A/5,A/10-Methylene-FH4 Glycine

Figure 4 Folic acid (A) and its coenzyme form. Activation requires folic acid to be converted into its tetrahydrofolate derivative (B). (C) Specific function of one of the tetrahydrofolate derivatives, N5,N10-methylene-FH4, in the synthesis of glycine from serine. Serine is thus able to donate a carbon to the coenzyme for a subsequent one-carbon transfer reaction.

is active. FH4 may have up to seven glutamic acid residues and exist in many different chemical forms, most of which are interconvertible.

The basic reactions take part at the N5 and N10 positions on the molecule, which serve as attachment points for one-carbon units in transit (Figure 4C). N10-formyl- and N5,N10-methenyl-FH4 are two synthetic forms that are biologically active. Complexes of N5-formyl-FH4 (folinic acid) transfer formyl groups to specific substrates. Active folic acid derivatives have carbon in the oxidation state of formate as well as formaldehyde (methylene) and a methyl derivative, N5-methyl-FH4, is known to take part in the enzymatic conversion of homo-cysteine to methionine. These observations reveal that the family of folic acid coenzymes is quite complex but all seem to involve the attachment of a single carbon atom to the substrate.

Reactivity Enzymes that require folic acid participate in what is referred to as 'one-carbon metabolism.' This takes the form of group transfers involving methyl groups, formyl groups, formimino groups, and methylene groups. Folic acid does not take part in acetylations or carboxylations. A typical reaction in higher vertebrates is the synthesis of glycine by the enzyme glycine synthase:

In perhaps its only major requirement as a methyl group donor, N5-methyl-FH4 is needed by the enzyme homocysteine methyltransferase to synthesize (regenerate) methionine from homocysteine. This reaction also uses a methylated derivative of vitamin B12 (see below) to mediate the group transfer. Another important reaction is the interconversion of serine and glycine. As shown in Figure 4C, the reaction requires the N5,N10-methylene-FH4 derivative. Today, the list of folate-catalyzed reactions is quite large and includes one-carbon units in the synthesis of a purine ring of nucleic acids, methylation of DNA and RNA, thymidine biosynthesis, choline and S-adenosylmethionine biosynthesis, and histidine and tyrosine catabolism.

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