UMP , synthesis

NADH DEHYDROGENASE UBIQUITIN-PROTEIN LIGASES UDENERIEND S REAGENT UMBRELLA, EEEECT UMP synthesis,... 

The pathway for UMP synthesis is shown in figure 23.13. It starts with the synthesis of carbamoyl phosphate, catalyzed by carbamoyl phosphate synthase. This enzyme is present in microorganisms and in the cytosol of all eukaryotic cells... 

De novo pathway of uridine-5 -monophosphate (UMP) synthesis. Enzymes (1) carbamoyl phosphate synthetase II (2) aspartate transcarbamoylase (3) dihydroorotase (4) dihydroorotate dehydrogenase (5) orotate phosphoribosyltransferase (6) orotidine-5 -monophosphate decarboxylase (orotidylate decarboxyla.se). 

In summary, pyrimidine metabolism in the kinetoplastids is functionally similar to that found in mammalian cells. In the de novo synthesis of UMP, these parasites differ in two respects dihydro-orotate oxidase is cytoplasmic and not mitochondrial and the last two enzymes of UMP synthesis are glycosomal instead of cytoplasmic. Pyrimidine salvage by these parasites is more diverse than that of mammalian cells but, unlike the purines, de novo synthesis plays the major role. 

There is good evidence for de novo pyrimidine synthesis in cestodes. Five of the six enzymes needed for UMP synthesis are present in Hymenolepis diminuta and aspartate transcarbamoylase activity has been found in Moniezia benedeni (81). Salvage of preformed pyrimidines by a cestode was first reported in Mesocestoides corti (70). Thymidine kinase is the only cestode H. diminuta) pyrimidine salvage enzyme that has been characterized (114). 

Hammond DJ, Gutteridge WE. UMP synthesis in the kinetoplastida. Biochim Biophys Acta 1982 718(1) 1-10. 

Although allopurinol and oxipurinol are potent inhibitors of UMP synthesis [120,131] through the inhibition of orotidylic acid decarboxylase (oxipurinol with a 2,4-diketo pyrimidine ring is capable of acting as an analogue of orotic acid, and 1-ribosyl-oxipurinol 5 -phosphate [132] is a... 

The results from different laboratories underline the importance of knowledge of the precursor uptake and pools for evaluation of biosynthetic processes [203-206]. Perfused regenerating livers produce 2.5 times as much UMP per gram of liver as do perfused normal livers [205]. However, the absolute amount of orotic acid converted into UMP is higher in perfused normal livers than in regenerating ones. It seems that the levels of total orotic acid uptake and UMP synthesis are similar in intact and regenerating livers of the same size and that the total amount of orotic acid taken up, and the size of the liver are what determine UMP production [205]. 

A common intermediate for all the nucleotides is 5-phosphoribosyl-l-diphosphate (PRPP), produced by successive ATP-dependent phosphorylations of ribose. This has an a-diphosphate leaving group that can be displaced in Sn2 reactions. Similar Sn2 reactions have been seen in glycoside synthesis (see Section 12.4) and biosynthesis (see Box 12.4), and for the synthesis of aminosugars (see Section 12.9). For pyrimidine nucleotide biosynthesis, the nucleophile is the 1-nitrogen of uracil-6-carboxylic acid, usually called orotic acid. The product is the nucleotide orotidylic acid, which is subsequently decarboxylated to the now recognizable uridylic acid (UMP). 

The major intermediates in the biosynthesis of nucleic acid components are the mononucleotides uridine monophosphate (UMP) in the pyrimidine series and inosine monophosphate (IMP, base hypoxanthine) in the purines. The synthetic pathways for pyrimidines and purines are fundamentally different. For the pyrimidines, the pyrimidine ring is first constructed and then linked to ribose 5 -phosphate to form a nucleotide. By contrast, synthesis of the purines starts directly from ribose 5 -phosphate. The ring is then built up step by step on this carrier molecule. 

De novo synthesis of purines and pyrimidines yields the monophosphates IMP and UMP, respectively (see p. 188). All other nucleotides and deoxynucleotides are synthesized from these two precursors. An overview of the pathways involved is presented here further details are given on p. 417. Nucleotide synthesis by recycling of bases (the salvage pathway) is discussed on p. 186. 

Mutation of one of the two enzyme activities of UMP synthase leads to orotic aciduria, characterized by accumulation of its first substrate orotic acid and insufficient levels of the product UMP, which reduces availability of uridine triphosphate (UTP) and cytidine triphosphate (CTP) for use in nucleic acid synthesis. 

B. Synthesis of UTP and CTP occurs via phosphoiylation of UMP and intercon-version of the bases. 

S ATP 4- UMP <4> (<4> the enzyme plays a crucial role in the formation of UDP, CDP and dCDP which are required for cellular nucleic acid synthesis... 

The common pyrimidine ribonucleotides are cytidine 5 -monophosphate (CMP cytidylate) and uridine 5 -monophosphate (UMP uridylate), which contain the pyrimidines cytosine and uracil. De novo pyrimidine nucleotide biosynthesis (Fig. 22-36) proceeds in a somewhat different manner from purine nucleotide synthesis the six-membered pyrimidine ring is made first and then attached to ribose 5-phosphate. Required in this process is carbamoyl phosphate, also an intermediate in the urea cycle (see Fig. 18-10). However, as we noted... 

The end-product of pyrimidine base synthesis is orotic acid, which is converted to the nucleotide OMP by the addition of ribose 6-phosphate (donated by PRPP). OMP is then converted to UMP, which is phosphorylated to UTP. UTP is then aminated to form CTP. A deficiency of the enzyme complex (UMP synthase) that converts orotic acid to UMP causes orotic aciduria. 

UDP-Gal From Gal-l-P and UTP with UDP-galactose pyrophosporylase From UDP-glucose with UDP-glucose epimerase From Gal-l-P and UDP-Glc with UDP-galactose uridyl transferase From UMP and galactose using cells of Torulopsis Candida By chemical synthesis... 

The small proteins thioredoxin and glutaredoxin are present in relatively high concentrations in bacteria, plants, and animals. For example, thioredoxin has a concentration of 15 pM in E. coli. Both proteins were discovered by their role as reducing agents in conversion of the ribonucleotides AMP, GMP, CMP, and UMP to the corresponding 2-deoxyribonucleo-tides which are needed for synthesis of DNA a/b... 

IMP Is Converted into AMP and GMP Synthesis of Pyrimidine Ribonucleotides de Novo UMP Is a Precursor of Other Pyrimidine Nucleotides... 

Biosynthesis of UMP. The parts of the intermediates derived from aspartate are shown in red. Bold type indicates atoms derived from carbamoyl phosphate. In contrast to purine nucleotide synthesis, where ring formation starts on the sugar, in pyrimidine biosynthesis the pyrimidine ring is completed before being attached to the ribose. 

Low activities of orotidine phosphate decarboxylase and (usually) orotate phosphoribosyltransferase are associated with a genetic disease in children that is characterized by abnormal growth, megaloblastic anemia, and the excretion of large amounts of orotate. When affected children are fed a pyrimidine nucleoside, usually uridine, the anemia decreases and the excretion of orotate diminishes. A likely explanation for the improvement is that the ingested uridine is phosphorylated to UMP, which is then converted to other pyrimidine nucleotides so that nucleic acid and protein synthesis can resume. In addition, the increased intracellular concentrations of pyrimidine nucleotides inhibit carbamoyl phosphate synthase, the first enzyme in the. naibwav of aro-tate synthesis. 

The biosynthetic pathway to UMP starts from carbamoyl phosphate and results in the synthesis of the pyrimidine orotate, to which ribose phosphate is subsequently attached. CTP is subsequently formed from UTP. Deoxyribonucleotides are formed by reduction of ribonucleotides (diphosphates in most cells). Thy-midylate is formed from dUMP. 

Jones, M. E., Pyrimidine nucleotide biosynthesis in animals Genes, enzymes and regulation of UMP biosynthesis. Ann. Rev. Biochem. 49 253-279, 1980. Authoritative outline of the regulatory properties of the two multifunctional proteins responsible for pyrimidine nucleotide synthesis in animals. 

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