Biosynthesis of Pterins

As shown in Figure 10.2, the pteridine nucleus is synthesized from GTP, in a sequence of reactions catalyzed by a different isoenzyme of GTP cyclohydrolase

Figure 10.2. Biosynthesis of folic acid and tetrahydrobiopterin. GTP cyclohydrolase I, EC 3.5.4.16; dihydropteroate synthase, EC 2.5.1.15; pyruvoyl-tetrahydrobiopterin synthase, EC 4.6.1.10; and sepiapterin reductase, EC 1.1.1.153.

from that involved in riboflavin synthesis (Section 7.2.6). The reaction sequence involves loss of C-8 of guanine as formate, followed by rearrangement of the ribose moiety, condensation, and ring closure to yield dihydroneopterin triphosphate. Dephosphorylation andloss of the side chainleads to the formation of dihydropteridine, the immediate precursor of folate. In mammals, GTP cyclohydrolase is inhibited by unconjugated reduced pterins; folate, which is not an end-product of the mammalian enzyme, is not a significant inhibitor (Thonyet al., 2000).

Mammals lack dihydropteroate synthetase, which catalyzes the condensation of dihydropteridine with p-aminobenzoic acid. The bacterial enzyme can utilize either p-aminobenzoate (yielding dihydropteroic acid) or p-amino-benzoyl-glutamate (yielding dihydrofolate directly). p-Aminobenzoyl-gluta-mate is not formed under normal conditions, although it is a product of mammalian catabolism of folate. The usual product of the reaction is dihydropteroic acid, followed by conjugation with glutamate. Dihydropteroate synthetase is inhibited by sulfonamides, which compete with p-aminobenzoate as substrate; this is the basis of their action as bacteriostatic agents. They deplete the organisms of pteridines by forming metabolically inactive sulfonamide analogs of dihydropteroate.

In both mammals and microorganisms, dihydrofolate is reduced to tetrahy-drofolate by dihydrofolate reductase, which will act on free folate or various polyglutamate conjugates, although the affinity of the enzyme for its substrate falls as the length of the polyglutamate chain increases. In microorganisms, this enzyme is important for the de novo synthesis of tetrahydrofolate, whereas in mammals it is mainly required to reduce the dihydrofolate formed in the reaction of thymidylate synthetase (Section 10.3.3). As discussed in Section 10.3.3.1, dihydrofolate reductase is an important target for chemotherapy of cancer, bacterial infections, and malaria.

The formation of biopterin involves dephosphorylation and reduction of the side chain of dihydroneopterin triphosphate, followed by inversion of the conformation of the two hydroxyl groups, by way of intermediate oxidation to (symmetrical) oxo-groups, catalyzed by sepiapterin reductase.

Patients with a variety of cancers and some viral diseases excrete relatively large amounts of neopterin, formed by dephosphorylation and oxidation of dihydroneopterin triphosphate, an intermediate in biopterin synthesis. This reflects the induction of GTP cyclohydrolase by interferon-y and tumor necrosis factor-a in response to the increased requirement for tetrahydrobiopterin for nitric oxide synthesis (Section 10.4.2). It is thus a marker of cell-mediated immune reactions and permits monitoring of disease progression (Werner et al., 1993,1998; Berdowska and Zwirska-Korczala, 2001).

10.3 METABOLIC FUNCTIONS OF FOLATE

The metabolic role of folate is as a carrier of one-carbon fragments, both in catabolism and biosynthetic reactions. As shown in Figure 10.3, tetrahydrofo-late can carry one-carbon fragments attached to N-5 (formyl, formimino, or methyl groups), N-10 (formyl), or bridging N-5 to N-10 (methylene or methenyl groups). The major sources of these one-carbon fragments, their major uses, and the interconversions of the substituted folates are shown in Figure 10.4.

The metabolically active forms of folate are all substituted tetrahydropteroyl polyglutamates. Whereas some folate-dependent enzymes will use the monoglutamate in vitro, most have a considerably lower Km for polyglutamates, and some have higher Vmax. In multienzyme complexes, in which the folate cofactor serves to transport one-carbon fragments from one catalytic site to another, the length of the polyglutamate tail may be especially important in anchoring the cofactor, but permitting considerable movement of the pteroyl moiety and in channeling intermediates between catalytic sites.

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