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Adenosine Kinase
Yuno Lee
What is adenosine?
• Adenosine is a nucleoside
comprised of adenine attached to a
ribose (ribofuranose) moiety via a βN9-glycosidic bond.
• Adenosine plays an important role in
biochemical processes, such as
energy transfer - as adenosine
triphosphate (ATP) and adenosine
diphosphate (ADP) - as well as in
signal transduction as cyclic
adenosine monophosphate, cAMP.
• If adenine is attached to a
deoxyribose ring, it is known as a
deoxyadenosine.
Adenosine: an endogenous
regulator of innate immunity
• Although inflammatory and immunological reactions protect
the host from invasion by microorganisms and eliminate
debris at sites of tissue injury, they can also be responsible
for significant tissue damage.
• Thus, regulatory mechanisms that limit damage from an
overly exuberant immune response have evolved.
• It is increasingly apparent that adenosine, a purine
nucleoside that is elaborated at injured and inflamed sites,
has a central role in the regulation of inflammatory
responses and in limiting inflammatory tissue destruction.
What is adenosine?
• Adenosine (ADO) is an extracellular signaling agent within
the central and peripheral nervous system.1
• Adenosine is an endogenous purine nucleoside that,
following its release from cells or after being formed
extracellularly, diffuses to the cell membrane of surrounding
cells where it binds specific cell-surface structures that
recognize it, termed adenosine receptors.2,3
What is adenosine receptor?
• There are four types of adenosine receptor, all of which are
members of the G protein-coupled family of receptors 3
• The genes for these receptors have been analyzed in detail
and they are designated A1, A2A, A2B and A3.4
• Activation of ADO receptors produces a variety of
homeostatic inhibitory cellular events that contribute to antinociceptive and anti-inflammatory actions in vivo.5
Adenosine of
under adverse conditions
• Under adverse conditions (e.g., pain, inflammation, tissue
damage, etc.), the local tissue levels of extracellular ADO are
markedly increased.6
• Strong evidence suggests that this protective pathway is
involved in pathological processes including neurodegeneration,
seizures, ischemia, inflammation and pain.7
What is adenosine kinase(AK)?
• Adenosine kinase (AK) is a ubiquitous intracellular enzyme,
which catalyzes the phosphorylation of adenosine(ADO) to
adenosine monophosphate, and therefore is a key enzyme
in the control of cellular concentrations of ADO.8
• It rapidly phosphorylates ADO, maintaining intracellular ADO
concentrations at low levels.9
• Because ADO uptake is driven by its concentration gradient,
AK inhibition reduces the cellular uptake of ADO, thus
potentiating the local concentration of ADO in the
extracellular compartment.9
Inhibition of AK
• Therefore, AK inhibition can enhance the release of
endogenous ADO to the extracellular space thus benefiting
from anti-nociceptive and anti-inflammatory actions of ADO.
• We can approach to treatment of pain and inflammation by
AK inhibition.
• AK inhibitors may have therapeutic potential as analgesic
and anti-inflammatory agents.
Interaction of adenosine receptor signaling and pattern
recognition receptor transduction pathways in APCs
•
Antigen-presenting cells (APCs) are equipped with adenosine receptors,
which on occupation regulate APC function. Adenosine receptor (AR)
occupancy signals through alterations of intracellular cyclic AMP and Ca2+
concentrations and activation of the mitogen-activated protein kinases p38
and p42/44.
•
AR occupancy on monocytes and macrophages diminishes production of
the proinflammatory mediators interleukin-12 (IL-12), tumor necrosis factorα (TNF-α), macrophage inflammatory protein-1α (MIP-1α), and nitric oxide
while augmenting secretion of the anti-inflammatory cytokine IL-10 and
vascular endothelial growth factor (VEGF).
•
Adenosine receptor ligation stimulates the chemotaxis of immature dendritic
cells (DCs).
•
Adenosine acting on A2a receptors suppresses IL-12 production by mature
DCs leading to diminished Th1- versus Th2-cell development.
References
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1. Ralevic, V.; Burnstock, G. Pharmacol. Rev. 1998, 50, 413; Williams, M.; Jarvis, M.
Biochem. Pharmacol. 2000, 59,1173.
2. V. Ralevic and G. Burnstock, Receptors for purines and pyrimidines. Pharmacol.
Rev. 50 (1998), pp. 413–492.
3. B.B. Fredholm et al., International union of pharmacology. XXV. Nomenclature and
classification of adenosine receptors. Pharmacol. Rev. 53 (2001), pp. 527–552.
4. Gyorgy Hasko and Bruce N. Cronstein, Adenosine: an endogenous regulator of
innate immunity. TRENDS in Immunology Vol.25 No.1 January 2004, 33-39.
5. Jarvis, M. F. Rev. Analgesia 2003, 7, 1.
6. Burnstock, G. Purinergic nerves. Pharmacol. Rev. 1972, 24, 509-581.
7. Kowaluk, E. A.; Bhagwat, S. S.; Jarvis, F. J. Current Pharm. Design 1998, 4, 404.
8. Richard J. Perner, Chih-Hung Lee, Meiqun Jiang, Yu-Gui Gu, Stanley DiDomenico,
Erol K. Bayburt, Karen M. Alexander, Kathy L. Kohlhaas, Michael F. Jarvis, Elizabeth L.
Kowaluk and Shripad S. Bhagwat. Synthesis and biological evaluation of 6,7disubstituted 4-aminopyrido[2,3-d]pyrimidines as adenosine kinase inhibitors.
Bioorganic & Medicinal Chemistry Letters 15 (2005) 2803-2807
9. Arthur Gomtsyan, Stanley Didomenico, Chih-Hung Lee, Mark A. Matulenko, Ki Kim,
Elizabeth A. Kowaluk, Carol T. Wismer, Joe Mikusa, Haixia Yu, Kathy Kohlhaas,
Michael F. Jarvis, and Shripad S. Bhagwat. Design, Synthesis, and Structure-Activity
Relationship of 6-Alkynylpyrimidines as Potent Adenosine Kinase Inhibitors. J. Med.
Chem. 2002, 45, 3639-3648