R

Oxidation state

5-formylTHF

—CHO

Formate

10-formylTHF

—CHO

Formate

5-formiminoTHF

—CH=NH

Formate

5,10-methenylTHF

—CH=

Formate

5,10-methyleneTHF

—CH2—

Formaldehyde

5-methylTHF

—CH3

Methanol

One-carbon units at various levels of oxidation are generated metabolically and are reactive only as moieties attached to the N5 and/or N10 positions of the folate molecule (Table 1).

The range of oxidation states for folate one-carbon units extends from methanol to formate as methyl, methylene, methenyl, formyl, or formimino moieties. When one-carbon units are incorporated into folate derivatives, they may be converted from one oxidation state to another by the gain or loss of electrons.

The source of one-carbon units for folate One-carbon units at the oxidation level of formate can enter directly into the folate pool as formic acid in a reaction catalyzed by 10-formylTHF synthase (Figure 2). Entry at the formate level of oxidation can also take place via a catabolic product of histidine, formaminoglutamic acid. The third mode of entry at the formate level of oxidation involves the formation of 5-formylTHF from 5,10-methenylTHF by the enzyme serine hydroxy-methyl transferase (SHMT). The 5-formylTHF may be rapidly converted to other forms of folate.

The enzyme SHMT is involved in the entry of one-carbon units at the formaldehyde level of oxidation by catalyzing the transfer of the ^-carbon of serine to form glycine and 5,10-methyleneTHF. Other sources of one-carbon entry at this level of oxidation include the glycine cleavage system and the choline-dependent pathway; both enzyme systems generate 5,10-methy-lene in the mitochondria of the cell.

The removal and use of one-carbon units from folate Single-carbon units are removed from folate by a number of reactions. The enzyme 10-formylTHF dehydrogenase provides a mechanism for disposing of excess one-carbon units as carbon dioxide. (Folate administration to animals enhances the conversion of ingested methanol and formate to carbon dioxide, diminishing methanol toxicity.) Additionally, single-carbon units from 10-formylTHF are used for the biosynthesis of purines (Figure 2).

The one-carbon unit of 5,10-methyleneTHF is transferred in two ways. Reversal of the SHMT reaction produces serine from glycine, but since serine is also produced from glycolysis via phos-phoglycerate this reaction is unlikely to be important. However, one-carbon transfer from 5,10-methyleneTHF to deoxyuridylate to form thymidylic acid, a precursor of DNA, is of crucial importance to the cell. While the source of the one-carbon unit, namely 5,10-methyleneTHF, is at the formaldehyde level of oxidation, the one-carbon unit transferred to form thymidylic acid appears at the methanol level of oxidation. Electrons for this reduction come from THF itself to generate dihydrofolate as a product. The dihydro-folate must in turn be reduced back to THF in order to accept further one-carbon units.

A solitary transfer of one-carbon units takes place at the methanol level of oxidation. It involves the transfer of the methyl group from 5-methylTHF to homocysteine to form methionine and THF. This reaction is catalyzed by the enzyme methionine synthase and requires vitamin B12 as a cofactor. The substance 5-methylTHF is the dominant folate in the body, and it remains metabolically inactive until it is demethylated to THF, whereupon polyglu-tamylation takes place to allow subsequent folate-dependent reactions to proceed efficiently.

Clinical implications of methionine synthase inhibition The inhibition of methionine synthase due to vitamin B12 deficiency induces megaloblastic anemia that is clinically indistinguishable from that caused by folate deficiency. The hematological effect in both cases results in levels of 5,10-methyleneTHF that are inadequate to sustain thymidylate biosynthesis. Clinically, it is essential to ascertain whether the anemia is the result of folate deficiency or vitamin B12 deficiency by differential diagnostic techniques. Vitamin B12 is essential for the synthesis of myelin in nerve tissue, a function probably related to methionine production from the methionine synthase reaction and the subsequent formation of S-adenosyl-methionine. Hence, vitamin B12 deficiency probably leads to nervous disorders in addition to the hematological effects. While the latter respond to treatment with folic acid, the neurological effects do not. Thus, inappropriate administration of folic acid in patients with vitamin B12 deficiency may treat the anemia but mask the progression of the neurological defects. Where possible, vitamin B12 and folate statuses should be checked before giving folate supplements to treat megaloblastic anemia. The main objection to fortifying food with folate is the potential to mask

Ingestion food folates (monoglutamates, polyglutamates, and folic acid) Excretion intact folate intact folate

(enterohepatic circulation):

Deconjugation

(conjugases)

folate catabolites + intact folate monoglutamates

IAbsorption (via small bowel)

I Transport (mainly 5-CH3-THF)

5,10-methylene tetrahydrofolate reductase folate catabolites + intact folate

I Transport (mainly 5-CH3-THF)

5,10-methylene tetrahydrofolate reductase

FADH,

5-formyltetrahydrofolate cyclodehydrase

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