A. 5-Phosphoribosyl-1-pyrophosphate synthesis 5-Phosphoribosyl-1-pyrophosphate (PRPP) is an activated pentose that participates in the synthesis and salvage of purines and pyrimidines. Synthesis of PRPP from ATP and ribose 5-phosphate is catalyzed by PRPP synthetase (Fig. 22.6). This X-linked enzyme is activated by inorganic phosphate and inhibited by purine nucleotides (end-product inhibition). [Note: Because the sugar moiety of PRPP is ribose, ribonucleotides are the end products of de novo purine synthesis. When deoxyribonucleotides are required for DNA synthesis, the ribose sugar moiety is reduced (see p. 297).] reaction. [Note: This is not the committed step of purine synthesis because PRPP is used in other pathways such as salvage (see p. 296).] = phosphate; Pi = inorganic phosphate; AMP = adenosine monophosphate; Mg = magnesium.
B. 5-Phosphoribosylamine synthesis
Synthesis of 5-phosphoribosylamine from PRPP and glutamine is shown in Figure 22.7. The amide group of glutamine replaces the pyrophosphate group attached to carbon 1 of PRPP. This is the committed step in purine nucleotide biosynthesis. The enzyme that catalyzes the reaction, glutamine:phosphoribosylpyrophosphate amidotransferase (GPAT), is inhibited by the purine 5′-nucleotides AMP and guanosine monophosphate (GMP, or guanylate), the end products of the pathway. The rate of the reaction is also controlled by the intracellular concentration of PRPP. [Note: The concentration of PRPP is normally far below the Michaelis constant (Km) for the GPAT. Therefore, any small change in the PRPP concentration causes a proportional change in rate of the reaction (see p. 59).] dioxide.
C. Inosine monophosphate synthesis
The next nine steps in purine nucleotide biosynthesis leading to the synthesis of inosine monophosphate ([IMP] whose base is hypoxanthine) are illustrated in Figure 22.7. IMP is the parent purine nucleotide for AMP and GMP. Four steps in this pathway require ATP as an energy source, and two steps in the pathway require N10-formyl-THF as a one-carbon donor (see p. 267). [Note: Hypoxanthine is found in tRNA (see Fig. 32.9 on p. 453).]
D. Synthetic inhibitors
Some synthetic inhibitors of purine synthesis (for example, the sulfonamides) are designed to inhibit the growth of rapidly dividing microorganisms without interfering with human cell functions (see Fig. 22.7). Other purine synthesis inhibitors, such as structural analogs of folic acid (for example, methotrexate), are used pharmacologically to control the spread of cancer by interfering with the synthesis of nucleotides and, therefore, of DNA and RNA (see Fig. 22.7).
Inhibitors of human purine synthesis are extremely toxic to tissues, especially to developing structures such as in a fetus, or to cell types that normally replicate rapidly, including those of bone marrow, skin, gastrointestinal (GI) tract, immune system, or hair follicles. As a result, individuals taking such anticancer drugs can experience adverse effects, including anemia, scaly skin, GI tract disturbance, immunodeficiency, and hair loss.
E. Adenosine and guanosine monophosphate synthesis