Kidney International Homocystein 2001

8/12/2019 Kidney International Homocystein 2001

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Kidney International, Vol. 59, Suppl. 78 (2001), pp. S-221S-229

HYPERHOMOCYSTEINEMIA IN UREMIA

The folate cycle and disease in humans

BRIAN

FOWLER

Metabolic Unit, University Childrens Hospital Basel (UKBB), Basel, Switzerland

The folate cycle and disease in humans. The prevalence of status [5] and adjuvant therapy, including folate, irre-hyperhomocysteinemia in renal disease patients, its treatment spective of hyperhomocysteinemia [6], plays an impor-by folate administration, and its aggravation by the 677 CT

tant role in the management of renal disease.mutation of methylene-tetrahydrofolate (methylene-THF) re-

In recent years, the link between folate homeostasisductase has established the folate cycle as an important factorand homocysteine metabolism has been established to bein the pathogenesis and management of renal disease. Proper

function of the folate cycle depends on normal function of important in a number of disease states, including variousinvolved enzymes adequate of the vitamin andits correct dispo- types of vascular disease [7] as well as in renal disease.sition within the body. Vital processes in folate disposition The prevalence of hyperhomocysteinemia in renal dis-include conversion of dietary folylpolyglutamates to monoglu-

ease patients [8, 9], its treatment by folate administrationtamates, intestinal absorption, receptor and carrier-mediated[10] and its aggravation by the 677 CT mutation oftransport across cell membranes, and cellular export. Folate

coenzymes are responsible for the one-carbon unit transfer in methylene-tetrahydrofolate (methylene-THF) reductaseintermediary metabolism and are required for several reactions [11] have established the folate cycle as an important fac-in key metabolic processes, for example of purine, pyrimidine

tor in the pathogenesis and management of renal disease.and methionine synthesis, and glycine and serine metabolism.This article reviews current knowledge of processesMethionine synthase and its recently discovered reducing pro-

tein as well as methylene tetrahydrofolate reductase are key involved in folate homeostasis and metabolism. Particu-folate enzymes in homocysteine metabolism. Deficiencies of lar emphasis is placed on folate enzymes directly relatedthese enzymes are important causes of severe disease in the

to homocysteine metabolism.rare remethylation defects causing homocystinuria.Knowledgeof their catalytic and molecular properties is important in un-derstanding possible causes of moderate hyperhomocysteine-

PROCESSING OF INGESTED FOLATE ANDmia, as for example, the well-known 677 CT transition ofINTESTINAL TRANSPORTmethylene tetrahydrofolate reductase.

The folic acid molecule is complex and consists of2-amino-4-hydroxy-pteridine linked to p-aminobenzoic

Folate is vital in humans for several metabolic reac- acid (that is, pteroic acid) combined with a variable num-tions involved in the formation and transfer of C1 units. ber (one to nine) of glutamic acid residues (Fig. 1). TheseAs with other vitamins such as B12 [1], a large number glutamate moeties are bound to pteroic acid and to eachof different physiological and metabolic processes are other by amide linkages involving the gamma carboxylnecessary to convert folic acid in the diet into intracellu- group of glutamate [12]. Dietary folates exist mainly aslar, metabolically active forms. These processes include 5-methyl- and 10-formyl-THF in polyglutamate formsinterconversion of polyglutamate and monoglutamate that cannot cross cell membranes [13] and must be enzy-forms of folate, intestinal uptake, transport across cell matically hydrolyzed by folylpolyglutamate conjugase

membranes, and export processes and metabolic reac- (E.C. 3.4.19.9) to the monoglutamyl form in the intestinetions catalyzed by specific enzymes. to be absorbed. The conjugases are widely distributed.Deficiency of folate caused by renal loss or poor nutri- The human conjugase isolated from jejunal brush bor-

tion may be important in relationship to renal disease. ders is a lysosomal exopeptidase cleaving terminal glu-For example, low dietary intake [2] and low blood levels tamate residues [1416]. A second distinct enzyme from[3] of folate in dialysis patients are well known, and jejunal mucosa is located intracellularly and is reportedanemia in renal failure patients, whether or not on dial- to have endopeptidase activity [17].ysis, is a common finding [4]. Monitoring of nutritional

Once folate has entered the enterocyte by specific mem-brane transport, intracellular polyglutamate synthesis oc-curs to meet the cellular needs for folate metabolismKey words: folic acid, hyperhomocysteinemia, methylene tetrahydrofo-

late reductase, vitamin B12, anemia, renal failure. and also to maintain a concentration gradient in favorof entry of folate monoglutamate into the cell. Reconver-2001 by the International Society of Nephrology

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Fowler: Folate cycle and disease in humansS-222

Fig. 1. Structure of folic acid and relatedcompounds.

sion of polyglutamates to monoglutamates allows trans- be related to folate absorption, and appears to be locatedin the plasma membrane at the basolateral surface [24].port across the basolateral membrane into the portalThe functional expression and mRNA distribution of acirculation, mainly as 5-methyl-THF, most of which isRFC-1 cDNA involved in folate transport have beennonspecifically bound to albumin [18].described [25]. Subsequent studies in the mouse revealeda higher capacity for 5-methyl-THF uptake in mature

CELLULAR TRANSPORT OF FOLATE absorptive cells than in proliferative crypt cells, and thiswas associated with RCF-1 gene expression, which codesTransport of folates across cell membranes is facili-for a 58 kD brush border membrane protein [24].tated by both receptor-mediated and carrier-mediated

Folate exit pumps, which are directly linked to adeno-mechanisms, which are variably expressed in differentsine 5-triphosphate (ATP) hydrolysis, will act in opposi-tissues. Membrane folate receptors, which are attachedtion to folate uptake so that maintenance of the trans-through glycosyl-phosphatidyl-inositol anchors, have amembrane folate gradient will depend on the net effect

high affinity for folic acid as well as for reduced folatesof these two processes [26, 27].

[19]. Their distribution in cell membranes is diffuse, andFinally, passive diffusion has also been shown to play

internalization of folate probably involves classic endo- a role in folate receptor-mediated transport across thecytosis [20]. Folate receptors have been described in human placenta [28].three isoforms, two of which are widely distributed, while Once transported into cells, monoglutamyl folatesone seems to be specifically associated with placenta and must be converted to their polyglutamyl forms by folyl-

is likely to be important in the maternal-fetal transfer poly-glutamate synthetase (EC 6.3.2.17), the latter be-of folate [21, 22]. ing preferentially retained in cells [29]. Cytosolic and

mitochondrial isoforms of folylpoly-glutamate synthe-Carrier-mediated systems (RFC) exhibit a much highertase exist, probably coded for by the same gene whoseaffinity for reduced folates (1 to 5 mol/L) than forvariable transcription has been proposed to regulate en-folic acid (about 200 to 400mol/L) and facilitate activezyme levels in different tissues [30]. The degree of poly-transport involving exchange with organic anions [23].glutamylation may be important in the effectiveness ofOne example of a folate uptake mechanism is thatantifolate drugs such as methotrexate [31].existing in the brush border membrane of rat small intes-

tine luminal epithelium with a pH optimum of 5.5 to 6FOLATE METABOLISMand high saturability (Km 5 mol/L), which can inter-

nalize all folate compounds, including folic acid. Another One carbon unit metabolism and coenzyme functioninvolve modification of the carbon atom existing at thesystem in mouse luminal epithelium does not appear to


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Fowler: Folate cycle and disease in humans S-223

Table 1. Summary of the main folate enzymes

Enzyme official name EC(other name) Reaction number Comments (human enzyme unless specified)

Formate-tetrahydrofolate ligase THF formate ATP 6.3.4.3 Trifunctional C1-THF synthetase(10 formyl-THF synthetase) 10 formyl-THF ADP P i Cytosolic

Methenyl-tetrahydrofolate 10 formyl-THF 3.5.4.9. Prot. Cry-Str. [70],cyclohydrolase 5,10-methenyl-THF H2O Enzyme kinetics [71],

Methylenetetrahydrofolate 5,10-methenyl-THF NADPH 1.5.1.5 DNA [34],dehydrogenase 5,10-methylene-THF NADP Chr-loc. 14q24 [72]

Formyltetrahydrofolate 10-formyltetrahydrofolate 1.5.1.6 Cytosolic,dehydrogenase tetrahydrofolate NADP Prot. [73]

H2O tetrahydrofolate DNA [74]CO2 NADPH

Glycine hydroxymethyltransferase 5,10 methylene-THF H2O 2.1.2.1 Cofactor PLP, cyt./mit. Cyt. Cry-Str. [75](serine hydroxymethyltransferase) glycine serine THF Cyt. DNA [40] Chr-loc. mit. 12q13,

cyt. 17p11.2 [39]

Methylenetetrahydrofolate 5,10-methylene-THF NAPH 1.5.1.20 Cofactor FAD, cytosolic. Prot. [45],reductase 5-methyl-THF NADP DNA, Chr-loc. 1p36.3 [49]

5-Methyltetra- hydrofolate:homocysteine homocysteine 5-methyl-THF 2.1.1.13 Cofactor cobalamin, cytosolic Prot. [59]S-methyltransferase methionine THF Cry-Str. E. Coli [56](methionine synthase) DNA, Chr-loc. 1q42.3-q44 [6264]

[methionine synthase]- cobalamin MS-cob(II)alamin NADPH 2.1.1.135 Cofactor S-adenosylmethionine, cytosolic,methyltransferase (cob(II)alamin AdoMet MS- DNA, Chr-loc. 5p15.3-15.2 [68]reducing) (Methionine synthase reductase) methylcob(I)alamin

AdoHcy NADP

Glutamate formimino transferase THF formiminoglutamate 2.1.2.5 Bifunctional protein, cofactor PLP,5-formiminoTHF glutamate Golgi associated. Cry-Str. [76]

Formimino-tetrahydrofolate FormiminoTHF 5,10-methenyl- 4.3.1.4 Prot./DNA Rat [36], canine kidney cells [37]cyclodeaminase THF NH3

Dihydrofolate reductase THF reduces to DHF 1.5.1.3 Cyt.Prot. Cry-Str. [77],Chr-loc. 5q11.1-q13.3 [78]

Abbreviations are: Chr-Loc, human chromosome location; Cry-Str, protein crystal structure; Cyt., cytosolic; DNA, cloning or gene structure details; FAD, flavineadenine dinucleotide; Mit., mitochondrial; PLP, pyridoxal 5phosphate; Prot., details on protein purification and/or structure; THF, tetrahydrofolate.

oxidation levels of formyl (HCO), methylene (CH2), methenyl-THF with 5,10-methylene-THF [33]. The cDNAcodes for a protein of 101 kD corresponding well with theor methyl (CH3; Fig. 1), and are covalently attachedproperties of the enzyme purified from human liver [34].to the nitrogen atoms at position 5 and/or 10. These10-formyl-THF can also be converted to THF and carbonmodifications involve several enzyme reactions relateddioxide in the reaction catalyzed by the liver-specific 10-to different essential metabolic pathways such as theformyl-THF dehydrogenase, whereby excess C-1 unitssynthesis of purines, pyrimidines and methionine, glycineare released and the THF pool is maintained [35].and serine metabolism, and the breakdown of histidine

[12]. Table 1 summarizes the main reactions and lists5,10-Methylene-THF

special features and references to main data on enzymes5,10-Methylene-THF is a central compound in the fo-of the folate cycle. The interactions of folate coenzymes

late cycle since (1) it provides the entry point of theand C1 unit metabolism are illustrated in Figure 2.quantitatively important supply of C1 units from serineFolate compounds must be in the reduced and polyglu-through the interconversion of glycine and serine cata-

tamate form to function as coenzymes. Reduction of folic

lyzed by serine hydroxymethyltransferase; (2) it linksacid or dihydrofolate to THF is catalyzed by dihydrofo- this supply of C1 units to the formation of thymidylatelate reductase. This enzyme plays an important role in

for the synthesis of pyrimidine nucleotides; and (3) it isfolate homeostasis and has received much attention as reduced to 5-methyl-THF by methylene-THF reductase.the site of action of cancer treatment [32]. This provides methyl groups for the formation of me-

thionine from homocysteine in the methionine synthaseC1-THF synthetase catalyzed reaction, which links folate metabolism intri-

Three enzymes, 10 formyl-THF synthetase, 5,10 meth- cately to homocysteine and finally allows THF to re-enyl-THF cyclohydrolase, and 5,10 methylene-THF de- enter the pool of reduced folates.hydrogenase, which constitute the multi-enzyme complex

Purine nucleotide synthesisC1-THF synthetase, are responsible for the interconver-sion of (1) 10-formyl-THF with THF and formate, (2) The folate cycle is also linked directly to purine nucleo-

tide synthesis through the provision of carbon atoms10-formyl-THF with 5,10-methenyl-THF, and (3) 5,10-


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Fig. 2. Summary of the metabolic interactions of folic acid, related derivatives, pathways, and enzymes. Abbreviations are: THF, tetrahydrofolate;DHF, dihydrofolate.

numbers 2 and 8 of the purine ring by 10-formyl-THF, Histidine metabolismwhich is the folate coenzyme in the formation of-N- Folate coenzymes are also involved in the breakdownformyl-glycinamide ribonucleotide and 5-phosphoribosyl- of histidine, which occurs in only a few tissues, such as5-aminoimidazole-4-carboxamide, catalyzed by 10 formyl- liver and kidney, and has minor importance in the totalTHF:5 aminoimidazole 4 carboxamide ribonucleotide turnover of C1 units. Histidine is converted to formiminoformyltransferase and 10 formyl-THF:glycinamide ribo- glutamate, whose formimino group is transferred to

THF-forming N5-formimino-THF. This is further con-nucleotide formyltransferase, respectively [12].


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verted to methenyl-THF, linking this amino acid to the ably advanced our knowledge of the molecular geneticsfolate cycle. The two reactions are catalyzed by a bifunc- of this important enzyme. They first cloned a cDNA thattional octameric enzyme with glutamate formimino codes for the expected amino acid sequence based ontransferase and N5 formimino-THF cyclodeaminase ac- data from the pig enzyme and maps to 1p36.3 [49]. Thistivities. Recent studies report cloning and characteriza- allowed elucidation of different mutations in patientstion of a rat bifunctional enzyme of 58 kD localized to with homocystinuria caused by severe methylene-THF

the Golgi apparatus [36, 37]. reductase deficiency [50]. The cDNA of 2.2 kb codes fora 70 kD protein in an expression system, whereas a

Serine metabolism and folate larger enzyme of 77 kD is found in tissues, suggestingSerine hydroxymethyltransferase plays a key role in the possibility of tissue-specific methylene-THF reduct-

C1-unit metabolism [38]. ase protein isoforms and a complex regulation of theBoth cytosolic and mitochondrial forms exist, and gene [51].

cDNAs have been cloned for the human enzyme [39, 40]. A thermolabile variant of this enzyme first describedThe genes for the cytosolic form and mitochondrial form by Kang et al [52] is due to a 677 CT transition [53]have been characterized [39], and a pseudo gene has and is a common polymorphism with incidences as highbeen found on chromosome 1p32.3-33 [41]. The exact as 23% in some populations [54].role of the different isoenzymes in C1 unit metabolismis not fully understood, but it has been proposed that 5-Methyl-THF: Homocysteine S-methyltransferase

their regulation might influence cell proliferation and be (methionine synthase)a target for antineoplastic drugs [42]. This complex enzyme catalyzes the transfer of aOne important role of the enzyme is the channeling methyl group from 5-methyl-THF to homocysteine-pro-

of C1 units of serine (carbon number 3), derived from ducing methionine and THF, that is, remethylation. Theintermediates of glycolysis, via 5,10-methylene-THF, into enzyme plays a vital role in the provision of methioninethe folate cycle with the concomitant formation of glycine. for S-adenosylmethioninedependent transmethylationGlycine cleavage occurs in only the mitochondria in a four

reactions. Much of our understanding of the mechanismreaction sequence involving the mitochondrial form of

stems from elegant studies by Matthews, and coworkersserine hydroxymethyltransferase [43]. The activity of the

on theEscherichia coli enzyme [5557] as well as infor-enzyme and degree of metabolism of glycine compared

mation on the human placenta [58] and the pig liverwith serine varies considerably between different tissues

enzymes [59]. The porcine enzyme is a monomer of 151[42]. In thereverse direction of this reaction, THF is regen-

to 155 kD molecular mass, contains one cobalt atom pererated from 5,10-methylene-THF, thereby converting gly-

mole of enzyme, and is dependent on S-adenosylmethio-cine to serine and completing the sequence whereby thenine for activity.

possibly toxic formate is converted to serine [38].Cloning of the genes revealed that much homology

exists between the human and E. coli forms, so that5,10-Methylene-THF reductaseinformation gained from the extensive studies of theThis enzyme, which catalyzes the nicotinamide ade-latter is indeed relevant for the human enzyme. Ournine dinucleotide phosphate (NADPH)-linked reduc-present understanding of the catalytic cycle is deducedtion of 5,10-methylene-THF to 5-methyl-THF, has beenfrom kinetic studies that suggest an ordered sequentialpurified from pig liver [44] and human liver [45] withmechanism [60] as well as molecular modeling [55, 56].similar properties. The reaction is essentially irreversibleIn this cycle, the methyl form of the B12coenzyme do-in vivo, and its activity is a control point for entry ofnates its methyl group to homocysteine yielding the re-folate coenzymes into the remethylation of homocys-duced form of the coenzyme cob(I)alamin and producingteine pathway [46]. The purified enzyme is a dimer of

methionine. The cob(I)alamin moeity is remethylated byequal subunits of 77 kD molecular mass, each of which5-methyl-THFforming THF. Thus, reductive remethyla-contains one mole of noncovalently bound flavinadeninetion of the cobalamin molecule is a vital part of the reac-dinucleotide. Flavin acts as a conductor of reducingtion, particularly since the cob(I)alamin form occasionallyequivalents from NADPH to the natural substrate or inbecomes oxidized to the cob(II)alamin form, which isartificial systems to alternative electron acceptors suchinactive. The methyl group is donated by S-adenosyl-as menadione. The binding of S-adenosylmethionine re-methionine in this process, and in E. coli, the electronsults in allosteric inhibition, which can be reversed byis furnished by reduced flavodoxin, a protein lacking inS-adenosylhomocysteine [47]. This inhibition by S-aden-mammals. Until its elucidation (discussed later in thisosylmethionine acts synergistically with the activation ofarticle), there was much speculation on the nature of thecystathionine-synthase and is an important factor inhuman reducing component. Evidence was obtained thatthe regulation of homocysteine metabolism [48].

The studies of Rozen and coworkers have consider- the mammalian enzyme utilizes two distinct proteins,


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which are not related subunits, to transfer electrons from treatment. Little is known on the molecular defect, butinvolvement of a folate transporter seems plausible.NADPH to the cobalamin moiety of the enzyme [61].

Three independent groups cloned the methionine syn- Other disorders of folate transport have been reportedsuch as a postulated defect of 5-methyl-THF uptake ofthase gene (designated MTR) at the same time, em-

ploying similar approaches and taking advantage of the into bone marrow cells. One patient with dyserythro-poiesis was shown to have reduced 5-methyl-THF uptakehighly conserved sequences in bacteria and C. elegans

[6264]. The cloned human gene encodes a protein of into erythrocytes.An adult with progressive sensorineural hearing loss,1265 amino acids with a predicted molecular weight of

140 kD and is localized to chromosome 1q42.3-1q44. dysarthria, dysgraphia, and gait ataxia was shown to havelow folate levels in CSF that was postulated to be dueMutations in theMTRgene have been identified in sev-

eral patients with the cblG form of homocystinuria to a defect of a folate binding protein of the choroidplexus.caused by methionine synthase deficiency [62, 65, 66].

Also, the 919 DG polymorphism of MTR has been Deficiency of dihydro-THF reductase has been re-ported but not substantiated as an inborn error of metab-reported to be a determinant of plasma total homocys-

teine concentrations, albeit to a modest degree [67]. olism [12].Also glutamate formiminotransferase/formimino-THF-An important advance in understanding the methio-

nine synthase function in humans was the discovery of cyclodeaminase deficiency has been observed in bothasymptomatic subjects and in patients with neurologicalthe gene for methionine synthase reductase. Leclerc et al

cloned a cDNA using consensus sequences for binding of abnormalities, including threewith associated malignancy,but not established as a cause of clinical abnormalities.potential reducing cofactors, FMN, FAD, and NADPH[68]. The isolated gene codes a mRNA of 3.6 kb and Several distinct, rare inherited disorders resulting in

deficient methionine synthase activity are known. Func-predicts a protein of molecular mass of 77,000 kD andtional deficiency of this enzyme, either isolated (due to698 amino acids belonging to the family of ferredoxin-the cblE or cblG cobalamin defects [79]) or combinedNADP reductases. Different mutations in this gene,with methylmalonyl CoA mutase deficiency (cblC/D [80]including large insertions or deletions caused by splicingor cblF defects [81]), leads to severe disease and earlydefects and small deletions and point mutations, havedeath, sometimes even in treated patients. Neurologicalbeen demonstrated in patients with the cblE form ofabnormalities, feeding difficulties, and delayed develop-homocystinuria [69]. This provides conclusive evidencement, together with megaloblastic anemia, usually mani-that this gene and its protein are indeed necessary forfesting in the first weeks or months of life, increasedproper function of human methionine synthase. Whetherhomocystine with low methionine levels, together withany additional reducing proteins are necessary for methi-methylmalonic aciduria in the combined defects are allonine synthase function remains to be established.hallmarks of this enzyme deficiency.

Metabolic importance of polyglutamate forms In both isolated and combined deficiencies, treatmentwith high doses of intramuscular hydroxocobalmin usu-The degree of polygutamylation of coenzymes playsally leads to a marked improvement of the biochemicalan important role in the regulation of folate enzymes asabnormalities, but neurological damage may be irrevers-well as in their retention in cells (discussed previouslyible. As in other remethylation defects, betaine and me-in this article). For example, the affinity of formyl-THFthionine can be given to increase further the ratio ofsynthetase for the substrate THF with four or five gluta-methionine to homocysteine as well as folic acid or folinicmate residues is 150 times higher than that for the mo-acid.noglutamate form of THF. Furthermore, the conversion

Acquired causes of methionine synthase deficiency areof glycine to serine by cytosolic serine hydroxymethyl-also known, such as exposure to nitrous oxide [82] andtransferase was three times higher with substrate con-also B12deficiency [83].taining five glutamate residues than with two [38].

Methylene-THF reductase deficiency is well known asa cause of severe hyperhomocysteinemia. Most patients

INHERITED DISORDERS OF have presented between the neonatal period and oneFOLATE METABOLISM year of age with severe neurological disease, including

Several rare congenital disorders of folate metabolism seizures, upper motor neuron signs, microcephaly, elec-are known [1]. troencephalogram (EEG) abnormalities, developmental

Hereditary folate malabsorption reported in less than delay, and psychomotor retardation. Later presenting20 cases exhibits megaloblastic changes, diarrhea, failure patients with milder features, gait abnormalities, andto thrive, and neurological abnormalities in the first few psychiatric disorder are known. Vascular abnormalitiesmonths of life. Serum and cerebrospinal fluid (CSF) fo- have been identified at post-mortem in some patients [1].

In addition to increased plasma levels of homocystinelate levels are low and respond poorly to oral folate


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4. LevinA: How shouldanaemia be managed in pre-dialysis patients?with low methionine, folates can be low in serum, redNephrol Dial Transplant14(Suppl 2):S66S74, 1999

cells, or CSF reflecting low 5-methyl-THF. Although a 5. McCarthy JT: A practical approach to themanagement of patientswith chronic renal failure.Mayo Clin Proc 74:269273, 1999few exceptional patients have responded to pharmaco-

6. Horl WH: Is there a role for adjuvant therapy in patients beinglogical doses of folate, most are unresponsive to specifictreated with epoietin? Nephrol Dial Transplant14(Suppl 2):S50

vitamin administration, and treatment is aimed at low- S60, 19997. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG: Aering homocysteine and correcting low methionine levels

quantitative assessment of plasma homocysteine as a risk factor[1]. Most patients have responded poorly to treatment, for vascular disease. JAMA 274:10491057, 1995and long-term outcome appears to be poor. 8. Loehrer FMT, Angst CP, Brunner FP, Haefeli WE, Fowler

B: Evidence for disturbed S-adenosylmethionine/S-adenosylhomo-Finally, although not described in humans, deficiencycysteine ratio in patients with end-stage renal failure: A cause forof 10 formyl-THF dehydrogenase has been discovereddisturbed methylation reactions?Nephrol Dial Transplant13:656

in a mouse model [84]. 661, 19989. Bostom AG, Gohh RY, Tsai MY, Hopkinsgarcia BJ, Nadeau

MR, Bianchi LA, Jacques PF, Rosenberg IH, Selhub J:Excessprevalence of fasting and postmethionine-loading hyperhomocys-CONCLUSIONteinemia in stable renal transplant recipients. Arterioscler Thromb

An important question is whether renal disease per Vasc Biol17:18941900, 199710. Beaulieu AJ, Gohh RY, Han H, Hakas D, Jacques PF, Selhubse can disturb folate metabolism. Clearly, if folate status

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folic acid supplementation in renal transplant recipients. Arte-vitamins, low folate levels may lead to reduced activity ofrioscler Thromb Vasc Biol19:29182921, 1999

folate enzymes, including those related to homocysteine 11. Fodinger M, Mannhalter C, Wolfl G, Pabinger I, Muller E,metabolism leading to pathology, for example, anemia. Schmid R, Horl WH, Sunder-Plassmann G:Mutation (677 C toT) in the methylenetetrahydrofolate reductase gene aggravatesConversely, if homocysteine elevation occurs because ofhyperhomocysteinemia in hemodialysis patients. Kidney Inta disturbance of metabolism at the level of methylene-52:517523, 1997

tetrahydrofolate reductase or methionine synthase, inde- 12. Rosenblatt DS: Inherited disordersof folate transport andmetab-olism, in the Metabolic and Molecular Bases of Inherited Diseasependent of folate status, this may lead to disturbed avail-(7th ed), edited by Scriver CR, Beaudet AL, Sly WS, Valle D,ability of reduced folates essential for cellular integrity.New York, McGraw-Hill Book Co., 1995, pp 31113128

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15. Chave KJ, Galivan J, Ryan TJ: Site-directed mutagenesis estab-this condition has a complex etiology with increasedlishes cysteine-110 as essential for enzyme activity in human

methylmalonic acid levels as well as deficiency of methio- gamma-glutamyl hydrolase. Biochem J343:551555, 1999nine synthase function. 16. Yao R, Schneider E, Ryan TJ, Galivan J:Human gamma-gluta-myl hydrolase: Cloning and characterization of the enzyme ex-Clearly, much work is still needed to elucidate bothpressed in vitro. Proc Natl Acad Sci USA 93:1013410138, 1996

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sis of the membrane folate receptor. Nutr Rev 56:8687, 1998ACKNOWLEDGMENTS 21. Prasad PD, Ramamoorthy S, Moe AJ, Smith CH, Leibach FH,

Ganapathy V:Selective expression of the high-affinity isoform ofThe author acknowledges the support of a grant from the Swissthe folate receptor (FR-alpha) in the human placental syncytiotro-

National Foundation (No. 32-5567.98) and thanks Mr. P. Litynski forphoblast and choriocarcinoma cells.Biochim Biophys Acta1223:71

his help in the preparation of the manuscript.75, 1994

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folate receptor a truncated receptor and receptor type beta inChildrens Hospital Basel (UKBB), Postfach 4005, Basel, Switzerland.

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