Biochemistry - Chemical Reactions in Living Cells Volume 2 - D. Metzler 1980

Coenzymes - specialized natural reagents of a distinct type
Tetrahydrofolic acid and other pterin coenzymes
Single-carbon groups and compounds in metabolic processes

Some single-carbon compounds and groups that play a crucial role in METABOLISM are listed in Table 8-5. The Coenzyme forms of tetrahydrofolic acid serve as carriers for single-carbon fragments corresponding to three distinct oxidation states (formic acid, formaldehyde, and the methyl group). Although methane, the fully reduced C₁ compound, cannot exist in a bound form, its Biosynthesis is an H₄Fol-dependent process, as is The biosynthesis of carbon monoxide. Figure 8-20 summarizes the known metabolic interrelationships of the compounds and groups presented in Table 8-5.

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FIG. 8-20. Tetrahydrofolic acid and its single-carbon derivatives.

In many organisms, Serine serves as the primary precursor of C₁ units. The ß-carbon of serine is cleaved off as formaldehyde via direct transfer to tetrahydrofolate, yielding methylene-H₄Fol and Glycine [Eq. (8-19)]. The latter, in turn, can give rise to another single-carbon unit with the loss of CO₂, catalyzed by the H₄Fol- and PLP-dependent glycine decarboxylase system [reaction (14-32)]. Free formaldehyde can also condense with H₄Fol to form methylene-H₄Fol [Eq. (8-69)] [155].

Table 8-5 Single-carbon compounds in order of oxidation states

In some organisms, particularly Bacteria capable of utilizing formate as their sole carbon source, formate first condenses with H₄Fol to yield 10-formyl-H₄Fol (lower left corner of Fig. 8-21).

The single-carbon residue at the formaldehyde oxidation level attached to H₄Fol can either be oxidized to 5,10-methenyl-H₄Fol and 10-formyl-H₄Fol, or reduced to 5-methyl-H₄Fol. Formate-utilizing organisms can correspondingly reduce 10-formyl-H₄Fol to methylene-H₄Fol and transfer the single-carbon unit to glycine to form serine.

The Role of 5-formyl-H₄Fol (leucovorin or the citrovorum factor)¹⁾ in metabolism is less well understood. It may be involved in The transfer of a formyl group derived from formylglutamate; an enzyme exists that converts 5-formyl-H₄Fol into 10-methenyl-H₄Fol with the simultaneous Cleavage of ATP. This compound is used in a specific manner in the Treatment of certain particularly malignant tumors. Following surgical removal of the tumor, the patient is periodically administered methotrexate in doses that are normally lethal. Then, 36 hours later, the patient is "rescued" by an injection of 5-formyl-H₄Fol. The Mechanism of this "rescue" action of 5-formyl-H₄Fol is not yet fully elucidated.

FIG. 8-21. The reaction providing substrate-level phosphorylation mediated by 10-formyl-H₄Fol in Clostridium bacteria.

Another metabolic source of single-carbon fragments is Histidine dissimilation, which occurs in both bacteria and animals via formiminoglutamic acid. The latter transfers a —CH=NH group to H₄Fol to form 5-formimino-H₄Fol, which is subsequently converted into 5,10-methenyl-H₄Fol and ammonia. In purine-fermenting bacteria, the intermediate is formiminoglycine. Here too, the formimino group is transferred to H₄Fol and deaminated, yielding 10-formyl-H₄Fol. The enzyme catalyzing The conversion of formate to 10-formyl-H₄Fol exhibits very high activity in these organisms [158]; it is believed to function in the reverse direction, driving ATP synthesis during this type of Fermentation (Fig. 8-21). Formyl phosphate is possibly formed as an intermediate [158a].

Both 5,10-methenyl-H₄Fol and 10-formyl-H₄Fol act as biological formylation agents, and both are required for purine synthesis (Chap. 14, Sec. L.3). A remarkable reaction occurs in the gas gland of the Physalia (Portuguese man-of-war), which produces large amounts of carbon monoxide, apparently derived from 10-formyl-H₄Fol. Carbon monoxide also arises naturally from bacterial metabolism. This aspect of environmental biochemistry has gained considerable relevance due to the influx of large quantities of CO into The Biosphere as a result of human activity: bacteria produce incomparably more of it than humans do.

Methylene-H₄Fol acts as the direct precursor of the 5-methyl group of thymine, as well as the hydroxymethyl group of hydroxymethylcytosine. During The formation of thymine, the coenzyme is oxidized to dihydrofolic acid [reaction (14-51)], which must be reduced by Dihydrofolate Reductase to complete the catalytic cycle. The reduction of methylene-H₄Fol to 5-methyl-H₄Fol serves as one of the sources of methane in bacterial metabolism (Sec. M.8) and, in All living organisms, provides the methyl groups required in large amounts for the synthesis of Methionine and the modification of Proteins, Nucleic Acids, and other biochemical compounds via the methylation of specific groups.

¹⁾ In 1949, it was established that N₅-formyl-H₄Fol is a growth factor for Leuconostoc citrovorum, which is how this compound acquired the name "citrovorum factor."