Nucleotides consist of a pentose sugar, a nitrogenous base (adenine, guanine, cytosine, uracil, or thymine), and one, two, or three phosphate groups (Fig. 22.24). Purines, such as A and G, and pyrimidines, such as C, U, and T, make up the nitrogenous bases. Ribonucleoside phosphates, like adenosine monophosphate (AMP), are nucleotides with ribose sugar and have various cellular functions, including RNA composition. Deoxyribonucleoside phosphates, such as deoxyAMP, have deoxyribose sugar and are predominantly found in DNA. The initial step in purine synthesis involves the use of 5-phosphoribosyl-1-pyrophosphate (PRPP) and nitrogen from glutamine to produce phosphoribosylamine. This process is catalyzed by the enzyme glutamine:phosphoribosylpyrophosphate amidotransferase and is regulated by PRPP activation and inhibition by AMP and guanosine monophosphate. Purine nucleotides can also be produced through salvage reactions utilizing adenine phosphoribosyltransferase (APRT) and hypoxanthine–guanine phosphoribosyltransferase (HGPRT) to convert preformed purine bases. HGPRT deficiency leads to Lesch-Nyhan syndrome, a severe inherited form of hyperuricemia associated with self-mutilation tendencies. The synthesis of deoxyribonucleotides from ribonucleotides occurs through the enzyme ribonucleotide reductase. This enzyme is tightly regulated and inhibited by deoxyadenosine triphosphate (dATP), which is overproduced in bone marrow cells of individuals with adenosine deaminase (ADA) deficiency causing severe combined immunodeficiency disease. The end product of purine degradation is uric acid, whose overproduction or undersecretion leads to hyperuricemia and the possibility of gout development due to monosodium urate crystal deposition and subsequent inflammatory response. The initial step in pyrimidine synthesis involves the production of carbamoyl phosphate by carbamoyl phosphate synthetase II, which is regulated by uridine triphosphate (UTP) inhibition and PRPP activation. UTP produced in this pathway can be converted to cytidine triphosphate. Thymidylate synthase can convert deoxyuridine monophosphate to deoxythymidine monophosphate and is targeted by anticancer drugs like 5-fluorouracil. The regeneration of tetrahydrofolate from dihydrofolate, produced in the thymidylate synthase reaction, is carried out by dihydrofolate reductase, an enzyme targeted by methotrexate. Pyrimidine degradation results in the formation of soluble products, including guanosine, cytidine, thymidine, and inosine monophosphates. The drug azaserine, known for its research applications, inhibits glutamine-dependent enzymes and is most likely to affect the incorporation of the nitrogen at position 9 in the generic purine structure.
Nucleotides are composed of a nitrogenous base (adenine = A, guanine = G, cytosine = C, uracil = U, and thymine = T); a pentose sugar; and one, two, or three phosphate groups (Fig. 22.24). A and G are purines, and C, U, and T are pyrimidines. If the sugar is ribose, the nucleotide is a ribonucleoside phosphate (for example, adenosine monophosphate [AMP]), and it can have several functions in the cell, including being a component of RNA. If the sugar is deoxyribose, the nucleotide is a deoxyribonucleoside phosphate (for example, deoxyAMP) and will be found almost exclusively as a component of DNA. The committed step in purine synthesis uses 5-phosphoribosyl-1-pyrophosphate ([PRPP], an activated pentose that provides the ribose 5-phosphate for de novo purine and pyrimidine synthesis and salvage) and nitrogen from glutamine to produce phosphoribosylamine. The enzyme is glutamine:phosphoribosylpyrophosphate amidotransferase and is inhibited by AMP and guanosine monophosphate (the end products of the pathway) and activated by PRPP. Purine nucleotides can also be produced from preformed purine bases by using salvage reactions catalyzed by adenine phosphoribosyltransferase (APRT) and hypoxanthine–guanine phosphoribosyltransferase (HGPRT). A near-total deficiency of HGPRT causes Lesch-Nyhan syndrome, a severe, inherited form of hyperuricemia accompanied by compulsive self-mutilation. All deoxyribonucleotides are synthesized from ribonucleotides by the enzyme ribonucleotide reductase. This enzyme is highly regulated (for example, it is strongly inhibited by deoxyadenosine triphosphate [dATP], a compound that is overproduced in bone marrow cells in individuals with adenosine deaminase [ADA] deficiency). ADA deficiency causes severe combined immunodeficiency disease. The end product of purine degradation is uric acid, a compound of low solubility whose overproduction or undersecretion causes hyperuricemia that, if accompanied by the deposition of monosodium urate crystals in joints and soft tissues and an inflammatory response to those crystals, results in gout. The first step in pyrimidine synthesis, the production of carbamoyl phosphate by carbamoyl phosphate synthetase II, is the regulated step in this pathway (it is inhibited by uridine triphosphate [UTP] and activated by PRPP). The UTP produced by this pathway can be converted to cytidine triphosphate. Deoxyuridine monophosphate can be converted to deoxythymidine monophosphate by thymidylate synthase, an enzyme targeted by anticancer drugs such as 5-fluorouracil. The regeneration of tetrahydrofolate from dihydrofolate produced in the thymidylate synthase reaction requires dihydrofolate reductase, an enzyme targeted by the drug methotrexate. Pyrimidine degradation results in soluble products.
guanosine, cytidine, thymidine, and inosine monophosphates; d = deoxy; PPi = pyrophosphate; PRPP = 5-phosphoribosyl-1-pyrophosphate.
Choose the ONE best answer.
2.1. Azaserine, a drug with research applications, inhibits glutamine-dependent enzymes. Incorporation of which of the ring nitrogens (N) in the generic purine structure shown would most likely be affected by azaserine?
A. 1 B. 3 C. 7 D. 9