Metabolism

Polyglutamyl side chains; There are at least five folate metabolites that have direct functional importance, including tetrahydrofolate (THF), di hydro folate. 5.10-methylene-THF, 5-methyl-THF, 5-formyl-THF. 10-formyl-dihydrofolate. and 10-formyl-THF. Additional forms are crucial intermediates of folate metabolism. All of these vitamers require polyglutamyl side chains of specific length to he fully active. The removal and addition of glutamyl groups as described above is an integral pan of folate metabolism that controls both retention and function.

NADPH NADP

H*C H

V }

rs

Dihydrofotate reductase

NH

c=o

1

R

R

Folate 7.B-Dihydrofotate

Figur» 10.30 D'hydrofoUte reductase activates folate

Folate 7.B-Dihydrofotate

Figur» 10.30 D'hydrofoUte reductase activates folate

NADPH NADP

Dlhydrofolate reductase

NADPH NADP

Dlhydrofolate reductase

Folate activation: Dihydrofolate reductase {EC1.5.1.3) catalyzes the NADP-dependent reduction of folate to 7,8-dihydro folate and then to 5,6,7,8-tctrahydrofo-late. This fblatc-activating enzyme is inhibited by the anticancer agent methotrexate. Folate reactivation: The reactions of folate metabolites are numerous and complex. Reactions that use one active form often generate another functionally important form. On the other hand, such reactions are essential to 'unload" one-carbon groups and regenerate free folate for other reactions. The picture is further complicated by the fact that some of these activities arc bundled Into multifunctional proteins, 5, W-Methylene THF: The conversion of serine to glycine by glycine hydroxymethyl-transfcrase (EC2.1.2.1) generates large quantities of 5.10-mcthylene-THF. Catabolism of glycine through the mitochondrial glycine cleavage system (am inomethy I transferase; EC2.1.2.10) also eliminates a carbon with 5,10-methylene-THE NADPH-dependcnt reduction of 5.10-methenyl-THE by methylenes I rahydro-folate dehydrogenase (MTHFD; EC 1.5.1.5). an activity of the CI-THF synthase, also generates 5.10-methylenc-THF. The tri functional CI-THE synthase protein combines m humans the acti\ ities of MTHFD. formate-tetrahydro folate ligase (EC6.3.4.31, and mcthenyi-tetrahydrofolatecyclohydrolase (EC3.5.4.9). 5,10-Methylene-THF can also be generated from 10-formyl-THF by the inethenyl-tetrahydrofolate cyclohydrolasc (EC3.5.4.9) activity ofCl-THF synthase.

5.10-Mcthylene-THF is the cofactor for dTMP synthesis by thymidylate synthase (EC2.1.1.45). This reaction releases dthydrofolate, which can be reduced to THF again. Alternatively, both the NADP1 f-dependent methvlenetetrahydrofolate reductase (EC 1.5.1.20.) and the FAD 1I r dependent 5.10-meihylenetclrahydrofolate reductase (ECI.7,99.5) can convert 5.10-methylene-THF into 5-methyl-THF. which must then be disposed of in turn. Both enzymes contain FAD as a prosthetic group.

NADP

5-Formyl-THF

dehydrogenase

NADP

5 FOrmyl DHF

Ferritin

5.10-Methylene-THF — NADP

Ci-THF

5.10-MOIheriyl-THF

Ci-THF

lO-Formyl-THF

purine synthesis

Figure 10,31 Folate interconversions

Glutamate lormimidoy l-\jransterase (PLP)

NADPH

F IGLU

5-Form-imidoyl-THF

glutamate

N-tomiyt

Glutamalelormimiduyl tjliitamals transferase (PLP)

qlulamale

5-Formyl-THF cycfoligase

Cyto-chromec

NADPH

5-AcJerwsyl- 5-Adenosyl homocysteine methionine

S-Methyl-THF homocysteine S ■ melhylrra nste rase (cobslamin)

Ferritin

10-Formyl lotate

Folate

15-Formyi-DHF

dTMP dUMP

Thymidytate synthase

NADPH

nrnim

NADP

Dihydrototate (DHF)

NADPH

NADP

Methyl-THF

Telrahydmlolato (THF)

serine, glycine, and ctroline calatralism

NADP

Methylene THF red (FAD)

Glutamate lormimidoy l-\jransterase (PLP)

NADPH

F IGLU

5-Form-imidoyl-THF

glutamate

5.10-Methylene-THF — NADP

N-tomiyt

Glutamalelormimiduyl tjliitamals transferase (PLP)

Ci-THF

NADPH

qlulamale

5.10-MOIheriyl-THF

5-Formyl-THF

5-Formyl-THF cycfoligase

Cyto-chromec dehydrogenase

NADPH

Ci-THF

NADP

5 FOrmyl DHF

lO-Formyl-THF

purine synthesis

pAPG

Figure 10,31 Folate interconversions

5,10-Methenyl-THF. The pyridoxal 5'-phosphate-dependent glutamate formimidoyt-transfcra.se (EC2,1.2.5) is a key enzyme of histidine metabolism, which moves a formidoyl group to THF. The resulting 5-formimino-THF is converted to 5.10-methcnyl-THF by formiminotetrahydrofolate eyclodeaminase (EC4.3.1.4), the second activity of the Afunctional protein forminiinolransferase-cyclodeaminase. S-Methyl-THF: The methytcoba lam in-containing 5-methy Itetnihy drofo I ate-homo-cystetne S-methyltransferase(EC2.1.1.13)and betaine:homocysteine methyltranslerase

(EC2.1.1.5) arc the only enzymes that utilize 5-mcthyl-THF in significant quantities. A reduction of their activities (particularly due to vitamin H12 deficiency) decreases the availability ofTHF for other reactions.

10-Formyl-THF: Phosphoribosylglycinamidc formy I transferase (EC2.1.2.2) and phosphoribosylaminoimidazoiecarboxamide formvltransferase (AICAR transfor-mylase: EC2.1.2.3) use 10-formyl-THF in purine synthesis. Both reactions release THE Alternatively, foraiy I tetrahy drofolate dehydrogenase (EC 1.5.1.6) can regenerate THE from 10-formyl-THF by splitting off carbon dioxide in an N ADPI I-generating reaction.

5-Formvl THF: This is a minor folate metabolite, which may come from food or from the reaction of N-formyl-L-glutamate with THF, catalyzed by glutamate formimi-doyltransferase (EC2.1.2.5, PLP). The ATP-driven enzyme 5-formy I tetrahy d rofolate cyclo-ligase (EC6.3.3.2, requires PLP) converts 5-formyl-THF to 5,10-methenvl-THF (Baggott et at., 2001).

10-Formyl dihydrofolate; This metabolite arises from the reaction of formate with dihydrofolate, catalyzed by formate-d¡hydrofolate ligase (EC6.3.4.17) as detailed below. 10-formyl dihydrofolate can serve as a cofactor for the penultimate step of IMP (purine) synthesis catalyzed by phosphoribosylamirtoimidazolecarboxamide formy I transferase (AICAR transformyla.se: EC2.1.2.3). Spontaneous oxidation is also possible, which generates the metabolically inert metabolite 10-formyl-folate (Baggott et at.. 2001).

Folate catabohsm: Dihydrofolate and 10-formyl-THF are particularly sensitive to oxidative degradation with the release of para-ami nobenzoic acid (pABG). It has been proposed that ferritin specifically facilitates the oxidative cleavage of 10-formyl-THF and that the degradation of this metabolite is an important modulator of intracellular folate concentration (Suh et at., 2001). Acetylation of pAPti by arylamine N-acety[transferases (EC2.3.1.5) facilitates the removal of inactive folate catabolitcs from cells.

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