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Nucleotide Degradation PDF
Nucleotide Degradation PDF
H Anne Simmonds, Guys Hospital, London, UK Albert H van Gennip, Laboratory for Metabolic Diseases and Cancer, Amsterdam, The
Netherlands
Secondary article
Article Contents
. Introduction . Enzymes Catalysing Dephosphorylation and Deamination of Purine Nucleotides . Species Differences in the Enzymes of Nucleoside Degradation . Removal of Metabolic Waste from Nucleotide Degradation: Uric Acid is the End-product of Purine Catabolism Only in Humans . Purine Ribonucleotide Catabolism in Healthy Humans . Enzymes Catalysing Dephosphorylation and Deamination of Pyrimidine Nucleotides . What Can We Learn from Genetic Metabolic Defects of Purine and Pyrimidine Metabolism? . Summary
Nucleotide degradation is an integrated process in all human cells, being intimately linked with the pathways of nucleotide synthesis and salvage. The clinical conditions associated with defects of enzymes catalysing nucleotide degradation provide valuable insight into the importance of this network.
Introduction
Nucleotides have very early origins
Purine and pyrimidine nucleotides were almost certainly the rst complex chemical structures to emerge from the primordial soup, the basic ring structure being synthesized rst through the action of ultraviolet light on mixtures of cyanide and methane, or urea. Addition of sugar and phosphate, also present at that time, could occur thereafter under abiotic conditions, resulting in the formation of purine and pyrimidine mononucleotides. More complex pathways that sustain these vital intracellular chemicals have developed subsequently. The diverse functions performed by nucleotides depends on an integrated network involving synthesis, degradation and salvage. This varies among species, and also within a given species, depending on the function of a particular cell or tissue. The multistep de novo pathways of nucleotide synthesis contrast with the less energetically expensive single-step salvage routes. This chapter focuses on the pathways of nucleotide degradation (Figure 1) that link these two and underlines how they dier in health and disease. Two types of nucleotides mononucleotides and polynucleotides are found in all nucleated cells and their routes of degradation vary, depending on the cell type and its function. Mononucleotides are composed of either purine or pyrimidine bases (Figures 1 and 2) with a pentose sugar attached at N9 for purines or N1 for pyrimidines (nucleosides), and additionally esteried with phosphoric acid (nucleotides). Most mononucleotides occur within the cell in the triphosphate form and these highly charged phosphorylated compounds do not normally cross cell membranes in the absence of carrier systems. Polynucleotides exist in two forms: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA is found principally in the nucleus, where the pentose is 2-deoxyribose (Figure 3a) and the bases are adenine (A), guanine (G), cytosine (C) and thymine (T). In RNA the pyrimidine uracil (U) replaces thymine and the pentose is ribose. Most of the RNA is produced in the nucleus on a DNA template, thereafter
being exported to the cytoplasm through pores in the nuclear membrane. In both DNA and RNA the pentose is linked to the C1 atom through a glycosidic linkage to the N9 atom of the purine group, or the N1 of the pyrimidine group (Figure 3a). DNA comprises two strands wound in the well-dened helical structure. Each nucleotide of one strand is associated through hydrogen bonding to a complimentary nucleotide on the other strand (AT and GC), with the deoxyribose and phosphate groups performing structural roles (Figure 3b,c). Genes, the hereditary material in the nucleus of human cells, are coded by long chains of double helical DNA packed into 23 chromosomes. The human genome is considered to contain between 70 000 and 100 000 genes. The four bases, the purines A and G and the pyrimidines T and C, linked through a sugarphosphate backbone, carry the genetic information of all prokaryotic and eukaryotic organisms, the innite variation in genetic programming being achieved by the particular sequence of these bases (Figure 3).
Nucleotide Degradation
PYRIMIDINE O Uridine HN 3 4 5 CH monophosphate O C 2 1 6 CH N OH2C 5 O P O O (DNA) (RNA) Ribose 1 O O H H 4 H 2 3 H TMP TMP C OH OH HN CH C Thymidine Cytidine Uridine O N H H CH OH2C H H OH Nucleosides C Nucleotides
PURINE O HN 1 HC
2
C
6
5C
N
7 8 CH 9
3 4C
N
1
H2C O 5 O
Ribose
2 3
H GMP
OH OH
Inosine
Guanosine
CH N H Thymine
CH N H Uracil
C N N Hypoxanthine H
N H Uric acid N
Figure 1 Metabolic end products of purine and pyrimidine degradation in humans. Routes of pyrimidine (green) and purine (red) mononucleotide degradation showing the structural formula and numbering of the atoms in the respective ring structures of UMP (uridine 5-monophosphate) and IMP (inosine 5-monophosphate), central intermediates in nucleotide degradation. CMP and UMP are degraded to uridine and largely recycled, since most human cells, except liver, lack uridine phosphorylase. A different battery of enzymes degrade TMP (thymidine 5-monophosphate) to thymine. The purine nucleotides IMP and GMP are degraded via the corresponding nucleosides to the constituent bases hypoxanthine and guanine respectively and recycled at this level. Further catabolism of nonrecycled degradation products in the liver leads to the formation of the metabolic end products b-alanine and baminoisobutyric acid for pyrimidines, uric acid for purines (blue).
NH2
5C 2 4 HC 3 C
N1
C
6
N
9 8 CH
O O
5
O O P O O
O P O O
expensive, recycling of the respective base, or nucleoside/ deoxynucleoside to which these ribo- and deoxyribonucleotides are degraded predominates (Figure 1), resulting in little loss of these vital chemicals to the body.
N
1
H2C O H
Ribose 2 3
P O
Nucleotide Degradation
NH2 N O
O 7 6 N 1 4 3 2 C CH
CH 8
5 4
C5
Adenine
DNA
P O
CH2 H
O H H
N
1
Deoxy ribose
O N C C C A NH C C Guanine H2N T C G G A A G T C A
3 2
H CH O H
O
O
P O
CH2 H H O
(b)
Cytosine A O C
P O
P O
HC C N CH2 O H H H H H
(a)
(c)
Figure 3 Part of a DNA chain. (a) Structural formulae of the four constituent bases, adenine and guanine (red), cytosine and thymine (green), showing that the deoxyribose has an H group at the 2 position on the pentose ring, instead of the OH group of ribose. These bases are linked via the 3-OH group of the deoxyribose-phosphate moiety to the 5-OH group of the next deoxyribose. (b) Schematic representation of the manner in which the above bases are linked on strands making infinite variation possible, depending on the order of these bases. (c) Schematic representation of the role of hydrogen bonding between bases on opposite strands in contributing to the stability of this double helical structure. The base pair guanine cytosine has three hydrogen bonds, that for adenine thymine two. Colour code for (b) and (c) as for (a).
toxic to invading organisms but not to human cells. Microorganisms in the gut catabolize exogenous nucleotides. In humans, purine nucleotide synthesis and degradation, unlike that for pyrimidines, is considered to be entirely endogenous. The gut mucosa contains a battery of enzymes capable of degrading dietary purine to uric acid (Figure 4), which thus adds to the endogenous uric acid pool, leading to the clinical syndrome of gout (Stone and Simmonds, 1991). By contrast, the gut mucosa lacks enzymes capable of degrading uridine, as evidenced by the successful treatment of hereditary oroticaciduria with oral uridine (Scriver et al., 1995). However, the gut ora may contain enzymes that degrade uridine to uracil (e.g. Escherichia coli). It is equally essential to realize that although multiple pathways for nucleotide degradation exist in all mammalian species, only certain of these may be functional in a particular cell. Furthermore, these pathways and controls on them can be very dierent in malignant cells.
Because standard texts rarely dene the organism or species from which the data were derived, there is potential confusion regarding routes of nucleotide degradation. This arises because much of the information has been obtained from studies in yeasts, E. coli, Drosophila or rats and mice, etc., as well as malignant cells. The dierences can be considerable and can lead to much wasted time and money in endeavours to develop analogues for the treatment of human disease. For example, such dierences can mean that potentially useful drugs for humans will fail their obligatory animal trials and, conversely, that drugs found to be safe in animals may prove to be toxic to humans.
Degradation of DNA, RNA and the mononucleotides ATP, GTP, UTP and CTP
In tissues with a high rate of cell turnover the skin, gut, lung, lymphoid and haematopoietic systems both
3
Nucleotide Degradation
CO2
CO2
Purines
Pyrimidines
XDH
Uric acid
Figure 4 Fate of oral purine and pyrimidine nucleotides in humans. (a) In the gut dietary purine is degraded first by gut bacteria to CO2 (up to 50%). Any purine not so degraded is broken down by a battery of enzymes present in the intestinal mucosa which include xanthine dehydrogenase (XDH), thereby ensuring their conversion to uric acid prior to absorption. (b) Dietary pyrimidines are partially degraded to CO2 in the gut by bacteria. Because uridine phosphorylase (URP) is not present in the intestinal mucosa in humans, only in the liver, dietary pyrimidines escaping bacterial degradation are absorbed in the form of uridine. Uridine can then be taken up by tissues lacking URP. Uridine reaching the liver is degraded to uracil by URP and catabolized further to amino acids, as shown in Figure 1.
polynucleotides and mononucleotides must be degraded, ve steps being involved. This contrasts with tissues where DNA is relatively stable and the principal nucleotide turned over will be ATP (Figure 2). The initial degradation of DNA and RNA which results in the release of the respective deoxyribo- and ribomononucleotides (Figure 1) is catalysed by enzymes collectively called nucleases. Subsequent degradation depends on the cell type and involves either direct dephosphorylation or dephosphorylation plus deamination to yield the corresponding riboor deoxyribonucleoside (Figure 1). Cleavage of the glycosidic bonds of the dierent nucleosides/deoxynucleosides then yields the bases hypoxanthine and guanine, or uracil and thymine, as described below.
phosphatases specic for the dierent nucleoside diphosphates. Degradation of monophosphates to nucleosides may be catalysed also by nonspecic acid or alkaline phosphatases, regardless of the base or the phosphate position (2, 3 or 5). AMP is generally rst deaminated at the nucleotide level by AMP deaminase (AMPDA; EC 3.5.4.6) prior to dephosphorylation (Figure 5). AMPDA has at least three tissue-specic isoforms (Gross, 1997; McKusick, 1998). Isozymes of GMP reductase have not been identied. Xanthosine monophosphate (XMP) is not a metabolic intermediate in human cells. The reductive deamination of GMP to inosine monophosphate (IMP) requires NADPH (reduced nicotinamideadenine dinucleotide phosphate), while the conversion of AMP to IMP requires no coenzyme. In some tissues, AMP dephosphorylation may occur rst, with subsequent deamination at the nucleoside level catalysed by adenosine deaminase (ADA; EC 3.5.4.4). Specic nucleotidases dephosphorylating AMP, IMP or GMP have been the subject of extensive research, particularly by those studying the pharmacological actions of adenosine (Stone and Simmonds, 1991). In general, these nucleotidases appear to be tissue dened and relate specically to the function of that tissue. 5-Nucleotidases may be ecto- (on the outer membrane), or endo-nucleotidases, depending on the particular tissue, their activity being controlled by factors which carefully regulate their expression. The role of ecto-5-nucleotidase (5-NT, also known as CD73), which is expressed by a variety of cell types, has been studied in depth. The highly variable distribution of 5-NT suggests a tissue-specic regulation of expression. In some tissues, 5-NT and ADA appear to be expressed in a reciprocal manner, suggesting that they share genetic elements which coordinate adenine nucleotide degradation. Deoxy-AMP is not a substrate for AMPDA in humans and must be degraded rst to deoxyadenosine and thereafter by ADA. By contrast there is no comparable enzyme capable of deaminating guanosine/deoxyguanosine to inosine/deoxyinosine, deamination occurring at the nucleotide level from GMP to IMP, which can then be dephosphorylated under appropriate conditions. Xanthosine is not found in human cells. Purine nucleoside phosphorylase (PNP; EC 2.4.2.1) catalyses the only route of degradation of purine nucleosides and deoxynucleosides in mammals. Adenosine and deoxyadenosine are not substrates for PNP. However, guanosine, inosine or their deoxyanalogues derived from either ATP, dATP, IMP, GTP or dGTP all feed into this pathway to be degraded to hypoxanthine or guanine respectively, making PNP possibly the most important enzyme of purine nucleotide catabolism in mammals. Although the reaction catalysed by PNP is essentially reversible, in vivo studies conrm that PNP in humans functions primarily in the direction of nucleoside breakdown, the concentration of inorganic phosphate being considerably greater than that of either
Nucleotide Degradation
Purines ATP DNA d-AMP AMP RNA AMPDA1 RNA IMP GMP GTP DNA d-GMP CTP RNA (d)-CMP UMPH-1 (d)-Adenosine ADA (d)-Inosine PNP Hypoxanthine XDH (d)-Guanosine Cytidine UTP
Pyrimidines TTP RNA (d)-UMP DNA TMP Nucleoside (d)-Uridine Thymidine Nucleotide
Polyamines
Adenine
Guanine
Thymine
Base
Dihydrothymine DPA -Ureodoisobutyric acid UP -Aminoisobutyric acid BAIBPAT Methylmalonic semialdehyde Metabolic waste
8-Hydroxyadenine
2,8-Dihydroxyadenine
Uric acid
Figure 5 Enzymes defective in inborn errors of nucleotide degradation. Metabolic pathways of purine (red) and pyrimidine (green) nucleotide degradation, via the nucleoside and base to the respective metabolic end products (blue), indicating the enzymes (pink) deficient in genetic disorders affecting these pathways. The extra-purine origin of adenine (end product of the polyamine pathway, cyan) and its degradation to 2,8-dihydroxyadenine by xanthine dehydrogenase (XDH), when the salvage enzyme adenine phosphoribosyltransferase is defective, is indicated in the inset on the left. Abbreviations: ADA, adenosine deaminase; AMPDA, myoadenylate deaminase; BAPAT, b-alanine pyruvate aminotransferase; BAKAT, b-alanine ketoglutarate aminotransferase; BAIBPAT, b-amino isobutyrate pyruvate aminotransferase; DHP, dihydropyrimidinase; DPD, dihydropyrimidine dehydrogenase; PNP, purine nucleoside phosphorylase; UMPH-1, UMP-hydrolase (or Py5-N, pyrimidine 5-nucleotidase); UP, ureidopropionase; XDH, xanthine dehydrogenase.
(2-deoxy) ribose-1-phosphate, or hypoxanthine and guanine (Figure 1). In the interests of whole body economy, most of the hypoxanthine and guanine formed is largely recycled, only a small fraction being lost to the body as metabolic waste. Thus purine nucleotide catabolism essentially stops at this point.
phosphoribosyltransferase (APRT; EC 2.4.2.7) is defective is degraded by xanthine dehydrogenase (XDH) to 2,8dihydroxyadenine (Figure 5). Considerable species dierences also exist in the activity of PNP, which is ubiquitously distributed in human cells, activity being extremely high in the erythrocyte. The release of inosine from ischaemic human but not rat heart illustrates the very low PNP activity in human heart, indicating considerable tissue-specic variation in expression for this enzyme too.
Removal of Metabolic Waste from Nucleotide Degradation: Uric Acid is the End-product of Purine Catabolism Only in Humans
The nal steps of nucleotide degradation leading to the irretrievable loss of the purine bases guanine and hypoxanthine are catalysed by guanine aminohydrolase (guanase; EC 3.5.4.3) and xanthine dehydrogenase (XDH; EC 1.2.1.37) respectively. Xanthine formed by either route is a metabolic end-product and does not normally accumulate, being further oxidized by XDH to uric acid
5
Nucleotide Degradation
(Figure 4). Expression of XDH is also tissue-specic and subject to considerable species variation, being conned exclusively to the liver and intestinal mucosa in humans and pigs only (Scriver et al., 1995). By contrast, it is ubiquitously distributed in rodents, dogs, cats and bovine species, while camels appear to lack XDH activity. Uric acid is the end-product of purine nucleotide catabolism only in humans, birds and some reptiles. Most mammalian species possess the enzyme uricase, which converts the insoluble uric acid to the more soluble allantoin. Although humans possess the gene for uricase the enzyme is not expressed (Scriver et al., 1995).
thence hypoxanthine. Thus, the cycle in the human heart involves the interconversion of AMP and adenosine and is geared to providing a rapid bolus of adenosine in times of hypoxia. Studies of ATP catabolism in human brain are scanty, but the brain is exquisitely sensitive to changes in ATP as well as oxygen supply. Brain has unusually high ATP requirements for both protein and nucleoprotein synthesis. This would involve a considerable turnover of both ATP and GTP. As in heart the Km for AMPDA is high. Changes in membrane lipid composition, induced by ageing or pathology, might thus inuence cellular metabolism by controlling the ow of adenine nucleotide metabolites toward adenosine production. By contrast, the kidney appears to combine elements of ATP degradation present in both skeletal and heart muscle, but the adenosine released when controls on AMPDA favour degradation via 5-nucleotidase acts as a vasoconstrictor, not a vasodilator (Stone and Simmonds, 1991). In liver, the nucleotide prole is much more complex than in muscle, undoubtedly due to the diverse synthetic and detoxifying functions. Knowledge of purine degradative pathways derives principally from fructose-loading studies, where rapid utilization of inorganic phosphate (Pi), results in GTP and Pi depletion, both potent inhibitors of liver AMPDA. ATP concentrations suer a 10-fold reduction, degradation occurring via AMPDA, not ADA. The fact that liver does not contain signicant amounts of fast mobilizable energy in the form of creatine phosphate, coupled with the high XDH activity, can result in the irretrievable loss of ATP as uric acid under appropriate conditions. Since most other human tissues lack XDH, there is normally very little loss of purines to the body as uric acid, as already discussed.
Nucleotide Degradation
enzymes essential to lymphocyte proliferation and apoptosis ensues (Stone and Simmonds, 1991). The companion T lymphocyte disorder, PNP deciency, has underlined the importance of PNP, as well as ADA, in degrading toxic DNA waste (Figure 5). PNP deciency generally presents rst with neurological abnormalities, similar to those in severe hypoxanthineguanine phosphoribosyltransferase (HPRT) deciency (Scriver et al., 1995). This nding highlights the importance of HPRT to the human brain, for although HPRT is not defective it cannot function without the substrates (hypoxanthine, guanine) normally provided by PNP. Interestingly, successful bone marrow transplantation has corrected the immunological problems in PNP deciency, but not the neurological abnormalities (Carpenter et al., 1996). Thus correction of the latter in both PNP and HPRT deciency will require strategies to deliver the enzyme directly to the brain. Deciency of XDH was the rst defect reported in humans (Scriver et al., 1995). Clinical problems (predominantly renal) relate solely to the insolubility of this metabolic waste. Classical xanthinuria results either from an isolated deciency of XDH type 1, or type 11. The latter is due to a deciency of both XDH and aldehyde oxidase (AOX; EC 1.2.3.1). AOX is considered to have arisen from XDH by gene duplication. These two enzymes, as well as sulphite oxidase (SO; EC 1.8.2.1) are non-functional in molybdenum cofactor deciency, when the clinical features of SO deciency overshadow those of XDH deciency. Presentation with neonatal tting, ocular lens dislocation and death in the rst year is common (Scriver et al., 1995). However, for all the above disorders there is considerable heterogeneity in clinical expression, both within and between families, and late presentation is not infrequent.
basis for XDH2 is undened. The MOCS1 gene (molybdenum cofactor synthesis, step 1) is unusual in that alternative open reading frames direct the synthesis of two dierent proteins from the same mRNA. Mutations aecting the function of either protein result in molybdenum cofactor deciency.
Nucleotide Degradation
reversible also, the in vivo concentration of (2-deoxy)ribose 1-phosphate is too low for it to proceed (Figure 1). Thymidine can be degraded to thymine by a specic thymidine phosphorylase (EC 2.4.2.4) which in humans only seems to be present in platelets and macrophages. Such cell-specic dierence can be used advantageously (e.g. to treat viral infections such as human immunodeciency virus (HIV) with pyrimidine analogues).
(Scriver et al., 1999). Defects of the rst three enzymes (DPD, DHP and UP), shared by uracil and thymine, present with a variable clinical picture comprising seizures, psychomotor retardation, microcephaly, dysmorphic features, growth retardation and ocular abnormalities (Van Gennip et al., 1997). DPD, DHP and UP deciency all lead to reduced concentrations of the neurotransmitter balanine. The one reported case with a complete deciency of BAKAT suered from hypotonia, hyporeexia, generalized tonic clonic seizures, intermittent lethargy and died in infancy. A deciency of this enzyme leads to accumulation of b-alanine. Partial deciency of BAKAT (50% of normal) leading to hyper-b-alaninaemia is associated with Cohen syndrome. A deciency of BAIBPAT in liver has been proposed as the cause of permanent hyper-b-aminoisobutyric aciduria. This genetically determined phenomenon is thought to be a benign polymorphism. Deciency of BAPAT has not yet been discovered in humans (Van Gennip et al., 1997).
What Can We Learn from Genetic Metabolic Defects of Purine and Pyrimidine Metabolism?
Defects of enzymes catalysing purine and pyrimidine nucleotides provide a valuable insight into the
Nucleotide Degradation
tissue-specic function of a particular enzyme. The broad spectrum of presentation, involving the immunological, haematological, neurological or renal systems also highlights the importance of particular steps to the integrated functioning of this network in humans. The altered concentrations of b-alanine resulting from the pyrimidine degradation defects may be of relevance with regard to understanding the cerebral dysfunction often seen in patients with these defects. The neurotransmitter b-alanine is a structural analogue of glycine and GABA (gaminobutyric acid), the major inhibitory neurotransmitters of the central nervous system (Van Kuilenberg et al., 1999). Thus altered levels might have a profound eect on the activation of glycine and GABA receptors as well as glial transport into glial cells, as has been demonstrated in chick spinal cord neurons and mouse brain. Both purine and pyrimidine enzyme defects can also be the cause of catastrophic responses to antimetabolite therapy (Scriver et al., 1995, 2000). Examples are deciencies in thiopurine methyltransferase (TPMT; EC 2.1.1.67) and XDH which provide alternative degradative routes for thiopurine analogues. Polymorphism for TPMT deciency occurs in 11% of caucasians. Deciency will thus increase the eective therapeutic dose, leading to lifethreatening bone marrow depression, even in TPMT carriers. Severe neurotoxicity due to 5-uorouracil (5FU), which may result from exposure of the nervous system to relatively high concentrations of 5-FU, leading to increased incorporation into cellular RNA, can also occur in individuals with less than 30% of normal DPD activity. Depletion of b-alanine by 5-FU acting as competitive substrate in partial DPD deciency may also contribute to this condition (Scriver et al., 1999). Similarly, although not yet reported, increased sensitivity to 5-FU may be expected in DHP deciency.
Furthermore, these pathways, and controls on them, can be very dierent in malignant cells, as well as varying greatly between humans and other mammals. Inborn errors of purine and pyrimidine metabolism have provided valuable insight into the relative importance of these pathways and their diering controls.
References
Carpenter PA, Ziegler JB and Vowels MR (1996) Late diagnosis of purine nucleoside phosphorylase deciency with allogeneic bone marrow transplantation. Bone Marrow Transplantation 17: 121124. De Korte D, Van Doorn CCH, Sijstermans JMJ, Van Gennip AH and Roos D (1989) Deciency of pyrimidine 5-nucleotidase in human leukocytes. Journal of Inherited Metabolic Disorders 12: 267272. Gross M (1997) Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deciency. Journal of Inherited Metabolic Disorders 20: 186192. Hamajima N, Kouwaki M, Vreken P et al. (1998) Dihydropyrimidinase deciency: structural organisation, chromosomal localization and mutation analysis of the human dihydropyrimidinase gene. American Journal of Human Genetics 63: 717726. McKusick VA (1998) Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders, 12th edn. Baltimore: Johns Hopkins University Press. Paglia DE, Valentine WN and Brockway RA (1984) Identication of thymidine nucleotidase and deoxyribonucleotidase activities among normal isoenzymes of 5-nucleotidase in human erythrocytes. Proceedings of the National Academy of Sciences of the USA 81: 588592. Scriver CR, Beaudet AL, Sly WS and Valle D (eds) (1995) The Metabolic and Molecular Basis of Inherited Disease, 7th edn, vol. II, chaps 4955, Purines and pyrimidines, pp. 16551940. New York: McGraw-Hill. Scriver CR, Beaudet AL, Sly WS et al. (eds) (2000) The Metabolic and Molecular Basis of Inherited Disease, 8th edn, Purines and pyrimidines. New York: McGraw-Hill. (In press). Stone TW and Simmonds HA (1991) Purines: Basic and Clinical Aspects. London: Kluwer. Van Gennip AH, Abeling NGGM, Vreken P and Van Kuilenburg ABP (1997) Inborn errors of pyrimidine degradation: clinical biochemical and molecular aspects. Journal of Inherited Metabolic Diseases 20: 203213. Van Kuilenburg ABP, Vreken P, Abeling NGGM et al. (1999) Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deciency. Human Genetics 104: 19.
Summary
Nucleotide degradation is part of an integrated network which ensures that the component base or nucleoside is recycled, thereby sparing nucleotide synthesis via the de novo route. A considerable amount of ATP and to a lesser extent GTP, DNA and RNA is turned over daily, but only a small fraction of this is lost to the body as uric acid or amino acids in humans. Although multiple pathways for nucleotide degradation exist in all species, only some of these may be functional in a particular cell type.
Further Reading
Henderson JF and Paterson ARP (1973) Nucleotide Metabolism: An Introduction. New York: Academic Press. Simmonds HA (1994) Purine and pyrimidine disorders. In: Holton JB (ed.) The Inherited Metabolic Diseases, chap. 6, pp. 297330. Edinburgh: Churchill Livingstone.