Formyl cobalamin

A relatively large number of agents have been utilized to treat this intractable disorder folinic acid (5-formyl-tetrahydrofolic acid), folic acid, methyltetrahydrofolic acid, betaine, methionine, pyridoxine, cobalamin and carnitine. Betaine, which provides methyl groups to the beta i ne ho mocystei ne methyltransferase reaction, is a safe treatment that lowers blood homocysteine and increases methionine. 

The effects of cobalamin deficiency are most pronounced in rapidy dividing cells, such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine. Such tissues need both Die N5-N10-methylene and N10-formyl forms of tetrahydrofolate for Ihe synthesis of nucleotides required for DNA replication (see pp. 291, 301). However, in vitamin B12 deficiency, the N5-methyl form of tetrahydrofolate is not efficiently used. Because the methylated fonn cannot be converted directly to other forms of tetrahydrofolate, tie Ns-methyl form accumulates, whereas the levels of the other forms decrease. Thus, cobalamin deficiency is hypothesized to lead to a deficiency of the tetrahydrofolate forms needed in purine and thymine synthesis, resulting in the symptoms of megaloblastic anemia. 

The interconversion of these forms of foiic acid takes place through various electron transfer reactions facilitated by specific enzyme systems and coenzymes, such as the reduced forms of fiavin-adenine dinucleotide (FADH2) and NADPH. The conversion between the N -, N -methylene form and -formyl forms is readily reversible, but the reduction of methylene to methyl and reduction of free THF to formyltetrahydrofolate is essentially irreversible. Conversion of N -methyltetrahydrofolate back to free THF. may require cobalamin. 

The activity of folacin is similar to the activity of cobalamins. It is linked with the transfer of one of the carbon functional groups, such as methyl (CH3-), methylene (-CH2-), formyl (-CH=0) and other groups whose donor is mainly chohne, glyoxyhc acid, serine and other compounds. These functional groups are bound... 

Figure 6.13. Four different routes for the synthesis of formyl methyl cobalamin (263). Reprinted with permission. Copyright 1974 by American Chemical Society.

In these sequences, formyl methyl cobalamin, the intermediate in the enzymatic conversion of ethylene glycol to acetaldehyde, is synthesized in four different ways. 

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