Pyrimidine synthesis: control

Pyrimidine synthesis is controlled at the first committed step. ATP stimulates the aspartate transcarbamoylase reaction, while CTP inhibits it. CTP is a feedback inhibitor of the pathway, and ATP is a feed-forward activator. This regulation ensures that a balanced supply of purines and pyrimidines exists for RNA and synthesis. 

Alternatively, if Cs>B, then C would activate the production of B and this again would tend to equalize the concentrations of B and C. This activation by C is usually the result of C competing for the same binding site as B on E[, and thus reducing the inhibition by B. The first enzyme of pyrimidine synthesis, aspartate carbamoyltransferase, in E. coli, is subject to this type of control (Example 8.5 Chap. 15) in this case B is CTP, C is ATP, and D is the nucleic acids. 

It enables separate control over urea and pyrimidine synthesis (Chap. 15). 

Which is the rate-controlling step of pyrimidine synthesis that exhibits allosteric inhibition by cytidine triphosphate (CTP) ... 

In this chapter we examine the synthesis and degradation of purines, pyrimidines, and hemes. These have complex structures, but are formed from simple precursors. All three can be synthesized in the body and have roles ranging from nucleic acids to hemoglobin. In addition to synthesis control of all three classes of compounds, a number of metabolic diseases associated particularly with purine and heme metabolism are discussed. The use of antimetabolites, as in chemotherapy, and the rationale for their use is presented. 

Control of pyrimidine synthesis. The control of pyrimidine synthesis is presented in outline form. Control for both bacteria and mammals (including humans) is shown. 

In humans, the control of pyrimidine synthesis lies with UTP inhibition of carbamoyl phosphate synthase II, the first step of pyrimidine synthesis. 

The major control step in pyrimidine synthesis in people is the formation of... 

Leflunomide (Arava) is a pyrimidine-synthesis inhibitor indicated for the treatment of adults with rheumatoid arthritis. This drug has found utility in the treatment of polyo-mavirus nephropathy seen in immunosuppressed renal transplant recipients and is increasingly being used for that purpose. There are no studies showing efficacy, however, compared with control patients treated with withdrawal or reduction of immune-suppression alone in BK virus nephropathy. The drug inhibits dihydro-orotate dehydrogenase in the de novo pathway of pyrimidine synthesis. It is hepa-totoxic and can cause fetal injury when administered to pregnant women. 

Pathways that use nitrogen to make amino acids, purines, and pyrimidines are controlled by feedback inhibition. The final product, such as CTP, inhibits the first or an early step in its synthesis. 

Feedback repression is the inhibition of formation of one or more enzymes in a pathway by a derivative of the end product. In many (but not all) amino acid biosynthetic pathways, the amino add end product must first combine with its transfer RNA (tRNA) before it can cause repression. Feedback repression is a widespread regulatory device especially for the synthesis of molecules intended for incorporation into macromolecules, e.g. amino adds, purines, and pyrimidines. Synthesis of vitamins also appears to be controlled by feedback repression, as well as by catabolite regulation (Birnbaum et al, 1967 Sasaki, 1965 Newell and Tucker, 1966 Wilson and Pardee, 1962 Papiska and Lichstein, 1968). Regulation of vitamin synthesis is important since only a small number (probably about 1000) of vitamin molecules are required per cell whereas many molecules of an average amino acid (probably 50 million) are required. An extremely wasteful case of vitamin overproduction would develop if enzymes for vitamin synthesis were produced at the same rate and were as active as the amino acid biosynthetic enzymes. 

The reduction in urinary excretion of both compounds following uridine therapy reflects the utilization of uridine for the formation of UMP by the salvage pathway. A similar phenomenon was observed in hereditary orotic aciduria following uridine replacement therapy which bypasses the congenital enzyme defect (Chapter 5). The reversal of 6-azauridine-induced orotic aciduria by hydroxyurea, methotrexate and cyclophosphamide [251] (i.e. by the drugs affecting the synthesis of DNA without any effect on orotic acid synthesis) suggests that the control of pyrimidine synthesis de novo is linked to DNA synthesis. 

The suggestion of a control of pyrimidine synthesis stems from the observation that pyrimidine-requiring mutants of E. coli in pyrimidine-free medium accumulated carbamylaspartic acid and, to a lesser extent, dihy-droorotic acid and orotic acid this accumulation was prevented by the addition of uracil and cytosine to the medium (443). It was shown further employing enzyme preparations that cytidine and particularly cytidine 5 -phosphate were effective inhibitors of carbamylaspartic acid synthesis, suggesting that the inhibition of this enzyme by a pyrimidine nucleotide was the mechanism for the feedback control of pyrimidine biosynthesis in bacteria. The decreased formation of dihydroorotic acid and orotic acid were probably secondary events reflecting the earlier metabolic block. 

The N-5 position is considerably more basic than the N-10 position, and this basicity is one of several factors that control certain preferences in the course of reactions involving tetrahydrofolate. Thus, for-mylation occurs more readily at N-10 while alkylation occurs more readily at N-5. Benkovic and Bullard (1973) have reviewed evidence for an iminium cation at N-5 as the active donor in formaldehyde oxidation-level transfers. Recently, Barrows et al. (1976) have further studied such a mechanism for folic acid. The interconversion of these forms of folate coenzymes by enzymatic means has been reviewed by Stokstad and Koch (1967), and the reader is directed there for further details. Folate coenzymes are involved in a wide variety of biochemical reactions. These include purine and pyrimidine synthesis, conversion of glycine to serine, and utilization and generation of formate. In addition, the catabolism of histidine, with the formation of formiminoglu-tamic acid (FIGLU), is an important cellular reaction involving folate. 

The problems in the nucleoside synthesis arise in the linkage of the 3-N atoms of the pyrimidines and the 9-N atoms of the purines with the l -C atom of ribose, not only without enzyme control, but also under conditions extant on the primordial Earth. How might such reactions occur There have naturally been many attempts... 

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