Pyrimidines metabolism

Although both pyrimidines and purines are components in nucleic acids, they are made in different ways. Likewise, the products of pyrimidine degradation are more water-soluble than are the products of purine degradation. 

Note CAA = Carbamoyl Aspartate DHOA = Dihydroorotate OMP = Orotidine Monophosphate 

Carbamoyl Phosphate Synthetase 11 (CPS-11) differs in several ways from its isoform (CPS-I), the enzyme which provides carbamoyl phosphate for the Urea cycle (see Protein Turnover / Ammonia Metabolism ). 

CPS-1 is found only in Liver and Kidney, CPS-11 in most tissues 

OMP is the first pyrimidine formed and is immediately decarboxylated to produce UMP. Nucleotides are then formed subsequently from UTP via CTP Synthetase. 

The primary site of regulation is Carbamoyl Phosphate Synthetase II (glutamine) which is allosterically inhibited by UTP. Elevated PRPP increases the CPS-II activity to help control PRPP levels. Feedback inhibition (control) is provided by TDP inhibition of PRPP synthesis and UMP inhibition of OMP Decarboxylase. 

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Sterol biosynthesis Bile acid biosynthesis C2rSteroid hormone metabolism Androgen and estrogen metabolism Nucleotide Metabolism Purine metabolism Pyrimidine metabolism Nucleotide sugar metabolism Amino sugar metabolism Amino Acid Metabolism Glutamate metabolism Alanine and aspartate metabolism Glycine, serine, and threonine metabolism... 

We should note at this point that the TCA cycle is more than just a means of producing NADH for oxidative phosphorylation. The pathway also provides a number of useful intermediates for other, often synthetic, pathways. For example, citrate is the starting substance for fat synthesis (Chapter 9) succinyl-CoA is required for haem production and 2-oxoglutarate and oxaloacetate in particular are involved with amino acid and pyrimidine metabolism. Pathways which have dual catabolic/anabolic functions are referred to as amphibolic . 

Enzyme activity on a D (non-natural) configuration, non-protein cyclic amino acid derivative appears unlikely. However the D-hydantoinase reaction is very similar to the dihydroxypyrimidase present in pyrimidine metabolism. The original hydantoinase used was obtained from calf liver, but subsequently many active microorganisms were found, particularly a strain of B. brevis. The resulting D-A-carbamoyl amino acid can then be converted into product by treatment with nitrous acid (Figure 4.11). 

Wadman SK, Berger R, Duran M et al. Dihydropyrimidine dehydrogenase defieieney leading to thymine-uraciluria an inborn error of pyrimidine metabolism. J Inherit Metab Dis 1985 8 Suppl 2 113-114. 

Sumi S, Kidouchi K, Ohba S et al. Automated screening system for purine and pyrimidine metabolism disorders using high performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1995 672 233-239. 

Febuxostat is a potent and selective inhibitor of xanthine oxidase, and thereby reduces the formation of xanthine and uric acid. No other enzymes involved in purine or pyrimidine metabolism are inhibited. In clinical trials, febuxostat at a daily dose of 80 mg or 120 mg was more effective than allopurinol at a standard 300 mg daily dose in lowering serum urate levels. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia—overproduction or underexcretion. 

Screening for Disorders of Purine and Pyrimidine Metabolism Using HPLC-Electrospray Tandem Mass Spectrometry... 

Concentrations of metabolites outside the reference ranges may constitute a typical pattern indicating the presence of an inborn error of purine or pyrimidine metabolism. However, altered excretions of purine and pyrimidines may also be a secondary phenomenon due to the presence of other metabolic disorders, such as a deficiency of the urea cycle [15]. Increased concentration of a single metabolite or combinations of metabolites may also result from bacterial contamination, sample conditions, medication, or dietary compounds [6]. 

Ito T, van Kuilenburg ABP, Bootsma AH, Haasnoot AJ, van Cruchten AG, Wada Y, van Gen-nip AH (2000) Rapid screening of high-risk patients for disorders of purine and pyrimidine metabolism using HPLC-electrospray tandem mass spectrometry of liquid urine or urine-soaked filter paper strips. Clin Chem 46 445-452... 

This four-volume set has good chapters on disorders of amino acid, porphyrin, and heme metabolism. See also the chapters on inborn errors of purine and pyrimidine metabolism. 

Berens, R.L., Krug, E.C. and Marr, J.J. (1995) Purine and pyrimidine metabolism. In Marr, J. and Muller, M. (eds) Biochemistry and Molecular Biology of Parasites. Academic Press, New York, pp. 89-117. 

Since D-hydantoinase was identified as dihydropyrimidinase, it is proposed that D-amino acid production from DL-5-monosubstituted hydantoins involves the action of the series of enzymes involved in the pyrimidine degradation pathway. Based on this proposal, D-decarbamoylase was thought to be identical with P-ureidopropionase (EC 3.5.1.6) which functions in pyrimidine metabolism. 

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