Adv Physiol Educ 35: 342–346, 2011;
doi:10.1152/advan.00068.2011.
Staying Current
Origin, utilization, and recycling of nucleosides in the central nervous system
Piero Luigi Ipata
Dipartimento di Biologia, Unità di Biochimica, Università di Pisa, Pisa, Italy
Submitted 14 July 2011; accepted in final form 6 October 2011
is unique among other organs in the extent to which the rates
of preformed NS anabolic and catabolic reactions modulate the
synthesis of RNA and DNA precursors, purine and pyrimidine
signaling molecules, and phosphatides, the main constituents
of synaptic membranes.
ectonucleosides; purine salvage; pyrimidine salvage; nucleotide release; purine and pyrimidine receptors
The release of nucleotides from brain cells. For most of the
last century, research on brain purines and pyrimidines was
mainly focused on their intracellular metabolism. New insights
into the importance of extracellular nucleotide and NS metabolism followed the recognition that ATP and Ado act as
extracellular signals. Extracellular ATP was identified as a
cotransmitter in sympathetic and parasymphatetic nerves in
1976 (5). Since then, there has been an ever-increasing stream
of new ideas and information related to the purinergic receptor
proteins (1, 6, 7) and to extracellular ATP metabolism in the
peripheral nervous system and CNS (3, 31, 32). After exocytotic neuronal vesicular release, ATP interacts with P2X receptor subtypes and exerts a robust excitatory and neuromodulator action (6, 7). There is also evidence for the vesicular
release of ATP from astrocytes (22, 23).
The existence of a plasma membrane pyrimidine-activated
receptor was first proposed in 1989 (27), and a direct demonstration of cellular release of UTP was provided by Lazarowski et al. (18) in 1997. To date, it is well established
that UTP, UDP, and Urd diphosphoglucose have important
signaling roles in the CNS via interactions with P2Y receptor subtypes (19).
Purine and pyrimidine signaling molecules are present in
vesicles, where the concentrations of ATP (⬃100 mM) and
UTP (⬃8 mM) are much higher than in the surrounding
cytoplasm (31). After the release of a single vesicle, the local
extracellular concentration of ATP lies in the range of 5–500
␮M, well above the limit for P2X receptor activation.
The extracellular breakdown of nucleotides in the brain. The
actions of ATP and UTP at their respective receptors are
THE BRAIN requires a continuous supply of preformed purine
and pyrimidine rings, mainly in the form of nucleosides (NSs),
to maintain its nucleotide pool in the proper qualitative and
quantitative balance (15). Adenosine (Ado), guanosine (Guo),
uridine (Urd), and cytidine (Cyd), the four main natural NSs,
can enter the brain through the blood-brain barrier (24). Alternatively, they can be locally produced in central nervous
system (CNS) from their respective NS triphosphates (NTPs)
by an enzyme cascade system that consists of a series of
ectonucleotidases located in the plasma membrane with their
active sites oriented toward the extracellular space (31, 32).
The products of the ectonucleotidases are then transported into
the brain cytosol via the concentrative NS transporter (CNT)
system and the equilibrative NS transporter (ENT) system (24).
An important source of extracellular NTPs is from synaptic
release (1, 32). The present article focuses on these aspects of
brain metabolism, with an emphasis on the cross talk between
intra- and extracellular metabolic networks. This topic is not
generally available in most textbooks. This article aims to
provide the key teaching concepts to be included in a two- to
three-lesson block based on recent information as well as on
traditional knowledge. Students should be aware that the brain
Address for reprint requests and other correspondence: P. L. Ipata, Dept. of
Biology, Unit of Biochemistry, Via San Zeno 51, Pisa 56127, Italy (e-mail:
[email protected]).
342
The Origin of Brain NSs
The brain has a very limited capacity of de novo synthesis of
purines and pyrimidines rings and relies on preformed NSs for
the synthesis of NTPs. NSs are actively synthesized de novo
from simple precursors in the liver and enter the brain through
the blood-brain barrier (Fig. 1). The final products of the de
novo pathway are nucleotides (21). NSs are not intermediates;
thus, cytosolic 5=-nucleotidases play a major role in NS generation in the liver. The liver possesses the entire set of
enzymes for NS degradation (21). It is conceivable that the
balance between the rates of synthesis and degradation and the
export into the bloodstream have a central role in maintaining
the homeostasis of circulating NSs to meet the requirement for
NTPs in the brain.
Extracellular NS Metabolism in the Brain
1043-4046/11 Copyright © 2011 The American Physiological Society
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Ipata PL. Origin, utilization, and recycling of nucleosides in the
central nervous system. Adv Physiol Educ 35: 342–346, 2011;
doi:10.1152/advan.00068.2011.—The brain relies on the salvage of
preformed purine and pyrimidine rings, mainly in the form of nucleosides, to maintain its nucleotide pool in the proper qualitative and
quantitative balance. The transport of nucleosides from blood into
neurons and glia is considered to be an essential prerequisite to enter
their metabolic utilization in the brain. Recent lines of evidence have
also suggested that local extracellular nucleoside triphosphate (NTP)
degradation may contribute to brain nucleosides. Plasma membranelocated ectonucleotidases, with their active sites oriented toward the
extracellular space, catalyze the successive hydrolysis of NTPs to
their respective nucleosides. Apart from the well-established modulation of ATP, ADP, adenosine (the purinergic agonists), UTP, and
UDP (the pyrimidinergic agonists) availability at their respective
receptors, ectonucleotidases may also serve the local reutilization of
nucleosides in the brain. After their production in the extracellular
space by the ectonucleotidase system, nucleosides are transported into
neurons and glia and converted back to NTPs via a set of purine and
pyrimidine salvage enzymes. Finally, nucleotides are transported into
brain cell vescicles or granules and released back into the extracellular
space. The key teaching concepts to be included in a two-to threelecture block on the molecular mechanisms of the local nucleoside
recycling process, based on a cross talk between the brain extracellular space and cytosol, are discussed in this article.
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343
terminated by rapid degradation, catalyzed by the ectonucleotidases (3, 32) (reactions 5– 8 in Fig. 2 and reactions 4 –7 in
Fig. 3). The ectonucleotidase enzyme chain includes ecto-NTP
diphosphohydrolase: ATP (UTP) ¡ ADP (UDP) ⫹ Pi or ADP
(UDP) ¡ AMP (UMP) ⫹ Pi, ecto-nucleotide pyrophosphatase/phosphodiesterase: (ATP) (UTP) ¡ AMP (UMP) ⫹ 2 Pi,
and ecto-5=-nucleotidase: (AMP) (UMP) ¡ Ado (Urd) ⫹ Pi.
The final product of the ectonucleotidase chain generally is the
NS (32). P1 receptor-mediated actions of Ado in inflammation,
sleep, memory, cognition, and ischemic injury have been
recognized for many years (9, 11, 17). No receptors for Urd
have been identified yet, but there is compelling evidence that
Urd is transported into neurons and astrocytes, where it plays
an essential role as a precursor of brain UTP, Urd diphosphoglucose, CTP, CDP-choline, and membrane phosphatides (8,
10, 19, 25, 30). In addition to ATP and UTP, other nucleotides,
such as GTP, GDP, GMP, inosine (Ino) monophosphate (IMP),
and possibly CTP, are stored in vesicles (31). Specific binding
sites for GTP (12) and Guo (29), two neurotrophic purines
(26), have been identified on the plasma membrane of cultured
neuronal cell models. Finally, no specific receptors have been
identified for Cyt and CTP. Nevertheless, CTP undergoes
successive extracellular dephosphorylation steps in the extracellular space and produces Cyt with the same temporal patterns of the sequential production of extracellular NS diphosphates (NDPs), NS monophosphates (NMPs), and NSs observed when ATP, UTP, and GTP were used as substrates of
the ectonucleotidase chain (3, 13, 14).
NS Transport in the Brain
A major function of ENT and CNT proteins is to control the
concentrations of NSs in the brain to maintain the qualitative
and quantitative balance of NTP pools for the stability of
genetic information and to regulate the trophic functions of
NSs.
The ENT proteins mediate the transport of NSs bidirectionally, depending on the concentration gradient across the plasma
membrane (15, 24). The Km values of ENT1 and ENT2, the
two major ENT proteins, are between 100 and 800 ␮M. Most
likely, they mediate the inwardly directed transport only when
NSs exceed their normal levels, e.g., when their concentrations
have been elevated experimentally or when NS derivatives are
administered and activated by antiviral or antitumoral drugs
inside the cells by the same enzymes of NS metabolism. CNT2,
a member of the family of Na⫹-dependent, high-affinity CNT
proteins, mediates the inwardly directed transport of Ado, Ino,
Guo, Urd, and Cyt. Most likely, CNT2 modulates the transport
of NSs under physiological conditions, because its Km value
for NSs is in the low micromolar range (9 – 40 ␮M) and plasma
levels of most NSs are subsaturating (⬃3–5 ␮M) (28). Moreover, Cyt is transported less efficiently than Urd (8). Hence, in
humans and laboratory rats, the major precursor of brain CTP
is Urd, not Cyt (Fig. 3).
Cytosolic NS Utilization in the Brain
The specificity and regulatory properties of brain NS
kinases. Two cytosolic NS kinases, Ado kinase (AdoK; reaction 3 in Fig. 2) and Urd kinase (UrdK; reaction 1 in Fig. 3),
have a high specificity for Ado and deoxyadenosine and for
Urd and Cyt, respectively. The Km value for Ado of AdoK is
⬃0.2 ␮M; thus, the kinase becomes saturated with Ado at a
low micromolar concentration and phosphorylates Ado at its
Vmax. Any excess Ado is irreversible deaminated to Ino by Ado
deaminase (AdoD; reaction 1 in Fig. 2), whose Km value for
Ado is ⬃50 ␮M. It may be speculated that brain Ado is
maintained at the lowest micromolar level among the NSs (16)
by the extent to which AdoK and AdoD are saturated by Ado,
their common substrate.
Guo and Ino are not directly phosphorylated to their respective NMPs because of the absence of kinases for the two NSs
in mammals. They undergo prior phosphorolysis to guanine
and hypoxanthine, respectively, before being anabolyzed to
their respective NMPs via phosphoribosyl pyrophosphate
(PRPP), requiring hypoxanthine-guanine phosphoribosyltrans-
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Fig. 1. The origin of brain nucleosides (NSs). The
brain relies on circulating preformed NSs to satisfy its
energy demand and to synthesize nucleic acids, lipid
and sugar conjugates, and extracellular purine and
pyrimidine signaling molecules. The dephosphorylation of NS monophosphates (NMPs), synyhesized de
novo in the liver, is the main source of brain NSs.
Once taken up from the blood into the brain cells, NSs
are salvaged to their respective ribonucleoside
triphosphates via three successive phosphorylation
steps. NSs may generate ribose-1-phosphate (Rib1P), a precursor of phosphoribosyl pyrophosphate
(PRPP), for the salvage synthesis of purine bases.
NDP, NS diphosphate; NTP, NS triphosphate.
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RECYCLING OF NUCLEOSIDES IN THE BRAIN
ferase (reactions 2, 9, and 12 in Fig. 2). Subsequently, NMPs
are further phosphorylated by AMP-specific adenylate kinase
(reaction 4 in Fig. 2) and by NMP kinase, specific for UMP,
CMP (reaction 2 in Fig. 3), and GMP (reaction 13 in Fig. 2).
IMP is not further phosphorylated in the brain cytosol (4). NDP
kinase generates UTP, CTP, and GTP from their respective
NDPs. ATP, the most abundant NTP in the brain (⬃4 mM), is
generated by mitochondrial oxidative phosphorylation of ADP.
The concentration of the other NTPs is ⬃1/10th that of ATP
(28). Brain Urd homeostasis is maintained by the relative rates
of its phosphorylation and phosphorolysis, catalyzed by UrdK
and Urd phosphorylase, the major entry steps in pyrymidine
salvage synthesis and catabolism, respectively (reactions 1 and
9 in Fig. 3). (2, 25). UrdK is competitively inhibited by UTP
and CTP, the final products of the pyrimidine salvage pathway.
Thus, at relatively low UTP and CTP levels, Urd is mainly
anabolyzed to Urd nucleotides, whereas at relatively high UTP
and CTP levels, Urd is mainly catabolyzes to uracil and
ribose-1-phosphate. The sugar phosphate is then transformed
into PRPP, which is used for the salvage of adenine, guanine,
and hypoxanthine. The UrdK-uridine phosphorylase system
might cross regulate the two processes of pyrimidine and
purine salvage synthesis in a district where the de novo
synthesis is lacking (2).
The transport of NSs, synthesized de novo in the liver, from
blood into neurons and glia is an essential prerequisite to enter
their metabolic utilization in the brain (Fig. 1). However, the
interrelated processes of NTP release into the brain extracellular space, NTP breakdown by the ectonucleotidase enzyme
chain, NS transport into brain cells, and cytosolic NS anabolism strongly suggest that, apart from the modulation of ligand
availability at nucleotide and NS receptors, the four processes
may also serve the recycling of NSs in the brain. The path of
NS recycling may be summarized as follows: NS (intracellular)
¡ ¡ ¡ NTP (intracellular) ¡ NTP (extracellular) ¡ ¡ ¡
NS (extracellular) ¡ NS (intracellular) (14). As shown in Fig.
2, Ado recycling requires the expenditure of three ATP molecules (reactions 3–5 in Fig. 2), and Urd and Cyt recycling
require the expenditure of three ATP molecules each (reactions
1–3 in Fig. 3). Guo recycling requires four ATP molecules
(reactions 9 and 12–14 in Fig. 2) because the synthesis of
PRPP from ribose-5-phosphate and ATP (reaction 11 in Fig.
2), needed for the salvage synthesis of GMP, generates an
AMP molecule rather than an ADP molecule. We recall that no
Guo kinase exists in mammals. It may be speculated that under
normal aerobic conditions, imported cytosolic NSs are mainly
anabolyzed to NTPs rather than being catabolyzed or exported
from brain cells, whereas NTPs are mainly catabolyzed in the
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Fig. 2. Metabolic interplay between extracellular NS production via purine nucleotide breakdown and intracelluar NS salvage leading to ATP-driven purine NS
recycling. Cytosolic vesicular ATP and GTP are released into the extracellular space and broken down to adenosine (Ado) and guanosine (Guo), respectively,
via ectonucleotidases. Ado, once taken up, is phosphorylated at its 5= position via Ado kinase. The AMP product is phosphorylated by adenylate kinase. Any
excess Ado is deaminated by Ado deaminase. Guo, once taken up, is salvaged as guanine (Gn) via PRPP-mediated hypoxanthine (Hyp) phosphoriosyl transferase.
Two relatively specific kinases, NS monophosphokinase and NS diphosphokinase, catalyze the successive phosphorylation of GMP to GTP. Reactions are as
follows: Ado deaminase (1), purine NS phosphorylase (2), Ado kinase (3), adenylate kinase (4), ecto-NTP diphosphohydrolase (5 and 7), ecto-NS
pyrophosphatase diphosphohydrolase (6), ecto-5=-NS (8), purine NS phosphorylase (9), phosphoribomutase (10), PRPP synthethase (11), Hyp phosphoribosyltransferase (12), NS monophosphokinase (13), and NS diphosphokinase (14). Membrane-bound ectonucleotidases and catalyzed reactions are indicated by filled
circles and triangles (ecto-NTP diphosphohydrolase), filled squares (ecto-NS pyrophosphatase diphosphohydrolase), and filled diamonds (ecto-5=-NS). Cylinders
represent the NS transporters [the concentrative NS transporter (CNT) or equilibrative NS transporter (ENT)]. The arrows indicating the movement of the
nucleotides from inside the cell to outside the cell represent vesicular release. Rib 5-P, ribose-5-phosphate; Ino, inosine; IMP, Ino monophosphate.
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345
extracellular space. In the hypoxic/ischemic brain, the low
ATP level would cause NS accumulation, thus favoring the
capacity of the brain to achieve reperfusion/recovery of lost
nucleotides.
AUTHOR CONTRIBUTIONS
General Conclusions
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It is safe to state that a cross talk exists between the
extracellular and intracellular metabolism of purine and pyrimidine NSs in the brain. The extracellular space is the major site
of brain NS production through successive dephosphorylations
of released NTPs, whereas the brain cytosol is the major site of
uptaken NS anabolism to NTPs through successive phosphorylation steps. This NS recycling process has an important role
in the CNS, since the brain maintains its nucleotide pools in the
proper qualitative and quantitative balance by salvaging preformed purine and pyrimidine rings, mainly in the form of NSs
(15). The local recycling of NSs allows their immediate reutilization without NS outflow into the bloodstream, thus avoiding the dilution of NSs, with a considerable spatial-temporal
advantage. Finally, students should be aware that dysfunctional
NS metabolism has been implicated in the etiopatology of a
wide spectrum of neurological, neurodegenerative, and neuropsychiatric disorders (20).
GRANTS
This work was supported by a grant from the Italian Ministero
dell’Istruzione, dell’Università e della Ricerca (National Interest Project:
“Mechanism of cellular and metabolic regulation of polynucleotides, nucleotides, and analogs”).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
P.L.I., performed the experiments; P.L.I., analyzed the data; P.L.I., edited
and revised the manuscript.
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Fig. 3. Metabolic interplay between extracellular NS production via pyrimidine nucleotide
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