Vitamin D hormone

485 Pages·2016·44.242 MB·English

by  Litwack, Gerald

Coverphotocredit:
Belorusova,A.Y.,Rochel,N.
StructuralStudiesofVitaminDNuclearReceptorLigand-BindingProperties
VitaminsandHormones(2016)100,pp.83–116
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Former Editors
ROBERT S. HARRIS KENNETH V. THIMANN
Newton, Massachusetts University of California
Santa Cruz, California
JOHN A. LORRAINE
IRA G. WOOL
University of Edinburgh
Edinburgh, Scotland University of Chicago
Chicago, Illinois
PAUL L. MUNSON
EGON DICZFALUSY
University of North Carolina
Chapel Hill, North Carolina Karolinska Sjukhuset
Stockholm, Sweden
JOHN GLOVER
ROBERT OLSEN
University of Liverpool
Liverpool, England School of Medicine
State University of New York
GERALD D. AURBACH at Stony Brook
Stony Brook, New York
Metabolic Diseases Branch
National Institute of DONALD B. MCCORMICK
Diabetes and Digestive and
Kidney Diseases Department of Biochemistry
National Institutes of Health Emory University School of
Bethesda, Maryland Medicine, Atlanta, Georgia
CONTRIBUTORS
JungmiAhn
DepartmentofMolecularMedicine/InstituteofBiotechnology,TheUniversityofTexas
HealthScienceCenteratSanAntonio,TexasResearchPark,SanAntonio,Texas,USA
LeggyA.Arnold
DepartmentofChemistryandBiochemistry,MilwaukeeInstituteforDrugDiscovery
(MIDD),UniversityofWisconsin-Milwaukee,Milwaukee,Wisconsin,USA
JorgeN.Artaza
DepartmentofHealth&LifeSciences,CharlesR.DrewUniversityofMedicineand
Science,andDepartmentofMedicine,DavidGeffenSchoolofMedicineatUCLA,
LosAngeles,California,USA
AnnaY.Belorusova
DepartmentofIntegrativeStructuralBiology,InstitutdeG(cid:1)en(cid:1)etiqueetdeBiologie
Mol(cid:1)eculaireetCellulaire(IGBMC),InstitutNationaldeSant(cid:1)eetdeRechercheM(cid:1)edicale
(INSERM)U964,CentreNationaldeRechercheScientifique(CNRS)UMR7104,
Universit(cid:1)edeStrasbourg,Illkirch,France
NancyA.Benkusky
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
AlakeshBera
DepartmentofMolecularMedicine/InstituteofBiotechnology,TheUniversityofTexas
HealthScienceCenteratSanAntonio,TexasResearchPark,SanAntonio,Texas,USA
MeganCampbell
DepartmentofMicrobiology,BiochemistryandMolecularGenetics,Rutgers,TheState
UniversityofNewJersey,NewJerseyMedicalSchool,Newark,NewJersey,USA
CarstenCarlberg
InstituteofBiomedicine,SchoolofMedicine,UniversityofEasternFinland,Kuopio,
Finland
AlexCarlson
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
BandanaChatterjee
DepartmentofMolecularMedicine/InstituteofBiotechnology,TheUniversityofTexas
HealthScienceCenteratSanAntonio,TexasResearchPark,andSouthTexasVeterans
HealthCareSystem,AudieLMurphyVAHospital,SanAntonio,Texas,USA
TaiC.Chen
ClinicalTranslationalScienceInstituteandDepartmentofMedicine,BostonUniversity
SchoolofMedicine,Boston,Massachusetts,USA
xiii
xiv Contributors
SylviaChristakos
DepartmentofMicrobiology,BiochemistryandMolecularGenetics,Rutgers,TheState
UniversityofNewJersey,NewJerseyMedicalSchool,Newark,NewJersey,USA
HectorF.DeLuca
DepartmentofBiochemistry,UniversityofWisconsin-Madison,Madison,Wisconsin,USA
PuneetDhawan
DepartmentofMicrobiology,BiochemistryandMolecularGenetics,Rutgers,TheState
UniversityofNewJersey,NewJerseyMedicalSchool,Newark,NewJersey,USA
RosemaryA.Fricker
SchoolofMedicineandInstituteforScienceandTechnologyinMedicine,KeeleUniversity,
Keele,UnitedKingdom
CarolA.Haussler
DepartmentofBasicMedicalSciences,UniversityofArizonaCollegeofMedicine,Phoenix,
Arizona,USA
MarkR.Haussler
DepartmentofBasicMedicalSciences,UniversityofArizonaCollegeofMedicine,Phoenix,
Arizona,USA
TeikichiIkura
MedicalResearchInstitute,TokyoMedicalandDentalUniversity,Tokyo,Japan
NobutoshiIto
MedicalResearchInstitute,TokyoMedicalandDentalUniversity,Tokyo,Japan
CandaceS.Johnson
DepartmentofPharmacologyandTherapeutics,RoswellParkCancerInstitute,Buffalo,
NewYork,USA
PeterW.Jurutka
DepartmentofBasicMedicalSciences,UniversityofArizonaCollegeofMedicine,Phoenix,
andSchoolofMathematicalandNaturalSciences,ArizonaStateUniversity,Glendale,
Arizona,USA
G.KerrWhitfield
DepartmentofBasicMedicalSciences,UniversityofArizonaCollegeofMedicine,Phoenix,
Arizona,USA
ZainabKhan
SchoolofMathematicalandNaturalSciences,ArizonaStateUniversity,Glendale,Arizona,
USA
IreneM.Kim
DepartmentofHealth&LifeSciences,CharlesR.DrewUniversityofMedicineand
Science,LosAngeles,California,USA
AtsushiKittaka
FacultyofPharmaceuticalSciences,TeikyoUniversity,Tokyo,Japan
M.KyleHadden
DepartmentofPharmaceuticalSciences,UniversityofConnecticut,Storrs,Connecticut,
USA
Contributors xv
SeongMinLee
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
WeiLuo
DepartmentofPharmacologyandTherapeutics,RoswellParkCancerInstitute,Buffalo,
NewYork,USA
KamilLupicki
DepartmentofMicrobiology,BiochemistryandMolecularGenetics,Rutgers,TheState
UniversityofNewJersey,NewJerseyMedicalSchool,Newark,NewJersey,USA
YingyuMa
DepartmentofPharmacologyandTherapeutics,RoswellParkCancerInstitute,Buffalo,
NewYork,USA
MarkB.Meyer
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
CharlotteMiddleditch
SchoolofMedicineandInstituteforScienceandTechnologyinMedicine,KeeleUniversity,
Keele,UnitedKingdom
EijiMunetsuna
DepartmentofBiotechnology,FacultyofEngineering,ToyamaPrefecturalUniversity,
Toyama,andDepartmentofBiochemistry,FujitaHealthUniversityforMedicalScience,
Toyoake,Japan
KeithC.Norris
DepartmentofMedicine,DavidGeffenSchoolofMedicineatUCLA,LosAngeles,
California,USA
MeldaOnal
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
RowanP.Orme
SchoolofMedicineandInstituteforScienceandTechnologyinMedicine,KeeleUniversity,
Keele,andCardiffInstituteofInfectionandImmunity,SchoolofMedicine,Cardiff,
UnitedKingdom
SulgiPark
DepartmentofMolecularMedicine/InstituteofBiotechnology,TheUniversityofTexas
HealthScienceCenteratSanAntonio,TexasResearchPark,SanAntonio,Texas,USA
J.WesleyPike
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
LoriA.Plum
DepartmentofBiochemistry,UniversityofWisconsin-Madison,Madison,Wisconsin,USA
NatachaRochel
DepartmentofIntegrativeStructuralBiology,InstitutdeG(cid:1)en(cid:1)etiqueetdeBiologie
Mol(cid:1)eculaireetCellulaire(IGBMC),InstitutNationaldeSant(cid:1)eetdeRechercheM(cid:1)edicale
(INSERM)U964,CentreNationaldeRechercheScientifique(CNRS)UMR7104,
Universit(cid:1)edeStrasbourg,Illkirch,France
xvi Contributors
MaryaS.Sabir
SchoolofMathematicalandNaturalSciences,ArizonaStateUniversity,Glendale,Arizona,
USA
HiroshiSaitoh
TeijinInstituteforBio-medicalResearch,TeijinPharmaLtd.,Tokyo,Japan
ToshiyukiSakaki
DepartmentofBiotechnology,FacultyofEngineering,ToyamaPrefecturalUniversity,
Toyama,Japan
RubySandoval
SchoolofMathematicalandNaturalSciences,ArizonaStateUniversity,Glendale,Arizona,
USA
SohelShamsuzzaman
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
ChungSeogSong
DepartmentofMolecularMedicine/InstituteofBiotechnology,TheUniversityofTexas
HealthScienceCenteratSanAntonio,TexasResearchPark,SanAntonio,Texas,USA
HillarySt.John
DepartmentofBiochemistry,UniversityofWisconsin–Madison,Madison,Wisconsin,USA
MasashiTakano
FacultyofPharmaceuticalSciences,TeikyoUniversity,Tokyo,Japan
KellyA.Teske
DepartmentofChemistryandBiochemistry,MilwaukeeInstituteforDrugDiscovery
(MIDD),UniversityofWisconsin-Milwaukee,Milwaukee,Wisconsin,USA
DonaldL.Trump
DepartmentofMedicine,RoswellParkCancerInstitute,Buffalo,NewYork,andInova
DwightandMarthaScharCancerInstitute,FallsChurch,Virginia,USA
VaishaliVeldurthy
DepartmentofMicrobiology,BiochemistryandMolecularGenetics,Rutgers,TheState
UniversityofNewJersey,NewJerseyMedicalSchool,Newark,NewJersey,USA
LaurenWaite
SchoolofMedicineandInstituteforScienceandTechnologyinMedicine,KeeleUniversity,
Keele,UnitedKingdom
RanWei
DepartmentofMicrobiology,BiochemistryandMolecularGenetics,Rutgers,TheState
UniversityofNewJersey,NewJerseyMedicalSchool,Newark,NewJersey,USA
OliviaYu
DepartmentofChemistryandBiochemistry,MilwaukeeInstituteforDrugDiscovery
(MIDD),UniversityofWisconsin-Milwaukee,Milwaukee,Wisconsin,USA
BaltazarZuniga
DepartmentofMolecularMedicine/InstituteofBiotechnology,TheUniversityofTexas
HealthScienceCenteratSanAntonio,TexasResearchPark,SanAntonio,and
TheUniversityofTexasatAustin,Austin,Texas,USA
PREFACE
Ultraviolet radiation in sunlight causes skin cells to convert a precursor,
7-dehydrocholesterol, to a precursor of the active form of vitamin D,
1,25-dihydroxy cholecalciferol (dihydroxyvitamin D3 or calcitriol). The
precursor is translocated to the liver where a hydroxyl group is added in
the 25 position and, after further translocation to the kidney, a second
hydroxyl group in added in the 1-position producing the active form of
the vitamin that can bind to and activate the vitamin D receptor. Many
essentialactivitiesareproducedbytheactivatedvitaminDreceptorinclud-
ingtheproductionofproteinsthattransportcalciumion,mineralizationof
bone,enhancementoftheimmunesystem,andmanyothers.Focusonthis
vitaminthatactsasahormoneinthebodyisimportantbecausealargepor-
tionofthepopulationisdeficientinvitaminD.Deficiencycanresultfrom
livinginaregionoflimitingsunlight,insufficientingestionofsourcesofthe
vitaminbyvegandiets,orbecauseofintestinaldiseasesandasaconsequence
of aging where the elderly utilize sunlight less efficiently than younger
persons.
InthisvolumearedescribedthehistoryofvitaminDresearch;thebasic
scienceonthevitaminandrelatedstructures,someofwhichareusedclin-
ically;aswellasthestructureofthevitaminDreceptoranditsinteractions
withcoregulatorandinteractionsofthevitaminDsystemwithmanytypes
of cells in normal systems and in diseases.
In the opening chapter, H.F. DeLuca presents the history of vitamin
research in “Vitamin D: historical overview.” This is followed by a series
of chapters on the basic science of the vitamin D system initiated by
“Genomic determinants of vitamin D-regulated gene expression” by
J. W. Pike, M.B. Meyer, N.A. Benkusky, S.-M. Lee, H. St. John,
A. Carlson. M. Onal, and S. Shamsuzzaman. K.A. Teske, O. Yu, and
L. A. Arnold present “Vitamin D receptor–coregulator interaction.”
A. Y. Belorusova and N. Rochel report on “Structural studies of vitamin
D receptor ligand-binding properties.” “Crystal structure of the vitamin
D receptor ligand-binding domain with lithocholic acids” is described
by T. Ikura and N. Ito. V. Veldurthy, R. Wei, M. Campbell, K. Lupicki,
P.Dhawan,andS.Christakosoffer“25-hydroxyvitaminD-24-hydroxylase
(CYP24A1): a key regulator of 1,25(OH)2D3 catabolism and calcium
homeostasis.” H.F. DeLuca and L.A. Plum relate “Analogs of
xvii
xviii Preface
1α,25-dihydroxyvitaminD3inclinicaluse.”M.R.Haussler,G.K.Whitfield,
C. A. Haussler, M.S. Sabir, Z. Kahn, R. Sandoval, and P.W. Jurutka
author“1,25-dihydroxyvitaminDandKlotho:ataleoftworenalhormones
coming of age.” M.K. Hadden writes on “Hedgehog and vitamin D
signaling pathways in development and disease.” “Molecular approaches
for optimizing vitamin D supplementation” is the contribution of
C.Carlberg.
In a group of chapters focusing on the effects of vitamin D on various
cell types including cancer, R.P Orme, C. Middleditch, L. Waite, and
R.A. Fricker report on “The Role of Vitamin D3 in the Development
and Neuroprotection of Midbrain dopamine neurons.” This is followed
by a report from I.M. Kim, K.C. Norris, and J.N. Artaza on “Vitamin D
and cardiac differentiation.” J. Ahn, S. Park, B. Zuniga, A. Bera,
C. S. Song, and B. Chatterjee describe “Vitamin D in prostate cancer.”
E. Munetsuna, A. Kittaka, T.C. Chen, and T. Sakaki discuss
“Metabolismandactionof25-hydroxy-19-nor-vitaminD3inhumanpros-
tate cells.” A. Kittaka, M. Takano, and H. Saitoh write on “Vitamin D
analogs with nitrogen atom at C2 substitution and effect on bone
formation.”Inthefinaltwochapters:Y.Ma,C.S.Johnson,andD.L.Trump
review “Mechanistic insights of vitamin D anticancer effects” and
W. Luo, C.S. Johnson, and D.L. Trump report on “Vitamin D signaling
modulators in cancer therapy.”
The cover illustration is reproduced from Fig. 2 of Chapter 4 by
A. Y. Belorusova and N. Rochel showing the crystal structure of the
ligand-binding domain of the vitamin D receptor.
Helene Kabes of Elsevier, Oxford, UK, and the group from Reed
Elsevier of Chennai, India, were instrumental in the production of this
volume.
SpecialthanksareduetoProfessorHectorDeLucaoftheUniversityof
Wisconsin for his contributions to this book.
GERALD LITWACK
North Hollywood, California
September 28, 2015
CHAPTER ONE
Vitamin D: Historical Overview
Hector F. DeLuca1
DepartmentofBiochemistry,UniversityofWisconsin-Madison,Madison,Wisconsin,USA
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. TheDiscoveryofVitaminD 1
2. TheDiscoveryofthePhysiologicalFunctionsofVitaminD 5
3. TheDiscoveryoftheHormonalFormofVitaminD 8
4. TheIsolationoftheFinalActiveFormofVitaminD 9
5. DiscoveryoftheVitaminDEndocrineSystem 11
6. OtherMetabolismofVitaminD 12
7. DiscoveryoftheVitaminDReceptor 13
References 15
Abstract
AhistoryofvitaminDhasbeenprovided,datingfromtheearliestdescriptionofrickets,
thediseaseresultingfromvitaminDdeficiency,toacurrentunderstandingofvitaminD
metabolism and the mechanism of action of its hormonal form in regulating gene
expressionintargetorgans.VitaminD isproduced inskinbyimpactof280–310nm
lighton7-dehydrocholesterol.ThevitaminDisthenconvertedinthelivertoacircu-
latingform,25-hydroxyvitaminDthatisconvertedlargely,ifnotexclusively,inthekid-
neytothefinalhormone,1α,25-dihydroxyvitaminD.Thishormonefunctionsthrougha
nuclear receptor that regulates expression of key genes in target organs. Among its
many resulting functions are increased intestinal calcium and phosphate absorption,
bonecalcium mobilization, andrenal reabsorption ofcalcium. Theresultant increase
inserumcalciumandphosphatesupportsbonemineralization,curingrickets,andoste-
omalacia.TherearemanyotherfunctionsofvitaminDthatremaintobedescribedthat
contributetoitshealthsupportingrole.
1. THE DISCOVERY OF VITAMIN D
Itseemslikelythatricketsappearedinthehumanpopulationfollow-
ingthemigrationfromAfricaintotheNorthernHemisphere.However,as
farasthisauthorisconcerned,thefirstdocumentationofthedeficiencydis-
easeofvitaminDisthatofWhistler(1645),whoclearlydescribedthedisease
VitaminsandHormones,Volume100 #2016ElsevierInc. 1
ISSN0083-6729 Allrightsreserved.
http://dx.doi.org/10.1016/bs.vh.2015.11.001
2 HectorF.DeLuca
in which the skeleton was poorly mineralized and deformed. Very likely,
this disease occurred only rarelyuntil urbanization of thehuman race took
placeinareaswheremarginalsunlightoccurred.Thediseasebecameanepi-
demicespeciallyinEnglandandinNorthernEuropeduringthenineteenth
century. In fact, the disease was called the “English Disease” because the
incidence in England and Scotland among children was as high as 70–
80% (Hess, 1929).
Ataboutthesametime,thebiologicalscientistsofthenineteenthcentury
wereconsideringthattheessentialcomponentsofadietwereprotein,carbo-
hydrate,fat,andminerals.Theideaofessentialmicronutrientshadnotyetsur-
faced.Magendie(1816),Funk(1911),Hopkins(1912),andothersattempted
togrowexperimentalanimalsonadietofpurifiedproteins,carbohydrates,fat,
andsaltsbuttheanimalsfailedtothriveandsurvive.Clearly,somethingwas
missing from these diets, which later proved to be organic micronutrients
knownasthevitamins.Oneofthefirstindicationsofthenecessityofthese
extra micronutrients was the experiment of Eijkman (1897) followed by a
Dutch colleague, Grijns (1901). Eijkman noted that prisoners suffering
beri-beriintheDutchEastIndieswerefeddehulledrice.Theberi-bericould
becorrectedbytheprovisionofthehulls,whichEijkmansuggestedneutral-
izedtoxinspresentinpolishedrice.Hiscolleague,Grijns(1901),however,
realized that it was an essential nutrient found in hulls that corrected the
beri-beri.Similarly,thewidespreaddisease,scurvyamongBritishsailorson
longvoyages,couldbecorrectedbyprovidinglimesorinthecaseofDutch
andGermansailors,sauerkraut.Ofcourse,wenowknowthatsauerkrautand
limescontainascorbicacidorvitaminC(Drummond,1920).
TheexistenceofvitaminswasfirstestablishedbytheworkofMcCollum
andDavis(1913)attheUniversityofWisconsininwhichratsthatwerefeda
highlypurifieddiet,developedaneyedisease,xerophthalmiathatcouldbe
cured with butter fat or cod liver oil. McCollum was very quick to realize
that this was an accessory food factor, which he termed “vitamin A”
(McCollum,Simmonds,&Pitz,1916).Somewhatlater,McCollum’sgroup
foundthatawater-solublesubstancepreventedthedisease,neuritis.Thishe
designatedas“vitaminB”(McCollumetal.,1916).Almostidenticalexper-
imentswereconductedbyOsborneandMendel(1917)clearlydemonstrat-
ing the existence of a fat-soluble micronutrient termed “vitamin A” and a
water-soluble nutrient termed “vitamin B.”
Thediscoveryofthevitaminswasundoubtedlyanimportantfactorthat
stimulated Sir Edward Mellanby in Great Britain to carry out a classical
experiment.Hewasabletoproducethediseasericketsindogsbyproviding
them the diet consumed by the Scotts, a population suffering the highest