5,10-Methylene tetrahydrofolate dehydrogenase

Figure 14.1. Proposed electron-transport pathway in the acetogenic bacteria M. thermoacetica and M. thermoautotrophica. Cyt., cytochrome MTi/FD//, methylene tetrahydrofolate dehydrogenase Fd, ferredoxin Fp, flavoprotein H2ase, hydrogenase.

MTHFD Methylene tetrahydrofolate dehydrogenase (NAD-dependent), methylenetetrahydrofolate cyclohydrolase... 

Methylene-, methenyl-, and 10-formyl-tetrahydrofolates are freely interconvertible. The two activities involved - methylene-tetrahydrofolate dehydrogenase and methenyl-tetrahydrofolate cyclohydrolase - form a trifunctional enzyme with 10-formyl-tetrahydrofolate synthetase (Paukert et al., 1976). This means that single-carbon fragments entering the folate pool in any form other than as methyl-tetrahydrofolate can be readily available for any of the biosynthetic reactions shown in Figure 10.4. 

CFD is further associated with the following inherited metabolic disorders 5,10-methylen-tetrahydrofolate reductase (MTHFR) deficiency [7], 3-phos-phoglycerate dehydrogenase (PGDH) deficiency [8], dihydropteridine reductase (DHPR) deficiency [9], as well as with Rett syndrome [10], and Aicardi-Gou res Syndrome [11]. Furthermore, folate deficiency may be associated with congenital folate malabsorption, severe malnutrition, and formiminotransferase deficiency. 

Dimethylglycine and sarcosine dehydrogenases in the catabolism of choline (Section 14.2.1). In these reactions, a methyl group in the substrate is oxidized by FAD, then the intermediate adduct undergoes hydrolysis to release formaldehyde, which reacts with tetrahydrofolate to form 5,10-methylene tetrahydrofolate. 

In experimental animals and with isolated tissue preparations and organ cultures, the test can be refined by measuring the production of G02 from [ C]histidine in the presence and absence of added methionine. If the impairment of histidine metabolism is the result of primary folate deficiency, the addition of methionine wUl have no effect. By contrast, if the problem is trapping of folate as methyl-tetrahydrofolate, the addition of methionine will restore normal histidine oxidation as a result of restoring the inhibition of methylene-tetrahydrofolate reductase by S-adenosylmethionine and restoring the activity of 10-formyl-tetrahydrofolate dehydrogenase, thus permitting more normal folate metabolism (Section 10.3.4.1). 

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