Tetrahydrofolate derivatives

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availabihty of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. 

Tetrahydrofolate derivatives are involved in one carbon unit transfer at the oxidation levels of formate, formaldehyde and methanol. At the formate level of oxidation, two derivatives, fV(5,10)-methenyltetrahydrofolate (23) andfV(10)-formyltetrahydrofolate (24), act as cofactors. Reactions involving one-carbon unit transfers at formaldehyde and methanol levels of oxidation utilize fV(5,10)-methylenetetrahydrofolate (25) and N(5)-methyltetrahydrofolate (26), respectively. 

Another group of inhibitors prevents nucleotide biosynthesis indirectly by depleting the level of intracellular tetrahydrofolate derivatives. Sulfonamides are structural analogs of p-aminobenzoic acid (fig. 23.19), and they competitively inhibit the bacterial biosynthesis of folic acid at a step in which p-aminobenzoic acid is incorporated into folic acid. Sulfonamides are widely used in medicine because they inhibit growth of many bacteria. When cultures of susceptible bacteria are treated with sulfonamides, they accumulate 4-carboxamide-5-aminoimidazole in the medium, because of a lack of 10-formyltetrahydrofolate for the penultimate step in the pathway to IMP (see fig. 23.10). Methotrexate, and a number of related compounds inhibit the reduction of dihydrofolate to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. These inhibitors are structural analogs of folic acid (see fig. 23.19) and bind at the catalytic site of dihydrofolate reductase, an enzyme catalyzing one of the steps in the cycle of reactions involved in thymidylate synthesis (see fig. 23.16). These inhibitors therefore prevent synthesis of thymidylate in replicating... 

Fig. 11.6. Interconversions of tetrahydrofolate derivatives. FH2 = dihydrofolic acid FH4 = tetrahydrofolic acid AICAR -= 5 aminoimidazole 4-carboxamide ribonucleotide FAICAR = formyl AICAR GAR = glycinamide ribonucleotide FGAR = formyl GAR Glu = glutamic acid FIGLU = formimino glutamic acid. (Modified from Mudd and Cantoni, 1964.)...

The correct answer = A. Resistant cells may have elevated levels of dihydrofolate reductase. Methotrexate inhibits dihydrofoiate reductase and, therefore, leads to lower than normal levels of the reduced tetrahydrofolate derivatives. Methotrexate does undergo metabolism by the host, but this is not a factor in resistance. The metabolic need for folate is high in all rapidly dividing cells. A decrease in influx may be associated with resistance. 

Table 15.4 lists the various one-carbon groups carried by tetrahydrofolate derivatives. 

Although the terms folic acid and folate are often used interchangeably, correctly/ofic acid refers to the oxidized compound, pteroyl monoglutamate, and the various tetrahydrofolate derivatives are collectively known as folates. 

Analysis of the enantiomeric ratios of several p-blocking drugs (l-aryloxy-3-isopropylamino-2-propanol derivatives) is carried out by HPLC with UV or fluorescence detection after derivatization with (R)-NEI or (i )-(+)-l-(l-phenyl)ethyl isocyanate (in a reversed-phase system), or (S)-NEI (on silica gel) only the amine function of the drugs reacts with the NEI the hydroxy group does not. Similar schemes for HPLC determination of enantiomeric purity of tetrahydrofolate derivatives and of fluoxetine are also reported. 

Several coenzymes are involved in the biosynthesis of their own precursors. Thus, thiamine is the cofactor of the enzyme that converts 1-deoxy-D-xylulose 5-phosphate (43) (the precursor of thiamine pyrophosphate, pyridoxal 5 -phosphate and of iso-prenoids via the nomnevalonate pathway) into 2 C-methyl-D-erythritol 4-phosphate (90, Fig. 11). Similarly, two enzymes required for the biosynthesis of GTP, which is the precursor of tetrahydrofolate, require tetrahydrofolate derivatives as cofactors (Fig. 3). When a given coenzyme is involved in its own biosynthesis, we are faced with a hen and egg problem, namely how the biosynthesis could have evolved in the absence of the cmcially required final product. The answers to that question must remain speculative. The final product may have been formed via an alternative biosynthetic pathway that has been abandoned in later phases of evolution or that may persist in certain organisms but remains to be discovered. Alternatively, the coenzyme under study may have been accessible by a prebiotic sequence of spontaneous reactions. An interesting example in this respect is the biosynthesis of flavin coenzymes, in which several reaction steps can proceed without enzyme catalysis despite their mechanistic complexity. 

These tetrahydrofolate derivatives serve as donors of one-carbon units in a variety of biosyntheses. Methionine is regenerated from homocysteine by transfer of the methyl group ofF -methyltetrahydrofolate, as will be discussed shortly. We shall see in Chapter 25 that some of the carhon atoms of purines are acquired from derivatives of N lO-formyltetrahydrofolate. The methyl group of thymine, a pyrimidine, comes from N, N lO-methylenetetrahydrofolate. This tetrahydrofolate derivative can also donate a one-carhon unit in an alternative synthesis of glycine that starts with CO2 and NH4 +, a reaction catalyzed by glycine synthase (called the glycine cleavage enzyme when it operates in the reverse direction). 

The inability to absorb Vitamin B12 occms in pernicious anemia. In pernicious anemia intrinsic factor is missing. The anemia results from impaired DNA synthesis due to a block in purine and thymidine biosynthesis. The block in nucleotide biosynthesis is a consequence of the effect of vitamin B12 on folate metabolism. When vitamin B-12 is deficient essentially all of the folate becomes trapped as the N -methyltetrahydrofolate derivative as a result of the loss of functional methionine synthase. This trapping prevents the synthesis of other tetrahydrofolate derivatives. required for the purine and thymidine nucleotide biosynthesis pathways. 

These tetrahydrofolate derivatives serve as donors of one-carbon units in a variety of hiosyntheses. Methio7iine is regenerated from homocysteine by transfer of the methyl group of methyl tetrahydrofolate, as will be dis-... 

Mechanism of Carbon-Carbon Bond Formation and Cleavage with Pyridoxal Phosphate and Tetrahydrofolate Derivatives... 

Metabolic interconversion of tetrahydrofolate derivatives and one-carbon transfer reactions 603... 

The hemopoietic problems associated with a B12 deficiency are identical to those observed in a folate deficiency and, in fact, result from a folate deficiency secondary to (i.e., caused by) the B12 deficiency (i.e., the methyl trap hypothesis). As the FH4 pool is exhausted, deficiencies of the tetrahydrofolate derivatives needed for purine and dTMP biosynthesis develop, leading to the characteristic megaloblastic anemia. 

What is conversion of dUTP to dTTP Another reaction specifically needed to produce substrates for DNA synthesis is the conversion of uracil to thymine. This pathway, which requires a tetrahydrofolate derivative as the carrier for one-carbon transfer, is a target for cancer chemotherapy. 

Which of the following answers completes the sentence correctly The major source of one-carbon units for the formation of the tetrahydrofolate derivative methylenetetrahydrofolate is the conversion of... 

Fig. 15.17. Infrared spectra of teirahydrofolate derivatives A) formiminotetrahydrofolate, (8) 5-formyltetrahydrofolate. Spectra were measured in KBr pellets with a Baird-Atomic infrared spectrophotometer. The tetrahydrofolate derivatives (1 mg) were pulverized in 100 mg of KBr by means of a mortar and pestle. (Uyeda and Rabinowitz, 1965.)...

The tetrahydrofolate derivative (Formula (6.16), II) of folic acid (I, pteroylmonoglutamic acid, PGA) is the cofactor of enzymes which trans-... 

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