Nucleotide metabolism pathways

IMP is an intermediate in de novo biosynthesis of purine nucleotides (Figure 22.4) and is found in several purine nucleotide metabolic pathways. 

In both intermediate and maximum rates of respiration, control is distributed between several different steps, including the activity of the adenine nucleotide translocator (Groen et al., 1983). It is now recognized that the idea of a simple rate-limiting step for a metabolic pathway is simplistic and that control is shared by all steps although to different extents (Kacserand Bums, 1978 Fell, 1992). Each step in a pathway has a flux control coefficient (FCC) defined as ... 

Deficiencies of enzymes involved in glycolysis, the hexose monophosphate pathway, the closely related glutathione metabolism and synthesis, and nucleotide metabolism have emerged as causes of hereditary nonspherocytic hemolytic anemias (Table 1) (F10, Fll, M27). Some enzyme deficiencies, such as diphospho-glycerate mutase deficiency, lactate dehydrogenase deficiency, and NADH cy-... 

The pyrimidine nucleotides (predominantly UMP, CMP, and dTMP) are hydrolysed to their respective bases (uracil, cytosine, and thymine) by reactions similar to those for metabolism of purine nucleotides. The pathways of... 

The pentose phosphate pathway (PPP, also known as the hexose monophosphate pathway) is an oxidative metabolic pathway located in the cytoplasm, which, like glycolysis, starts from glucose 6-phosphate. It supplies two important precursors for anabolic pathways NADPH+H+, which is required for the biosynthesis of fatty acids and isopren-oids, for example (see p. 168), and ribose 5-phosphate, a precursor in nucleotide biosynthesis (see p. 188). 

Antimetabolites are enzyme inhibitors (see p. 96) that selectively block metabolic pathways. The majority of clinically important cytostatic drugs act on nucleotide biosynthesis. Many of these are modified nucleobases or nucleotides that competitively inhibit their target enzymes (see p. 96). Many are also incorporated into the DNA, thereby preventing replication. 

Contain details of metabolic pathways that are only shown in outline in the main text for reasons of space. This applies in particular to the synthesis and degradation of the amino acids and nucleotides, and for some aspects of carbohydrate and lipid metabolism. 

The final product(s) generated by a sequence of enzyme-catalyzed steps within a metabolic pathway. End products frequently act as potent inhibitors of the first commited step in a metabolic pathway leading to their synthesis. End products are also known to accelerate the rate of another metabolic pathway leading to a different set of end products. The highly coordinated biosynthesis of adenine and guanine nucleotides provides examples of negative and positive effects of end products of each pathway. 

Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis interference with the formation of DNA and RNA and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia. 

Chapters 20 through 22 describe the major anabolic pathways by which cells use the energy in ATP to produce carbohydrates, lipids, amino acids, and nucleotides from simpler precursors. In Chapter 23 we step back from our detailed look at the metabolic pathways—as they occur in all organisms, from Escherichia coli to humans—and consider how they are regulated and integrated in mammals by hormonal mechanisms. 

Altering the control of metabolic pathways can also be achieved by genetic manipulation. As proteins are generated using the template stored as a fragment of DNA, the structure of the allosteric enzyme may be altered so that there is little or no regulatory control. It is therefore possible to generate mutants that over-produce metabolites, and techniques based on this principle have been most widely exploited in amino-acid and nucleotide production 2 . 

Chapter 23, Nucleotides, deals with the biosynthesis of ribonucleotides, deoxyribonucleotides, the roles of these biomolecules in metabolic processes, and the pathways for their degradation. Medically related topics such as nucleotide metabolism deficiencies or the use of nucleotide analogs in chemotherapy are also considered. 

Fig. 4.7 Metabolic pathways for the degradation of ISIS 104838. Upper-case letters indicate 2 -MOE modified nucleotides lower-case letters indicate deoxynucleotides.

The salvage pathways in nucleotide metabolism are not capable of which procedure ... 

Among the most important reactions in biochemistry are those that involve substitution at phosphorus in phosphates. These reactions are involved in energy transduction, replication, transcription and recombination of nucleic acids, metabolic regulation, and metabolic pathways including biosyntheses of nucleotides, amino acids, proteins, complex lipids and complex carbohydrates. They are among the most intensively studied proteins in biochemistry, both because of their fundamental importance and because they present special challenges as research subjects. 

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