Folic Acid and Folates

443 Pages·2008·9.28 MB·English

by  Gerald Litwack (Eds.)

C
ONTRIBUTORS
EmineErcikanAbali
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School,
University of Medicine and Dentistry of New Jersey, New Brunswick,
NewJersey08903
YehudaG.Assaraf
Towhomcorrespondenceshouldbeaddressed;Email:[email protected]
CarolE.Cass
Department of Experimental Oncology, Cross Cancer Institute, Edmonton,
Alberta T6G 1Z2, Canada and Department of Oncology, University of Alberta,
Edmonton,AlbertaT6GIZ2,Canada
HilalCelikkaya
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School,
University of Medicine and Dentistry of New Jersey, New Brunswick,
NewJersey08903
KarenE.Christensen
MontrealChildren’sHospitalResearchInstitute,Montreal,QC,CanadaH3Z2Z3
JamesK.Coward
Departments of Medicinal Chemistry and Chemistry, University of Michigan,
3813Chemistry,930N.University,AnnArbor,Michigan48109
VijayaL.Damaraju
Departments of Experimental Oncology, Cross Cancer Institute, Edmonton,
Alberta T6G 1Z2, Canada and Department of Oncology, University of Alberta,
Edmonton,AlbertaT6G1Z2,Canada
JeremyP.Derrick
Faculty of Life Sciences, Manchester Interdisciplinary Biocentre, University of
Manchester,Manchester,UnitedKingdom
Chheng-OrnEvans
Department of Neurosurgery and Laboratory of Molecular Neurosurgery and
Biotechnology,EmoryUniversitySchoolofMedicine,Atlanta,Georgia30322
MichaelFenech
CSIROHumanNutrition,AdelaideBC,Adelaide,SouthAustralia5000
xiii
xiv Contributors
JenniferT.Fox
Graduate Field of Biochemistry, Molecular and Cellular Biology, Cornell
University,Ithaca,NewYork14853
ZhanjunHou
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute,
WayneStateUniversitySchoolofMedicine,Detroit,Michigan48201
Yi-ChingHsieh
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School,
University of Medicine and Dentistry of New Jersey, New Brunswick,
NewJersey08903
IlanIfergan
The Fred Wyszkowski Cancer Research Laboratory, Department of Biology,
Technion-IsraelInstituteofTechnology,Haifa32000,Israel
AnnL.Jackman
Institute of Cancer Research, Section of Medicine, Sutton, Surrey, SM2 5NG
UnitedKingdom
ChristopherP.Leamon
Endocyte,Inc.,WestLafayette,Indiana47906
DavidLaBorde
Department of Neurosurgery and Laboratory of Molecular Neurosurgery and
Biotechnology,EmoryUniversitySchoolofMedicine,Atlanta,Georgia30322
ZigmundLuka
DepartmentofBiochemistry,VanderbiltUniversitySchoolofMedicine,Nashville,
Tennessee37232
RobertE.MacKenzie
DepartmentofBiochemistry,McGillUniversity,Montreal,QC,CanadaH3G1Y6
LarryH.Matherly
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute,
WayneStateUniversitySchoolofMedicine,Detroit,Michigan48201
JohnJ.McGuire
GraceCancerDrugCenter,RoswellParkCancerInstitute,Buffalo,NewYork14263
H.F.Nijhout
DepartmentofBiology,DukeUniversity,Durham,NorthCarolina27705
NelsonM.Oyesiku
Department of Neurosurgery and Laboratory of Molecular Neurosurgery and
Biotechnology,EmoryUniversitySchoolofMedicine,Atlanta,Georgia30322
Contributors xv
StephenW.Ragsdale
Department of Biological Chemistry, University of Michigan Medical School,
AnnArbor,Michigan48109-0606
M.C.Reed
DepartmentofMathematics,DukeUniversity,Durham,NorthCarolina27705
MichaelB.Sawyer
Departments of Experimental Oncology, Cross Cancer Institute, Edmonton,
Alberta T6G 1Z2, Canada and Department of Oncology, University of Alberta,
Edmonton,AlbertaT6G1Z2,Canada
ThomasB.Shea
Center for Cellular Neurobiology and Neurodegeneration Research,
UMass(cid:1)Lowell,Lowell,Massachusetts01854
NancyE.Skacel
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School,
University of Medicine and Dentistry of New Jersey, New Brunswick,
NewJersey08903
PatrickJ.Stover
DivisionofNutritionalSciences,CornellUniversity,Ithaca,NewYork14853
FlaubertTchantchou
UniversityofMaryland,Baltimore,Maryland
PhilipThomas
CSIROHumanNutrition,AdelaideBC,Adelaide,SouthAustralia5000
C.M.Ulrich
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle,
Washington98109
CongjunYao
Department of Neurosurgery and Laboratory of Molecular Neurosurgery and
Biotechnology,EmoryUniversitySchoolofMedicine,Atlanta,Georgia30322
P
REFACE
Formanyyears,folicacid,itsrelatives,andantifolateshavebeenthecenter
of much attention in one-carbon metabolism and in relation to cancer
research. So much progress has occurred in the last decade in relation to
cancer research and the mechanism of enzyme action as well as in the
mechanism by which folate is transported that the overall subject deserves
a current review.
We begin with contributions on one-carbon metabolism, the methio-
ninecycle,andfolate deficiency.ThefirstofthesepapersisfromJ.T.Fox
and P. J. Stover entitled ‘‘Folate-mediated one carbon metabolism.’’
F. Nijhout, M. C. Reed, and C. M. Ulrich report on ‘‘Mathematical
models of folate-mediated one-carbon metabolism.’’ This is followed by a
treatise on ‘‘Folate deprivation, the methionine cycle, and Alzheimer’s
disease’’ by F. Tchantchou and T. B. Shea. Authors I. Ifergan and Y. G.
Assaraf complete the introductory section with ‘‘Molecular mechanisms of
adaptation to folate deficiency.’’
Thenextgroupofpapersdealswiththefolatetransporterandreceptor.
‘‘Structureandfunctionofthereducedfolatecarrier:Aparadigmofamajor
facilitator superfamily mammalian nutrient transporter’’ is contributed by
L.H.MatherlyandZ.Hou.AuthorsV.L.Damaraju,C.E.Cass,andM.B.
Sawyer review ‘‘Renal conservation of folates: Role of folate transport
proteins.’’ C. P. Leamon and A. L. Jackman present ‘‘Exploitation of the
folate receptor in the management of cancer and inflammatory disease.’’
AnotherreportoncancerisgivenbyC.-O.Evans,C.Yao,D.Leborde,and
N.M.Oyesiku:‘‘Folatereceptorexpressioninpituitaryadenomas:Cellular
and molecular analysis.’’
Thethirdandfinalsectionconcentratesonenzymes.Inthefirstofthese,
E. E. Abali, N. E. Skacel, H. Celikkaya, and Y.-C. Hsieh have written on
‘‘Regulation of human dihydrofolate reductase activity and expression.’’
S.W.Ragsdalecovers‘‘Catalysisofmethylgrouptransfersinvolvingtetra-
hydrofolate and B .’’ ‘‘Methyltetrahydrofolate in folate-binding protein
12
glycine N-methyltransferase’’ is authored by Z. Luka. J. K. Coward and
J. J. McGuire review ‘‘Mechanism-based inhibitors of folylpoly-g-gluta-
matesynthetaseandg-glutamylhydrolase:Controloffolylpoly-g-glutamate
homeostasis as a drug target.’’ P. Thomas and M. Fenech report on
‘‘Methyltetrahydrofolate reductase, common polymorphisms, and relation
to disease.’’ This is followed by a contribution from K. E. Christensen
and R. E. McKenzie on ‘‘Mitochondrial methylenetetrahydrofolate
xvii
xviii Preface
dehydrogenase, methylenetetrahydrofolate cyclohydrolase, and formylte-
trahydrofolate synthetases.’’ The final treatise is on ‘‘The structure and
mechanism of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase’’
by J. P. Derrick.
The structure on the cover comes from the Protein Data Bank and is,
1HFP, the assumed biological molecular structure of human dihydrofolate
reductase from V. Cody et al. (1998). Anti-Cancer Drug Des. 13, 307–315.
Afterthesemanuscriptshavebeenreviewedbytheeditorandassembled,
the Preface and front and back matter are prepared and forwarded to the
publisher.Then,withtheguidanceofRenskevanDijkandTariBroderick,
theproductionprocessbegins.Inmyview,AcademicPress/Elsevierdoesa
commendable job of getting these volumes into print.
Gerald Litwack
[email protected]
Toluca Lake, California
December 8, 2007
C H A P T E R O N E
Folate-Mediated One-Carbon
Metabolism
Jennifer T. Fox* and Patrick J. Stover*, †
Contents
I. Overview 2
II. IntroductiontoCytoplasmicOne-CarbonMetabolism 4
A. Enzymesthatgenerateone-carbonunits 5
B. Folate-interconvertingenzymes 13
C. Biosyntheticenzymes 18
D. Folate-bindingproteins 24
III. IntroductiontoMitochondrialOne-CarbonMetabolism 24
A. Enzymesthatgenerateone-carbonunits 25
B. Folate-interconvertingenzymes 27
C. Biosyntheticenzymes 28
IV. NuclearFolate-MediatedOne-CarbonMetabolism 28
Acknowledgments 29
References 29
Abstract
Tetrahydrofolate(THF)polyglutamatesareafamilyofcofactorsthatcarryand
chemically activate one-carbon units for biosynthesis. THF-mediated one-
carbonmetabolismisametabolicnetworkofinterdependentbiosyntheticpath-
waysthatiscompartmentalizedinthecytoplasm,mitochondria,andnucleus.
One-carbon metabolism in the cytoplasm is required for the synthesis of
purinesandthymidylateandtheremethylationofhomocysteinetomethionine.
One-carbon metabolism in the mitochondria is required for the synthesis of
formylated methionyl-tRNA;thecatabolism ofcholine, purines,andhistidine;
andtheinterconversionofserineandglycine.Mitochondriaarealsotheprimary
source of one-carbon units for cytoplasmic metabolism. Increasing evidence
indicates that folate-dependent de novo thymidylate biosynthesis occurs in
the nucleus of certain cell types. Disruption of folate-mediated one-carbon
metabolismisassociatedwithmanypathologiesanddevelopmentalanomalies,
* GraduateFieldofBiochemistry,MolecularandCellularBiology,CornellUniversity,Ithaca,
NewYork14853
{ DivisionofNutritionalSciences,CornellUniversity,Ithaca,NewYork14853
VitaminsandHormones,Volume79 #2008ElsevierInc.
ISSN0083-6729,DOI:10.1016/S0083-6729(08)00401-9 Allrightsreserved.
1
2 JenniferT.FoxandPatrickJ.Stover
yet the biochemical mechanisms and causal metabolic pathways responsible
fortheinitiationand/orprogressionoffolate-associatedpathologieshaveyet
tobeestablished.Thischapterfocusesonourcurrentunderstandingofmam-
malianfolate-mediatedone-carbonmetabolism,itscellularcompartmentation,
and knowledge gaps that limit our understanding of one-carbon metabolism
anditsregulation. (cid:1)2008ElsevierInc.
I. Overview
The reduced tetrahydrofolates (THFs) serve as a family of enzyme
cofactorsthatchemicallyactivateandcarryone-carbonunitsontheN5and/
or N10 of THF at the oxidation level of formate (e.g., 10-formylTHF),
formaldehyde(e.g.,5,10-methyleneTHF),ormethanol(e.g.,5-methylTHF)
(Appling,1991;Girgisetal.,1997;SchirchandStrong,1989;Wagner,1995).
Folate derivatives also contain a covalently bound polyglutamate peptide of
varying length. Serum folates contain a single glutamate residue, whereas
intracellularfolatescontainapolyglutamatepeptideusuallyconsistingoffive
to eight glutamate residues that are polymerized through unusual g-linked\
peptide bonds (Moran, 1999; Shane, 1995). The polyglutamate pep-
tide increases the affinity of THF cofactors for folate-dependent enzymes
and-bindingproteins,andpreventstheireffluxfromthecellandintracellular
organelles (Schirch and Strong, 1989). THF polyglutamates are coenzymes
that donate or accept one-carbon units in a network of reactions known as
one-carbon metabolism that occurs in three specific and isolated cellular
compartments: the mitochondria, nucleus, and cytoplasm (Fig. 1.1; Porter
et al., 1985; Shane, 1989; Woeller et al., 2007a). The one-carbon forms of
THF can beinterconvertedenzymatically (Fig. 1.1), although each cofactor
form is specific to a particular biosynthetic pathway. The formyl group of
10-formylTHF is incorporated into the C2 and C8 of the purine ring
in the cytoplasm and is used to synthesize formylated methionyl-tRNA
in mitochondria (Fig.1.1). The one-carbonmoiety of5,10-methyleneTHF
is required to convert uridylate to thymidylate, and the one carbon
carried by 5-methylTHF is required to remethylate homocysteine to
methionine. The cellular concentration of folate-binding proteins exceeds
that of folate derivatives, and therefore the concentration of free folate
in the cell is negligible (Schirch and Strong, 1989; Strong et al., 1990;
Suh et al., 2001). This implies that each folate-dependent biosynthetic
pathway competes for a limiting pool of folate cofactors (Scott et al., 1981;
Suh et al., 2001).
Epidemiological studies implicate impaired folate metabolism in several
pathologies and developmental anomalies including neural tube defects
(NTDs) (Scott, 2001; van der Put and Blom, 2000), cardiovascular disease
(GerhardandDuell,1999;LindenbaumandAllen,1995;Uelandetal.,2000),
Mitochondria Cytoplasm
6
THF
THF 10 CO2
5,10-MethenylTHF 10-FormylTHF
11,12
Formate 10-FormylTHF Purines
5 fMet-tRNA 7 8 Formate 9
THF 13 16
Histidine
5,10-MethenylTHF 5-formylTHF
5,10-MethyleneTHF THF Purines 14,15
17
THF 17
Dimethylglycine 4 1 Serine Serine 5,10-MethyleneTHF Thymidylate
3 2
Sarcosine Glycine 16glycine 19
Sarcosine Glycine 20
Glycine CO2,NH3 5-MethylTHF Methionine
21
16,22
Nucleus Homocysteine AdoMet
5-MethylTHF
5,10-MethyleneTHF
Sequestered AdoHcy
Glycine dUMP
16 19 Methylation reactions
dTMP
Serine
23
THF DHF
Figure 1.1 Compartmentation of folate-mediated one-carbon metabolism in the cytoplasm, mitochondria, and nucleus. One-carbon
metabolisminthecytoplasmisrequiredforthedenovosynthesisofpurinesandthymidylateandfortheremethylationofhomocysteineto
methionine. One-carbon metabolism in mitochondria generates one-carbon units for cytoplasmic one-carbon metabolism by generating
formate from serine, glycine, sarcosine, and dimethylglycine. One-carbon metabolism in the nucleus synthesizes dTMP from dUMP and
serine. 1, Mitochondrial serine hydroxymethyltransferase; 2, Aminomethyltransferase; 3, Sarcosine dehydrogenase; 4, Dimethylglycine
dehydrogense; 5, 5,10-Methylenetetrahydrofolate dehydrogenase (NAD-dependent); 6, 5,10-Methenyltetrahydrofolate cyclohydrolase;
4 JenniferT.FoxandPatrickJ.Stover
andcancer(Ames,2001;Blountetal.,1997;ChoiandMason,2000;Kim,
1999; Pogribny et al., 1995). One-carbon metabolism can be impaired by
folate and other vitamin B deficiencies and/or common, penetrant genetic
mutations and polymorphisms (Bailey, 1995; McNulty, 1995; Scott, 1998;
van der Put and Blom, 2000). However, the biochemical mechanisms and
causalmetabolicpathwaysresponsiblefortheinitiationand/orprogressionof
folate-associatedpathologieshaveyettobeestablished.Infact,therearestill
majorgapsinourfundamentalunderstandingofone-carbonmetabolismand
its regulation, including the potential for identifying putative ‘‘missing’’
enzymes and their associated genes whose discovery may be necessary to
complete the assembly of the folate-dependent metabolic network. This
chapterfocusesonourcurrentunderstandingofmammalianfolate-mediated
one-carbonmetabolism,itscellularcompartmentation,andknowledgegaps
thatlimitourunderstandingoffolatemetabolismanditsregulation.
II. Introduction to Cytoplasmic One-Carbon
Metabolism
Folate-mediated one-carbon metabolism in the cytoplasm is a meta-
bolicnetworkofinterdependentbiosyntheticpathwaysthatarerequiredfor
the biosynthesis of purines and thymidylate, and the remethylation of
homocysteine to methionine (Fig. 1.1). Methionine can be adenosylated
toS-adenosylmethionine(AdoMet),acofactor,andmethylgroupdonorfor
numerousmethylationreactionsincludingthemethylationofneurotransmit-
ters and other small molecules, phospholipids, proteins including histones,
RNA, and cytosine bases within CpG islands in DNA. Many AdoMet-
dependent methylation reactions, including those involved in chromatin
methylation, serve regulatory functions by affecting gene transcription
(Miranda and Jones, 2007), protein localization (Winter-Vann et al., 2003),
and the catabolism of small molecules (Stead et al., 2004). The sources of
one-carbon moieties for cytoplasmic one-carbon metabolism include
formate,serine,histidine,andpurines.
7, Methionyl-tRNA formyltransferase; 8, 10-Formyltetrahydrofolate synthetase;
9, 10-Formyltetrahydrofolate synthetase; 10, 10-Formyltetrahydofolate dehydroge-
nase; 11 and 12, Phosphoribosylglycinamide formyltransferase and Phosphoribo-
sylaminoimidazolecarboxamide formyltransferase; 13, 5,10-Methenyltetrahydrofolate
cyclohydrolase; 14 and 15, Glycine formiminotransferase/formimidoyltetrahydrofolate
cyclodeaminaseandGlutamateformiminotransferase/formimidoyltetrahydrofolatecyclo-
deaminase;16,Cytoplasmicserinehydroxymethyltransferase;17,Methenyltetrahydrofo-
latesynthetase;18,5,10-Methylenetetrahydrofolatedehydrogenase(NADP-dependent);
19, Thymidylate synthase; 20, Methylenetetrahydrofolate reductase; 21, Methionine
synthase;22,GlycineN-methyltransferase;23,Dihydrofolatereductase.