Metabolism pyrimidine, regulation

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Goordinated regulation of purine and pyrimidine nucleotide biosynthesis ensures their presence in proportions appropriate for nucleic acid biosynthesis and other metabolic needs. 

For the regulation of metabolic pathways metabolites are often used which are a product of that pathway. The basic strategy for the regulation is exemplified in the mechanisms employed in the biosynthetic and degradation pathways of amino acids, purines, pyrimidines, as well as in glycolysis. In most cases a metabolite (or similar molecule) of the pathway is utilized as the effector for the activation or inhibition of enzymes in that pathway. 

The purine and pyrimidine bases play an important role in the metabolic processes of cells through their involvement in the regulation of protein synthesis. Thus, several synthetic analogues of these compounds are used to interrupt the cancer cell growth. One such example is an adenine mimic, 6-mercaptopurine, which is a well known anticancer drug. 

The manner in which the reduction of ribonucleotides to deoxyribonucleotides is regulated has been studied with reductases from relatively few species. The enzymes from E. coli and from Novikoff s rat liver tumor have a complex pattern of inhibition and activation (fig. 23.25). ATP activates the reduction of both CDP and UDP. As dTTP is formed by metabolism of both dCDP and dUDP, it activates GDP reduction, and as dGTP accumulates, it activates ADP reduction. Finally, accumulation of dATP causes inhibition of the reduction of all substrates. This regulation is reinforced by dGTP inhibition of the reduction of GDP, UDP, and CDP and by dTTP inhibition of the reduction of the pyrimidine substrates. Because evidence suggests that ribonucleotide reductase may be the rate-limiting step in deoxyribonucleotide synthesis in at least some animal cells, these allosteric effects may be important in controlling deoxyribonucleotide synthesis. 

Nucleotides are the building blocks of the nucleic acids. They also regulate metabolism and transfer energy. The purine and pyrimidine nucleotides are synthesized in both de novo and salvage pathways. 

See also Regulation of Enzyme Activity, Pyrimidine Nucleotide Metabolism (from Chapter 22), Figure 22.10... 

Purine and pyrimidine nucleotides are fundamental to life as they are involved in nearly all biochemical processes. Purine and pyrimidine nucleotides are the monomeric units of both DNA and RNA, ATP serves as the universal cellular energy source, adenine nucleotides are components of three key coenzymes (NAC", FAD and Co A), they are used to form activated intermediates, such as UDP-glucose, and they serve as metabolic regulators. 

Pyrimidines play a central role in cellular regulation and metabolism. They are substrates for DNA and RNA biosynthesis, regulators of biosynthesis of some amino acids, and cofactors in the biosynthesis of phospholipids, glycolipids, sugars, and polysaccharides (17B45). Pyrimidine biosynthesis is very complicated and involves formic acid, glutamate, and aspartate as starting materials in a series of enzymatic reactions to eventually form orotic acid. Orotic acid, or uracil-... 

The reaction of carbamoyl phosphate with aspartate to produce W-carbamo-ylaspartate is the committed step in pyrimidine biosynthesis. The compounds involved in reactions up to this point in the pathway can play other roles in metabolism after this point, A -carbamoylaspartate can be used only to produce pyrimidines—thus the term committed step. This reaction is catalyzed by aspartate transcarbamoylase, which we discussed in detail in Ghapter 7 as a prime example of an allosteric enzyme subject to feedback regulation. The next step, the conversion of A-carbamoylaspartate to dihydroorotate, takes place in a reaction that involves an intramolecular dehydration (loss of water) as well as cyclization. This reaction is catalyzed by dihydroorotase. Dihydroorotate is converted to orotate by dihydroorotate dehydrogenase, with the concomitant conversion of NAD to NADH. A pyrimidine nucleotide is now formed by the reaction of orotate with PRPP to give orotidine-5 -monophosphate (OMP), which is a reaction similar to the one that takes place in purine salvage (Section 23.8). Orotate phosphoribosyltransferase catalyzes this reaction. Finally, orotidine-5 -phosphate decarboxylase catalyzes the conversion of OMP to UMP... 

Biosynthesis metabolism Asp is formed from oxaloacetic acid by aspartate aminotransferase (EC 2.6.1.1) and serves as starting material in the biosyntheses of threonine, methionine, and lysine. The first step is catalysed by aspartate kinase (EC 2.7.24) which only occurs in plants and microorganisms. This enzyme exists as 3 isozymes in Escherichia coli and exhibits a typical example of feedback regulation. Asp plays a central role in the biosyntheses of pyrimidines and purines. In the urea cycle Asp condenses with " citrulline to aigininosuccinate, a stimulating neuro-transmitter. ... 

Purines and pyrimidines are functionally operative as nucleotide derivatives. These are present as intracellular pool ingredients and are used as major components of nucleic acids, as well as many coenzymes. Regulation of a variety of metabolic processes is required to ensure optimal amounts and a balanced distribution of the many different forms purine and pyrimidine classes, ribose and deoxyribose derivatives, and mono-, di-, and triphosphates. 

For details of the metabolic and enzymatic reactions covered here, the reader is referred to a number of excellent monographs [1-5]. Several phases of the regulation of purines and pyrimidines have also been covered in some recent reviews [6-9a]. 

---