ygen to water,

which involves heme D, the site of

o(ygen reduction in many types of

bacteria.+: 0nother cytochrome,

>YA+@0), operates in a similar

fashion to cataly!e the hydro(ylation of

the +@ carbon of ),+#'$+D #see

7igure @$ ),+D to form inactive

+@,+#'$+D+@,+-'D, which is later e(creted in urine.E

Fi(ure +!3 6inding of ),+D to >YA+@0) located in theinner mitochondrial membrane. 2he heme group #red dotted

sphere$ reduces o(ygen to hydro(ylate ),+D.++



Vitamin D in the *rain

0bout : years after the discovery of vitamin D, researchers began to find

evidence of vitamin D in the brain. 'ne crucial discovery was that of the e(pression of

>YA+<6) in human and rat brains. Bmmunohistochemistry revealed the distribution of

>YA+<6) and VD= in the brain. =esearchers found that microglial cells #macrophages in

the brain$, glial cells, and Aur"in8e cells #located in the cerebral corte($ in the brain$

actively produced ),+#'$+D),+D, the active form of vitamin D. 2his was done via

>YA+<6), which seemed to be restricted to 8ust the cytoplasm of those cells.

?

Bn

addition, VD= was also shown to be e(pressed e(tensively throughout the human and rat

brain of both neurons and glial cells. Unli"e >YA+<6), VD= was found solely in the

nucleus of brain cells.E ): 2he supraoptic and paraventricular nuclei of the hypothalamus

and the substantia nigra, which is located in the midbrain and important to the bodyGs

reward system, showed the most substantial e(pression of >YA+<6) and VD=1 this same

pattern of distribution is seen with other neurosteroids.,E?,): Host locations in the brain

that had >YA+<6) also had VD=. Bnterestingly, the distribution of VD= in the brain was

stri"ingly similar in both humans and rodents.E ): >YA+@0) was also found in glial cells

hydro(ylating and inactivating ),+D. ? 2he presence of both >YA+<6) and >YA+@0)

in brain cells reveals that the brain is capable of regulating the amount of active vitamin

D in the brain. 0nother study has shown that vitamin D metabolites are able to cross the

blood brain barrier. owever, the mechanism by which it they does so areis still

un"nown.<))



2his growing body of evidence demonstrates the presence of vitamin D in the

brain1 however, the effects of vitamin D are still being discovered. Bn 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 DGs effects on the brain. Loo"ing through the literature, there are studies showing

that vitamin D can alter dopamine, acetylcholine, and noradrenaline neurotransmission1

helps prevent onset of Aar"insonGs, schi!ophrenia, depression, and other mental illnesses1

and plays a multifaceted role in brain development. ,<?,))

Function of VDR, Vitamin D Receptor

Li"e all molecules in the body, vitamin D needs other cofactors and receptors in

order to function properly. Bn )?E?, more than forty years after vitamin D was discovered,

the nuclear vitamin D receptor #VD=$ was also found. VD= 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. 0s a result of this flurry of research, it appears that there are two

main categories of action carried out by the so-called IVD&-VD= conformational

ensemble model. Not only can the vitamin D receptor carry out important genomic

functions, as evidenced by the presence of VD= in the immune system, bone marrow,

adipose cells, etc., but it can also carry out rapid responses #==$ that could occur within

minutes to an hour. 2his 2his source of rapid responses comes fromis derived from the

"nowledge that VD= regulates gene transcription. 'nce again, structure can yield

insights into function1 the structural and stereospecific aspects of the VD&-VD= model



can e(plain how vitamin D regulates both nongenomic and genomic response via specific

ligand-binding poc"ets.

VD= fits into the nuclear receptor superfamily, which isare a class of

transcriptional regulators in animals. Nuclear receptors are ligand-activated1 in the case of

VD=, vitamin D would be the ligand that Iactivates transcription. 2issues that contain

VD= #over 4<$ define specific locations where vitamin D can initiate biological

responses. &ome of these responses include

the classic calcium homeostasis system,

along with five other systems, including the brain, whichh we will be focused on later.

2hee ligand-receptor comple( is what produces the biological reactions.

VDR Structure and Function,

7urthermore, Vitamin D is considered a

conformationally fle(ible molecule1 the side chain that

contains five single carbon-carbon bonds is

the source of this fle(ibility #see figure @ -

0$.9)+ . 7urthermore, the cyclohe(ane ring has

the ability to interchange rapidly between

alpha and beta chair conformations #6$.

Arobably the most practical observation is that

the three different ligand shapes that appear in

nuclear locali!ed VD=, membrane-caveloae

locali!ed VD=, and plasma D6A #7$.

Fi(ure +, &hapes of the optimal ligands for VD=-

mediated responses and for ==, as well as for vitamin D

binding protein #D6A$. 2here is a characteristic ligandshape for each type of response.



Ultimately, the conformational fle(ibility enables vitamin D to carry out a of variety

functions via VD=. 2he two ma8or classes are the rapid cytoplasmic or membrane

responses #"inetically favored$ and

the slow genomic responses

#thermodynamically favored$.

2he first class of response that

can be induced isare the traditional

genomic responses. VD= is a DN0-

binding transcription factor consisting

of a heterodimer #two different

molecules bound together, usually

macromolecules ; in this case, the

VD= with the vitamin D ligand, as

well as an unoccupied retinoid K

receptor #=K= ; see figure E$9.)4

0fter the ligand binds to the VD= genomic poc"et #FA$, there is a conformational change

to allow it to serve as a platform for coactivator binding. 2he coactivator allosterically

stabili!es the VD=-=K= heterodimer, then allowing it to be phosphorylated by serine

protein "inases. 2his new comple( can positively and negatively regulate gene

transcription by recogni!ing vitamin D response elements #VD=5s$ in DN0. 2he VD=-

=K= then recruits additional comodulators to help initiate transcription. 2here are many

hypotheses concerning how e(actly thisof how e(actly happensthis happens1 Dr.

ausslerGs team proposes that there is a simultaneous binding of multiple factors in a

Fi(ure -+, &hapes of the optimal ligands for VD=-mediated

responses and for ==, as well as for vitamin D binding protein

#D6A$. 2here is a characteristic ligand shape for each type of response.



supercomple( at the promoter, based on the

model =0NL gene promoter. 0ctivated

VD= can also interact with transcriptional

coregulators to control gene e(pression.

VD= consists of @+< amino acids with two

main functional groups3 a !inc finger DN0

binding domain near the N-terminus, and a

vitamin D ligand binding domain near the

>-terminus. 0 structure consisting of )+ *-

helices allows VD= to heterodimeri!e with

the retinoid K receptor.)4

2he practical implications come

from finding the genes that are directly regulated by this VD= comple(. &o far, at least

eleven genes that encode bone and mineral homeostasis #the traditional target of VD=$

have been found, including gene products that facilitate intestinal calcium inta"e. 0nother

networ" that has been found to be regulated by VD= is theare encoding factors that

impact cell lifecancer, the immune system, and metabolism. 2hese come from inducing

and repressing various genes involved in diseases such as type B diabetes, multiple

sclerosis, and arthritis. Bt has even been found to blunt various genes involved in

inflammatory responses, thus reducing the ris" of heart disease and 0l!heimerGs. Bt is

clear that there are many areas regulated by VD=, and there will certainly be more to

come.

Fi(ure .-, &tructure-function relationships and

proposed mechanism of gene induction and repression



Vitamin D also plays a role in a second category of responses3 rapid responses.

2his cannot be e(plained by VD=-mediated gene transcription, as was shown in the

classical genomic responses. 2his is a relatively new area of research1 the first rapid

responses were discovered in the )?9:s from the rapid hormonal simulation of intestinal

calcium absorption in chic"s. 2he transfer of calcium to the intestine was noticed only

after @- minutes after transfer of vitamin D to the celiac artery. 2he main difference that

separates genomic and rapid responses is the time delay1 genomic responses often ta"e

days while the rapid response pathway ta"es mere minutes. owever, rapid responses are

also often induced through a different mechanistic pathway. 2he first clue came after it

was noticed that only the E-s-cis loc"ed and not the E-s-trans loc"ed analog was capable

of producing rapid responses in the chic" model. 2his also means that the VD= also can

adopt different

conformers ; the

so called IVD=-

FA for genomic

responses, the

membrane

caveolae locali!ed IVD=-0A for alternative binding, and the plasma vitamin D-binding

protein #D6A$.

Bn particular, it has been found that the caveolae is the source of many rapidly

responding signal transduction pathways. >aveolae are located in the plasma membrane

and are enriched in sphingolipids and cholesterol. Bt was demonstrated both that vitamin



D showed the same binding affinities to VD= in the caveolae as observed with nuclear

VD=, and that vitamin D locali!ed in vivo in the plasma membrane caveolae?.)@

7inally, the IVD= 0A site was proposed to resolve the VD= parado( #see 7igure

<$.+4 2raditionally, only a

single ligand binding

domain has been

recogni!ed ; the one that

binds only the E-s-trans shape. owever, the

rapid response

conformer is not able

to doc" to this specific

binding site. >omputational wor" showed that there is an alternative binding site

available. 2his conformational model was proposed by Dr. aussler and his team,

whereby the VD= could accommodate differently shaped ligands to initiate both genomic

and rapid responses. 2he steroid hormone would essentially Itest the waters and form a

receptor-hormone comple( with the receptor species that provided the highest affinity

and most stability. 7igure 9E shows the main differences between the genomic and rapid

response pathways.) :. Bt seems as though the two categories are vastly different, but a

small portion of VD=s at the membrane is now believed to regulate the e(pression of

genes, thus regulating the activity of many "inases, phosphatases, and ion channels.

owever, more research needs to be done to further elucidate the mechanisms behind this

process.

Fi(ure ., Different mechanisms by which vitamin D and VD= can induce chemical

responses in the body. 'n the left, the caveolae-related pathway leads to activation of the

secondary messenger system to elicit short term responses. 'n the right, ),+D caninteract with VD= locali!ed in the cell nucleus to produce genomic responses through

gene transcription.

Fi(ure /, 2he proposed VD&-VD= conformational ensemble model. 2he left panel

shows the conformational fle(ibility of VD&, the middle panel shows the different binding sites on VD=, with the yellow oval showing overlap between the two regions.

2he right panel shows specific conformational dynamics of VD= 07+ domain1 the6olt!mann distribution is altered depending on the nature of the ligand, changing the

energy landscape of VD= ensemble members to bias a specific downstream event.

Fi(ure /, 2he proposed VD&-VD= conformational ensemble model. 2he left panel shows theconformational fle(ibility of VD&, the middle panel shows the different binding sites on VD=,

with the yellow oval showing overlap between the two regions. 2he right panel shows specificconformational dynamics of VD= 07+ domain1 the 6olt!mann distribution is altered depending

on the nature of the ligand, changing the energy landscape of VD= ensemble members to bias a

specific downstream event.



Implications of

Vitamin D0VDR

and Sleep,

&ince VD= has recently been found in the brain, some interesting new hypotheses

have emerged concerning the function of vitamin D in the brain .)9 ). 'ne of these concerns

the role of vitamin D in sleep. Normally, sleep is highly organi!ed. umans typically go

to sleep at the same time every night, going through specific phases, such as =5H, slow-

wave, etc. %a"ing up from sleep is involuntary and also occurs in a fairly stable manner.

2his seems to imply that sleep is not caused by a buildup of sleep-inducing hormones and

substances1 rather, it is a result of a circadian rhythm type function where sleep is highly

coordinated by the time of day. 2his 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 spea". 0ntidiuretic hormone is produced to limit urine

production, melatonin levels increase, and so on. 2he brain also induces paralysis as deep

sleep arrives, activating specific neurotransmitters to turn off the signals responsible for

wa"efulness. 2hese two categories, timing and paralysis, are essential to sleep. &aper and

colleagues suggest an on-off switch mechanism, which is responsible for sleep1 one part

of the brainstem is active while the other is suppressed.)E + &pecifically, the hypothalamus

is thought to be involved because the stimulation of the posterior hypothalamus induces

arousal, while stimulation of the anterior hypothalamus and ad8acent basal forebrain

region causes sleep.)4)< . Now, how does this tie in with vitamin DM Vitamin D targeted

Fi(ure ., Different mechanisms by which vitamin D and VD= can induce chemical

responses in the body. 'n the left, the caveolae-related pathway leads to activation of the

secondary messenger system to elicit short term responses. 'n the right, ),+#'$+D),+D can interact with VD= locali!ed in the cell nucleus to produce genomic responses

through gene transcription.



neurons have been discovered in specific brain and spinal cord locations in multiple

animals. 2his suggests a possible role of vitamin D in regulating sleep. 0 +-year

uncontrolled trial of vitamin D supplementation in ):: patients with neurological

complaints and sleep problems saw improvements in both these functions.)@ )9 7urther

research needs to be done in this area, as sleep is also influenced by sociological and

psychological factors. 7or e(ample, pain has been shown to influence the uality of sleep,

but pain has also been lin"ed to vitamin D.)? 2herefore, vitamin D may ameliorate the

uality of sleep through a multitude of factors ; not only through chemical pathways in

the brain, but also through alleviating pain. 2here is a delicate balance between these

factors1 vitamin D could directly impact sleep, which could then improve feelings of

pain. Vitamin D could also improve a multitude of variables, including mood, uality of

life, etc. which could also improve pain #a sub8ective feeling that could be influenced by

psychology$. 7urther 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. 2he

involvement of vitamin D in vital bodily processes, from bone health to even regulating

gene e(pression, reveals how potent this single hormone is to human health. New models

to elucidate the nature of vitamin D and VD= 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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>hristophe >osio, Ahilip Fraceffa, et al . PNA# !22!, ??, 9::4-9::9.



22. I>rystal &tructure of >YA+@0), a Hitochondrial >ytochrome A@:

Bnvolved in Vitamin D Hetabolism 0ndrew J. 0nnalora, David 6. Foodin, %en-

Ku ong, et al . Journal of Molecular iology !212, 4?E, @@)-@).

23. Hi!wic", Hatthew, and 0nthony Norman. O2he Vitamin D &terol;Vitamin

D Receptor 4nsemle 5odel 6ffers 7ni8ue Insi(hts into *oth 9enomic and

Rapid:Response Si(nalin(); Sci. Signal !)/- $!223&, n) pa() Print)

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http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D

http://ajcn.nutrition.org/content/95/6/1357.long

http://ajcn.nutrition.org/content/95/6/1357.long

http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D



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Vitamin D Final Draft