The covalent linkage between the ribose and pyrimidine occurs at position C1 of the ribose unit, which contains a pyrophosphate, and N1 of the pyrimidine ring. (EC 126.96.36.199) catalyzes the net reaction: Orotate + 5-Phospho-alpha-D-ribose 1-diphosphate = Orotidine 5'-phosphate + Pyrophosphate (C01103) is decarboxylated by (EC 188.8.131.52).
Nucleotide degradation is an integrated process in all human cells that is intimately linked with the pathways of nucleotide synthesis and salvage. The clinical conditions associated with defects of enzymes catalysing nucleotide degradation provide a valuable insight into the importance of this network.
We expected that the first step, in which PRPP is synthesized, would besubject to regulation because of the prominence of PRPP in other biosyntheticreactions, including that of pyrimidine nucleotides. Increasing levels of ADPand GDP have a negative feedback effect on the enzyme Ribose phosphatepyrophosphokinase. The enzyme catalyzing the second step of the pathway,Amidophosphoribosyl transferase, is inhibited by all of the adenine and guaninenucleotides, the adenine nucleotides binding to one inhibitory site on theenzyme and the guanine nucleotides to another separate site. This enzyme is also"activated" by the increase in the level of PRPP and this is called a"feedforward activation".
The basic idea here is that there is exquisite control of the amounts ofpurine nucleotides available for synthesis of nucleic acids, and that thepathways are individually regulated at the cellular level. Furthermore, therelative amounts of ATP and GTP are also controlled at the cellular level.
Van Kuilenburg ABP,Stroomer AEM,Van Lenthe H et al.(2004)New insights in dihydropyrimidine dehydrogenase deficiency. A pivotal role for β‐aminoisobutyric acid?.Biochemical Journal379: 119–124.
What's really interesting here is that the ribose sugar is recycled in theform of ribose-1-phosphate, which can be incorporated into PRPP which, as we nowknow, is integral to the biosynthesis of purines, pyrimidines, histidine andtryptophan. That's a really efficient way to run a cell!
Nucleotides play a variety of important roles in all cells. They are the activated precursors of DNA and RNA. ATP, an adenine nucleotide, is a universal currency of energy in biological systems. GTP is an essential carrier of chemical energy. Adenine nucleotides are components of the coenzymes NAD+, NADP+, FMN, FAD and Coenzyme A. IMP is synthesized from ribose 5-phosphate. There are 11 reactions in the formation of IMP. Nucleoside monophosphates are converted to nucleoside diphosphates by base specific monophosphate kinases. Purine nucleotide synthesis is regulated by feedback inhibitor – AMP, GMP and IMP. Recycling of purines formed by the degradation of nucleotides is possible. Pyrimidine ring is synthesized as free pyrimidine and then it is incorporated into the nucleotide. Nucleotides of a cell undergo continuous turnover. Uric acid is the breakdown product of purine nucleotide. Gout is a disease characterized by elevated levels of uric acid in body fluids. Pyrimidines on degradation give rise to carbon dioxide, ammonia, β-alanine and β-amino isobutyrate.
What this shows is that the overall effect of combining these two reactionsis a net result of deaminating an aspartate to a fumarate at the expense of aGTP molecule. This cycle of reactions is know as the and it is ofphysiologic importance in muscle metabolism. Muscle tissue replenishes itscitric acid cycle intermediates via the purine nucleotide cycle rather thanthrough the usual "replenishing reactions", the most important ofwhich is the generation of oxaloacetate from pyruvate catalyzed by pyruvatecarboxylase. The fumarate generated in the purine nucleotide cycle feeds intothe citric acid cycle to regenerate malate, oxaloacetate, and so forth.
Nucleotides are the components of many enzyme cofactors. Adenosine is a part of their structure in a variety of enzyme cofactors serving a wide range of chemical functions. Coenzyme A is synthesized from pantothenic acid and ATP.
The key molecule in the synthesis of the pyrimidine ribonucleotides isuridine monophosphate (UMP), as it is the final product of the six-stepsynthesis pathway and from which CTP is subsequently derived. Thepyrimidine ring, in the form of dihydroorotate, is formed first (note that thisis not the case for the pyrimidine bases) following attachment toribose-5-phosphate.
(4) The attachment of the pyrimidine base to the ribose phosphate ring iscatalyzed by orotate phosphoribosyl transferase (OPRT) and PRPP provides theribose-5-phosphate moeity. Hydrolysis of the PPi that is split off ofthe PRPP makes this reaction irreversible.
When ATP appears as a reactant, it can generally participate in two ways:part of the ATP molecule can be transferred to an acceptor molecule or ATPhydrolysis can drive an otherwise unfavorable reaction. The Pi, PPi,adenyl or adenosinyl groups can be transferred, as in the first step in thepurine biosynthetic pathway. In such instances, the substrate is said to be"activated" by the transfer. When the free energy of ATP hydrolysisdrives an endergonic reaction, the overall mechanism must involve transfer of aPi group somewhere along the way, even though, in the final analysis,it will appear as Pi in the reaction ATP + H20 -->ADP + Pi. Otherwise, there would be no way to couple thereactions.