Folic acid compounds

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

Walter, R. D., and Konigk, E. (1974a). Biosynthesis of folic acid compounds in plasmodia. Purification and properties of the 7,8-dihydropteroate-synthesizing enzyme from Plasmodium chabaudi. Hoppe Seylers. Z. Physiol. Chem. 355,431-437. 

Naturally occurring folic acid compounds which have been separated through TLC are usually evaluated bioautographically on the layer [3]. 

May et al. (1950a,b, 1951) originally considered that ascorbic acid was necessary for the conversion of pteroylglutamic acid to citrovorum factor. In monkeys fed on diets deficient both in ascorbic acid and folic acid, megaloblastic anemia developed. This could be relieved by ascorbic acid, by folic acid in large doses, or by small doses of citrovorum factor. Later May et al. (1953) reported that ascorbic acid was not required for the conversion of folic acid to citrovorum factor. The severe deficiency of folic acid compounds occurring in scorbutic monkeys was probably due to nonspecific factors operating in scurvy. 

The spontaneous occurrence of megaloblastic anemia in association with infection in infants and in monkeys is described by May ei al. (1952a,b). The low content of folic acid compounds in the liver in both natural and experimental infections and the elimination of megaloblasto-sis from the marrow by folic acid, but not by vitamin Bij or ascorbic acid, led to the conclusion that infection can cause a deficiency of folic acid compounds. 

Another active folic acid compound was formed during the conversion of serine to glycine. This compound, a hydroxymethyl derivative of FH , was enzymically oxidized to iV ,JVi -anhydroformyl-FH4 (108, IIS). The anhydro derivative was also produced in the catabolism of formiminoglycine (114, 115) and formiminoglutamic acid (114) via AT -formimino-FH4. An active formyl-FH4 derivative, presumably JVi -formyl-FH4, also arose when IMP and FH4 reacted to produce AICAR (108) (see Section II, B, 5). iV -Formyl-FH4 reacted with glutamic acid to form iV-formyl utamic acid... 

The reaction of a one-carbon compound with 5-amino-4-imidazolecar-boxamide ribonucleotide (AICAR) (Fig. 3) completed the purine ring and resulted in the formation of inosinic acid (IMP). AICAR had been postulated earlier as an intermediate in purine syntheris and a stimulatory effect of JV -formyltetrahydrofolic acid (JV -formyl-FH4) on the entry on the one-carbon unit was observed (68). Also, glycine accepted the one-carbon unit from position 2 of IMP, which resulted in the formation of serine and AICAR (143). The reaction was reversible, since AICAR was converted to IMP in the presence of serine (144)- The reaction of AICAR with serine required-TPN and K" ", in addition to a folic acid compound (either Ar5,ATio.anhydroformyl-FH4 or iV -anhydroformyl-FH4) (143). The equation for the reaction is ... 

Amino-4-imidazolecarboxamide ribonucleotide transfoimylase catalyzes the formylation of AICAR to form 5-formamido-4-imidazolecarboxa-mide ribonucleotide (FAICAR) (Fig. 11). Various formylated folic acid compounds donated their formyl groups to AICAR (76,96,107). However, when the transformylase enzyme was purified and freed from cyclohydrolase (see Section II, B, 1 for a discussion of interconversions of folic acid derivatives), a specific requirement for V -formyl-FH4 was demonstrated (109). The equation for the reaction is ... 

The known role of vitamin B12 and folic acid in the formation of labile methyl groups (339) helps to explain the replaceability of folic acid (330) or vitamin B12 (331) by thymidine in certain deficient oi anisms. Also of interest is the role of folic acid compounds in the pathway leading to formation of the thymine methyl group. Low concentrations of a folic acid antimetabolite, aminopterin, blocked the utilization of deoxyiuidine for thymidine synthesis (333). The antimetabolite effects of aminopterin on the utilization of one-carbon donors have been known for some time (333, 334). The details of thymine biosynthetis will be discassed elsewhere in this volume (Chapter 24). 

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