One-carbon pool

Biotin metabolism Folate biosynthesis One carbon pool by folate Retinol metabolism Porphyrin and chlorophyll metabolism Terpenoid biosynthesis Xenobiotics metabolism Ubiquinone biosynthesis Flavonoids, stilbene, and lignin biosynthesis... 

TFIF is formed from the vitamin folate through two reductions catalyzed by dihydrofolate reductase shown in Figure 1-17-4. It picks up a one-carbon unit from a variety of donors and enters the active one-carbon pool. Important pathways lequirii forms of THF from this pool include the synthesis of all purines and thymidine, wfakh in turn are used for DNA and RNA synthesis during cell growth and division. 

Sanders et al. (1988) administered u-butyl [2,3- 4C]acrylate to rats orally at doses of 4, 40 and 400 mg/kg bw and intravenously at 40 mg/kg bw. After oral administration, n-but l aciy late was very rapidly absorbed and hydrolysed to acrylic acid, with more than 75% of the dose eliminated as its metabolic end product 4CO2 Some 10% of the dose was excreted in the urine, two metabolites being identified as the mercapturic acid N-acct>l-.S -(2-carboxycthyl)cystcinc and its sulfoxide. The elimination pattern of was essentially identical at all doses, but additional unidentified C peaks were present in the urine at 400 mg/kg. Comparison of the data from the two routes of administration suggested that u-butyl acrylate exhibited a first-pass efiect after oral dosing, but this was not investigated further. -Butyl acrylate was rapidly and extensively excreted, the tissues being cleared of -C by 24-72 h. After an initial rapid reduction, a small amount of O was retained in whole blood and adipose tissue, possibly by incorporation of C via the one-carbon pool. 

The pathway from N-demethylation to exhaled C02 involves a number of steps many of which are also metabolic, but catalyzed by several enzyme systems distinct from the initiating CYP isoform. A critical assumption is that all steps prior to (e.g., absorption for a probe that is not administered parenterally) or subsequent to N-demethylation are not rate limiting. In general, the steps involved in intermediary metabolism of the one-carbon pool meet this criterion. However, a percentage, estimated to be between 37% and 57%, of labeled... 

Histidine (his) is first deaminated, then the ring is opened and the formamino group is then donated to the one-carbon pool (see later). Two of these reactions are irreversible so his is essential. 

Other examples of folate-requiring one-carbon pool reactions ... 

The one-carbon carrier N, N -methylenetetrahydrofolate is derived from reactions of the one-carbon pool (Chapter 27). [The term one-carbon pool refers to all single-carbon-containing metabolites (e.g., -CH3, -CHO, NH=C-, etc.) that can be utilized in biosynthetic reactions such as formation of purine and pyrimidine.] These reactions include oxidation of glycine by glycine cleavage enzyme complex (glycine synthase) ... 

Tryptophan is an essential amino acid involved in synthesis of several important compounds. Nicotinic acid (amide), a vitamin required in the synthesis of NAD+ and NADP+, can be synthesized from tryptophan (Figure 17-24). About 60 mg of tryptophan can give rise to 1 mg of nicotinamide. The synthesis begins with conversion of tryptophan to N-formylkynurenine by tryptophan pyrrolase, an inducible iron-porphyrin enzyme of liver. N-Formylkynurenine is converted to kynurenine by removal of formate, which enters the one-carbon pool. Kynurenine is hydroxylated to 3-hydroxykynurenine, which is converted to 3-hydroxyanthranilate, catalyzed by kynureninase, a pyridoxal phosphate-dependent enzyme. 3-Hydroxyanthranilate is then converted by a series of reactions to nicotinamide ribotide, the immedi-... 

One-carbon pool Folate derivatives that carry a single carbon in various oxidation states (formyl, methenyl, methylene, and methyl) for transfer to acceptor molecules that is, transfer to deoxyuridine monophosphate to form deoxythymidine monophosphate transfer to homocysteine to form methionine. 

Fig. 40.1. Overview of the one-carbon pool. FH4 C indicates tetrahydrofolate (FH4) containing a one-carbon unit that is at the formyl, methylene, or methyl level of oxidation (see Fig. 40.3). The origin of the carbons is indicated, as are the final products after a one-carbon transfer.

Tetrahydrofolate Tetrahydrofolate, which is produced from the vitamin folate, is the primary one-carbon carrier in the body. This vitamin obtains one-carbon units from serine, glycine, histidine, formaldehyde, and formate (Fig. 40.1). While these carbons are attached to FH4 they can be either oxidized or reduced. Because of this, folate can exist in a variety of chemical forms. Once a carbon has been reduced to the methyl level (methyl-FHf, however, it cannot be re-oxidized. Collectively, these one-carbon groups attached to their carrier FH4 are known as the one-carbon pool. The term folate is used to represent a water-soluble B-complex vitamin that functions in transferring single-carbon groups at various stages of oxidation. 

One-carbon groups transferred by FH4 are attached either to nitrogen or or they form a bridge between and N °. The collection of one-carbon groups attached to FH4 is known as the one-carbon pool. While attached to FFl4, these one-carbon units can be oxidized and reduced (Fig. 40.3). Thus, reactions requiring a carbon at a particular oxidation state may use carbon from the one-carbon pool that was donated at a different oxidation state. 

Table 40.1. One-Carbon Pool Sources and Recipients of Carbon...

Because the conversion of serine to glycine is readily reversible, glycine can be converted to serine by drawing carbon from the one-carbon pool. 

During the synthesis of the purine bases, carbons 2 and 8 are obtained from the one-carbon pool (see Chapter 41). TV" -Formyl-FH4 provides both carbons. Folate deficiency would also hinder these reactions, contributing to an inability to replicate DNA because of the lack of precursors. 

When serine-3- C (0.5%) was added to the medium, the specific activity of the N-methyl group of pyocyanine was 20% of that of the serine added and 75 % of that of the whole pyocyanine molecule. Sheikh and MacDonald (1964) concluded that the methyl group of methionine was a more immediate precursor of the N-methyl group of pyocyanine than was carbon-3 of serine. They also implied that in the biosynthesis of pyocyanine, an intact methyl group transfer from methionine was more likely than oxidation through a one-carbon pool, but they did not give any further experimental evidence to prove this point. 

Incorporations of p- C-tryptophan (29a) and p- C-tryptophan (29b) quickly established that this amino acid is the biological precursor to the C and D rings (41). Kuhn-Roth oxidation of labeled (1) derived from (29 a), followed by Schmidt degradation of the resulting acetic acid, located all of the radioaetivity at C-3 of (1). This result was later confirmed by NMR analysis of streptonigrin derived from (29b). Other experiments showed that while methionine had labeled the four methyls of (1) equally, C-3 of serine — the major precursor to the biological one-carbon pool — labeled the three 0-methyls almost exclusively (41). 

A lower degree of enrichment was observed at C-3a, which is derived from the one-carbon pool)... 

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