Mice reveal the off switch for inflammation - Science News of the week - role of adenosine in fighting inflammation - Brief Article J. Travis
Working with genetically engineered mice, scientists have identified a crucial natural mechanism that rodents, and presumably people, use to shut down inflammation before it does harm.
The discovery may suggest both new types of anti-inflammatory treatments and ways to promote inflammation when it's desired. The finding also raises the possibility that caffeine-laden drinks may interfere with this switch.
Inflammation is a double-edged sword, notes Michail Sitkovsky of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Md. Chemicals and immune cells that produce inflammation protect a body from infection. Endless or misdirected inflammation, however, can interfere with wound healing and promote heart disease and autoimmune disorders such as arthritis.
The new report centers on a nitrogen-containing molecule called adenosine, which the body uses to store energy. Buildup of adenosine in the brain may also trigger sleepiness (SN: 5/24/97, p. 316).
For more than a decade, some researchers have suggested that adenosine has anti-inflammatory powers. Consider the rheumatoid arthritis drug methotrexate. Bruce Cronstein of New York University School of Medicine and his colleagues established years ago that methotrexate thwarts inflammation by triggering the release of adenosine.
In the Dec. 20/27 NATURE, Sitkovsky and his NIAID colleague Akio Ohta report determining which of the body's several adenosine receptors--the cell-surface proteins that recognize the molecule--is essential to adenosine's role in inflammation. By mutating the rodent gene for the so-called A2a receptor, the biologists created mice unable to limit inflammation in a variety of situations.
In one case, they gave the mutant mice and normal mice a drug that triggers inflammation in the liver. The normal mice developed little organ damage, but the mutant mice didn't turn off the induced inflammation and suffered extensive, sometimes fatal, liver damage. Similarly, the mutant mice couldn't dampen their inflammatory response when they were injected with pieces of the bacteria that trigger the dangerous disease sepsis.
"We proposed a long time ago that adenosine that comes out of injured, dying, or dead tissue can turn off inflammation, and [Sitkovsky] has shown the specific receptor involved in that," says Cronstein.
There may be many ways to control inflammation, but they may all converge on this pathway, suggests Michael Yeadon of Pfizer in Sandwich, England.
Companies such as Pfizer are investigating whether drugs that activate the A2a adenosine receptor can thwart inflammation. A major concern, however, is that such drugs may have dangerous side effects because adenosine also regulates blood pressure via this receptor.
As a result, Pfizer is initially developing adenosine-receptor drugs as topical agents for direct application to sites of inflammation. People with inflammatory diseases of the skin, eyes, and lungs might benefit from such drugs, says Yeadon.
Sitkovsky notes that caffeine's stimulant properties stem from its ability to block adenosine's action. He suggests that people suffering from short-term inflammation may prolong their condition by drinking coffee and tea that contain caffeine.
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Adenosine is a nucleoside comprised of adenine attached to a ribose (ribofuranose) moiety via a β-N9-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. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal, with levels increasing with each hour an organism is awake.
Contents [hide] 1 Pharmacological effects 1.1 Anti-inflammatory Properties 1.2 Action on the heart 1.3 Dosage 1.4 Drug Interactions 1.5 Contraindications 1.6 Side effects 2 Metabolism 3 See also 4 External links
[edit] Pharmacological effects Adenosine is an endogenous purine nucleoside that modulates many physiologic processes. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes (A1, A2A, A2B, and A3), all of which are seven transmembrane spanning G-protein coupled receptors. These four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity. The A2A and A2B receptors couple to Gάs and mediate the stimulation of adenylate cyclase, while the A1 and A3 adenosine receptors couple to Gάi which inhibits adenylate cyclase activity. Additionally, A1 receptors couple to Gάo, which has been reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and A3 receptors also couple to Gάq and stimulate phospholipase activity. Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g. in inflammatory or ischemic tissue), these concentrations are quickly elevated (600-1,200 nM). Thus, in regards to stress or injury, the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of hypoxia, ischemia, and seizure activity. Activation of A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory.
[edit] Anti-inflammatory Properties Adenosine is a potent anti-inflammatory agent, acting at its four G-protein coupled receptors. Topical treatment of adenosine to foot wounds in diabetes mellitus has been shown in lab animals to drastically increase tissue repair and reconstruction. Topical administration of adenosine for use in wound healing deficiencies and diabetes mellitus in humans is currently under clinical investigation.
[edit] Action on the heart When administered intravenously, adenosine causes transient heart block in the AV node. This is mediated via the A1 receptor, inhibiting adenyl cyclase, reducing cAMP and so causing cell hyperpolarisation by increasing outward K+ flux. It also causes endothelial dependent relaxation of smooth muscle as is found inside the artery walls. This causes dilatation of the "normal" segments of arteries where the endothelium is not separated from the tunica media by atherosclerotic plaque. This feature allows physicians to use adenosine to test for blockages in the coronary arteries, by exaggerating the difference between the normal and abnormal segments.
In individuals suspected of suffering from a supraventricular tachycardia (SVT), adenosine is used to help identify the rhythm. Certain SVTs can be successfully terminated with adenosine. This includes any re-entrant arrhythmias that require the AV node for the re-entry (e.g., AV reentrant tachycardia (AVRT), AV nodal reentrant tachycardia (AVNRT). In addition, atrial tachycardia can sometimes be terminated with adenosine.
Adenosine has an indirect effect on atrial tissue causing a shortening of the refractory period. When administered via a central lumen catheter, adenosine has been shown to initiate atrial fibrillation because of its effect on atrial tissue. In individuals with accessory pathways, the onset of atrial fibrillation can lead to a life threatening ventricular fibrillation.
Fast rhythms of the heart that are confined to the atria (e.g., atrial fibrillation, atrial flutter) or ventricles (e.g., monomorphic ventricular tachycardia) and do not involve the AV node as part of the re-entrant circuit are not typically converted by adenosine, however the ventricular response rate will be temporarily slowed.
Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class V antiarrhythmic agent. When adenosine is used to cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular asystole for a few seconds. This can be very disconcerting to a normally conscious patient, and is associated with very unpleasant sensations in the chest.
Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain. They are presented here side by side for comparison.The pharmacological effects of adenosine may be blunted in individuals who are taking large quantities of methylxanthines (e.g., caffeine (found in coffee) and theophylline (found predominantly in tea)).
Caffeine's stimulatory effects are primarily (although not entirely) credited to its inhibition of adenosine by binding to the same receptors. By nature of caffeine's purine structure it binds to some of the same receptors as adenosine, effectively blocking adenosine receptors in the central nervous system. This reduction in adenosine activity leads to increased activity of the neurotransmitters dopamine and glutamate.
[edit] Dosage When given for the evaluation or treatment of an SVT, the initial dose is 6 mg, given as a fast IV/Intraosseous IO push. Due to adenosine's extremely short half-life, start the IV line as proximal to the heart as possible, such as the antecubital fossa. It is also recommended to follow the IV push with an immediate flush of 5-10ccs of saline. If this has no effect (e.g., no evidence of transient AV block), a 12mg dose can be given 1-2 minutes after the first dose. If the 12mg dose has no effect, a second 12mg dose can be administered 1-2 minutes after the previous dose. Some clinicians may prefer to administer a higher dose (typically 18 mg), rather than repeat a dose that apparently had no effect. When given to dilate the arteries, such as in a "stress test", the dosage is typically 0.14 mg/kg/min, administered for 4 or 6 minutes, depending on the protocol.
Consider increasing the recommended dose in patients on theophylline since methylxanthines prevent binding of adenosine at receptor sites. Consider decreasing the dose in patients on dipyridamole (Persantine) and diazepam (Valium) because adenosine potentiates the effects of these drugs.
Consider decreasing the recommended dose in half in patients who are presenting Congestive Heart Failure, Myocardial Infarction, shock, hypoxia, and/or hepatic or renal insufficiency.
Consider decreasing the recommended dose in half for elderly patients.
[edit] Drug Interactions Beta blockers and dopamine may precipitate toxicity in the patient.
WPW- adenosine may be administered if equipment for cardioversion is immediately available as a backup. A-flutter W/rvr - when it first presents with SVT
[edit] Side effects Many individuals experience facial flushing, lightheadedness, diaphoresis, or nausea after administration of adenosine. These symptoms are transitory, usually lasting less than one minute.
[edit] Metabolism When adenosine enters the circulation, it is broken down by adenosine deaminase, which is present in red cells and the vessel wall.
Dipyridamole, an inhibitor of adenosine deaminase, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation.
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Adenosine 5'-triphosphate (ATP) is a multifunctional nucleotide that is most important as a "molecular currency" of intracellular energy transfer. In this role, ATP transports chemical energy within cells for metabolism. It is produced as an energy source during the processes of photosynthesis and cellular respiration and consumed by many enzymes and a multitude of cellular processes including biosynthetic reactions, motility and cell division. ATP is also incorporated into nucleic acids by polymerases in the processes of DNA replication and transcription. In signal transduction pathways, ATP is used as a substrate by kinases that phosphorylate proteins and lipids, as well as by adenylate cyclase, which uses ATP to produce the second messenger molecule cyclic AMP.
The structure of this molecule consists of a purine base (adenine) attached to the 1' carbon atom of a pentose (ribose). Three phosphate groups are attached at the 5' carbon atom of the pentose sugar. When ATP is used in DNA synthesis, the ribose sugar is first converted to deoxyribose by ribonucleotide reductase. ATP was discovered in 1929 by Karl Lohmann,[1] and was proposed to be the main energy-transfer molecule in the cell by Fritz Albert Lipmann in 1941
Physical and chemical properties ATP consists of adenosine--itself composed of an adenine ring and a ribose sugar--and three phosphate groups (triphosphate). The phosphoryl groups, starting with the group closest to the ribose, are referred to as the alpha (α), beta (β), and gamma (γ) phosphates. ATP is highly soluble in water and is quite stable in solutions between pH 6.8-7.4, but is rapidly hydrolysed at extreme pH, consequently ATP is best stored as an anhydrous salt.[3]
The system of ATP and water under standard conditions and concentrations is extremely rich in chemical energy; the bond between the second and third phosphate groups is loosely said to be particularly high in energy. Strictly speaking, the bond itself is not high in energy (like all chemical bonds it requires energy to break), but energy is produced when the bond is broken and water is allowed to react with the two products. Thus, energy is produced from the new bonds formed between ADP and water, and between phosphate and water.[4] The net change in enthalpy at Standard Temperature and Pressure of the decomposition of ATP into hydrated ADP and hydrated inorganic phosphate is −20.5 kJ / mole, with a change in free energy of 3.4 kJ/mole.[5] This large release in energy makes the decomposition of ATP in water extremely exergonic, and hence useful as a means for chemically storing energy. The energy is released by cleaving either a phosphate (Pi) or pyrophosphate (PPi) unit from ATP, in hydrated conditions:
ATP + H2O → ADP(hydrated) + Pi(hydrated) + H+(hydrated) ΔG˚ = -30.54 kJ/mol (−7.3 kcal/mol) ATP + H2O → AMP(hydrated) + PPi(hydrated) + H+(hydrated) ΔG˚ = -45.6 kJ/mol (−10.9 kcal/mol) (Note the values given for the Gibbs free energy for this reaction are dependent on a number of factors, including overall ionic strength and the presence of alkaline earth metal ions such as Mg2+ and Ca2+. Under typical cellular conditions, ΔG is approximately −50 kJ/mol (−12 kcal/mol).) [6]
[edit] Ionization in biological systems ATP has multiple ionizable groups with different acid dissociation constants. In neutral solution, ATP is ionized and exists mostly as ATP4−, with a small proportion of ATP3−.[7] As ATP has several negatively-charged groups in neutral solution, it can chelate metals with very high affinity. The binding constant for various metal ions are (given as per mole) as Mg2+ (9 554), Na+ (13), Ca2+ (3 722), K+ (8), Sr2+ (1 381) and Li+ (25).[8] Due to the strength of these interactions, ATP exists in the cell mostly in a complex with Mg2+.[9][7]
Space-filling model of ATP Ball-and-stick model of ATP
Biosynthesis ATP can be produced by redox reactions using simple and complex sugars (carbohydrates) or lipids as an energy source. For ATP to be synthesized from complex fuels, they first need to be broken down into their basic components. Carbohydrates are hydrolysed into simple sugars, such as glucose and fructose. Fats (triglycerides) are metabolised to give fatty acids and glycerol.
The overall process of oxidizing glucose to carbon dioxide is known as cellular respiration and can produce up to 36 molecules of ATP from a single molecule of glucose.[10] ATP can be produced by a number of distinct cellular processes; the three main pathways used to generate energy in eukaryotic organisms are glycolysis and the citric acid cycle/oxidative phosphorylation , both components of cellular respiration; and beta-oxidation. The majority of this ATP production by a non-photosynthetic aerobic eukaryote takes place in the mitochondria, which can make up nearly 25% of the total volume of a typical cell.[10]
[edit] Glycolysis Main article: glycolysis In glycolysis, glucose and glycerol are metabolized to pyruvate via the glycolytic pathway. In most organisms this process occurs in the cytosol, but in some protozoa such as the kinetoplastids, this is carried out in a specialized organelle called the glycosome.[11] Glycolysis generates a net two molecules of ATP through substrate phosphorylation catalyzed by two enzymes: PGK and pyruvate kinase. Two molecules of NADH are also produced, which can be oxidized via the electron transport chain and result in the generation of additional ATP by ATP synthase. The pyruvate generated as an end-product of glycolysis is a substrate for the Krebs Cycle.
[edit] Citric acid cycle Main articles: Citric acid cycle and oxidative phosphorylation In the mitochondrion, pyruvate is oxidized by the pyruvate dehydrogenase complex to acetyl CoA, which is fully oxidized to carbon dioxide by the citric acid cycle (also known as the Krebs Cycle). Every "turn" of the citric acid cycle produces two molecules of carbon dioxide, one molecule of the ATP equivalent guanosine triphosphate (GTP) through substrate-level phosphorylation catalyzed by succinyl CoA synthetase, three molecules of the reduced coenzyme NADH, and one molecule of the reduced coenzyme FADH2. Both of these latter molecules are recycled to their oxidized states (NAD+ and FAD, respectively) via the electron transport chain, which generates additional ATP by oxidative phosphorylation. The oxidation of an NADH molecule results in the synthesis of about 3 ATP molecules, and the oxidation of one FADH2 yields about 2 ATP molecules.[12] The majority of cellular ATP is generated by this process. Although the citric acid cycle itself does not involve molecular oxygen, it is an obligately aerobic process because O2 is needed to recycle the reduced NADH and FADH2 to their oxidized states. In the absence of oxygen the citric acid cycle will cease to function due to the lack of available NAD+ and FAD.[10]
The generation of ATP by the mitochondrion from cytosolic NADH relies on the malate-aspartate shuttle (and to a lesser extent, the glycerol-phosphate shuttle) because the inner mitochondrial membrane is impermeable to NADH and NAD+. Instead of transferring the generated NADH, a malate dehydrogenase enzyme converts oxaloacetate to malate, which is translocated to the mitochondrial matrix. Another malate dehydrogenase-catalyzed reaction occurs in the opposite direction, producing oxaloacetate and NADH from the newly transported malate and the mitochondrion's interior store of NAD+. A transaminase converts the oxaloacetate to aspartate for transport back across the membrane and into the intermembrane space.[10]
In oxidative phosphorylation, the passage of electrons from NADH and FADH2 through the electron transport chain powers the pumping of protons out of the mitrochondrial matrix and into the intermembrane space. This creates a proton motive force that is the net effect of a pH gradient and an electric potential gradient across the inner mitochondrial membrane. Flow of protons down this potential gradient - that is, from the intermembrane space to the matrix - provides the driving force for ATP synthesis by the protein complex ATP synthase. This enzyme contains a rotor subunit that physically rotates relative to the static portions of the protein during ATP synthesis.[13]
Most of the ATP synthesized in the mitochondria will be used for cellular processes in the cytosol; thus it must be exported from its site of synthesis in the mitochondrial matrix. The inner membrane contains antiporters that are integral membrane proteins used to exchange newly-synthesized ATP in the matrix for ADP in the intermembrane space.[14]
[edit] Beta-oxidation Main article: beta-oxidation Fatty acids can also be broken down to acetyl-CoA by beta-oxidation. Each turn of this cycle reduces the length of the acyl chain by two carbon atoms and produces one NADH and one FADH2 molecule, which are used to generate ATP by oxidative phosphorylation. Because NADH and FADH2 are energy-rich molecules, dozens of ATP molecules can be generated by the beta-oxidation of a single long acyl chain. The high energy yield of this process and the compact storage of fat explain why it is the most dense source of dietary calories.[15]
[edit] Anaerobic respiration Main article: anaerobic respiration Anaerobic respiration or fermentation entails the generation of energy via the process of oxidation in the absence of O2 as an electron acceptor. In most eukaryotes, glucose is used as both an energy store and an electron donor. The equation for the oxidation of glucose to lactic acid is:
C6H12O6 2CH3CH(OH)COOH + 2 ATP In prokaryotes, multiple electron acceptors can be used in anaerobic respiration. These include nitrate, sulfate or carbon dioxide. These processes lead to the ecologically-important processes of denitrification, sulfate reduction and acetogenesis, respectively.[16][17]
[edit] ATP replenishment by nucleoside diphosphate kinases ATP can also be synthesized through several so-called "replenishment" reactions catalyzed by the enzyme families of nucleoside diphosphate kinases (NDKs), which use other nucleoside triphosphates as a high-energy phosphate donor, and the ATP:guanido-phosphotransferase family, which uses creatine.
ADP + GTP ATP + GDP
[edit] ATP production during photosynthesis In plants, ATP is synthesized in thylakoid membrane of the chloroplast during the light-dependent reactions of photosynthesis in a process called photophosphorylation. Here, light energy is used to pump protons across the chloroplast membrane. This produces a proton-motive force and this drives the ATP synthase, exactly as in oxidative phosphorylation.[18] Some of the ATP produced in the chloroplasts is consumed in the Calvin cycle, which produces triose sugars.
[edit] ATP recycling The total quantity of ATP in the human body is about 0.1 mole. The majority of ATP is not usually synthesised de novo, but is generated from ADP by the aforementioned processes. Thus, at any given time, the total amount of ATP + ADP remains fairly constant.
The energy used by human cells requires the hydrolysis of 100 to 150 moles of ATP daily which is around 50 to 75 kg. Typically, a human will use up their body weight of ATP over the course of the day.[19] This means that each ATP molecule is recycled 1000 to 1500 times during a single day (100 / 0.1 = 1000). ATP cannot be stored, hence its consumption closely follows its synthesis.
[edit] Regulation of biosynthesis ATP production in an aerobic eukaryotic cell is tightly regulated by allosteric mechanisms, by feedback effects, and by the substrate concentration dependence of individual enzymes within the glycolysis and oxidative phosphorylation pathways. Key control points occur in enzymatic reactions that are so energetically favorable that they are effectively irreversible under physiological conditions.
In glycolysis, hexokinase is directly inhibited by its product, glucose-6-phosphate, and pyruvate kinase is inhibited by ATP itself. The main control point for the glycolytic pathway is phosphofructokinase (PFK), which is allosterically inhibited by high concentrations of ATP and activated by high concentrations of AMP. The inhibition of PFK by ATP is unusual, since ATP is also a substrate in the reaction catalyzed by PFK; the biologically active form of the enzyme is a tetramer that exists in two possible conformations, only one of which binds the second substrate fructose-6-phosphate (F6P). The protein has two binding sites for ATP - the active site is accessible in either protein conformation, but ATP binding to the inhibitor site stabilizes the conformation that binds F6P poorly.[12] A number of other small molecules can compensate for the ATP-induced shift in equilibrium conformation and reactivate PFK, including cyclic AMP, ammonium ions, inorganic phosphate, and fructose 1,6 and 2,6 biphosphate.[12]
The citric acid cycle is regulated mainly by the availability of key substrates, particularly the ratio of NAD+ to NADH and the concentrations of calcium, inorganic phosphate, ATP, ADP, and AMP. Citrate - the molecule that gives its name to the cycle - is a feedback inhibitor of citrate synthase and also inhibits PFK, providing a direct link between the regulation of the citric acid cycle and glycolysis.[12]
In oxidative phosphorylation, the key control point is the reaction catalyzed by cytochrome c oxidase, which is regulated by the availability of its substrate--the reduced form of cytochrome c. The amount of reduced cytochrome c available is directly related to the amounts of other substrates:
which directly implies this equation:
Thus, a high ratio of [NADH] to [NAD+] or a low ratio of [ADP][Pi] to [ATP] imply a high amount of reduced cytochrome c and a high level of cytochrome c oxidase activity.[12] An additional level of regulation is introduced by the transport rates of ATP and NADH between the mitochondrial matrix and the cytoplasm.[14]
[edit] Functions in cells ATP is generated in the cell by energy-releasing processes and is broken down by energy-consuming processes, in this way ATP transfers energy between spatially-separate metabolic reactions. ATP is the main energy source for the majority of cellular functions. This includes the synthesis of macromolecules, including DNA, RNA, and proteins. ATP also plays a critical role in the transport of macromolecules across cell membranes, e.g. exocytosis and endocytosis.
ATP is critically involved in maintaining cell structure by facilitating assembly and disassembly of elements of the cytoskeleton. In a related process, ATP is required for the shortening of actin and myosin filament crossbridges required for muscle contraction. This latter process is one of the main energy requirements of animals and is essential for locomotion and respiration.
[edit] Cell signaling
[edit] Extracellular signaling ATP is also a signaling molecule. ATP, ADP, or adenosine are recognized by purinergic receptors.
In humans, this signaling role is important in both the central and peripheral nervous system. Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors known as P2.[20] The P2Y receptors are metabotropic, i.e. G protein-coupled and modulate mainly intracellular calcium and sometimes cyclic AMP levels. Fifteen members of the P2Y family have been reported (P2Y1-P2Y15), although some are only related through weak homology and several (P2Y5, P2Y7, P2Y9, P2Y10) do not function as receptors that raise cytosolic calcium. The P2X ionotropic receptor subgroup comprises seven members (P2X1-P2X7) which are ligand-gated Ca2+-permeable ion channels that open when bound to an extracellular purine nucleotide. In contrast to P2 receptors (agonist order ATP > ADP > AMP > ADO), purinergic nucleotides like ATP are not strong agonists of P1 receptors which are strongly activated by adenosine and other nucleosides (ADO > AMP > ADP > ATP). P1 receptors have A1, A2a, A2b, and A3 subtypes ("A" as a remnant of old nomenclature of adenosine receptor), all of which are G protein-coupled receptors, A1 and A3 being coupled to Gi, and A2a and A2b being coupled to Gs.[21]
[edit] Intracellular signaling ATP is critical in signal transduction processes. It is used by kinases as the source of phosphate groups in their phosphate transfer reactions. Kinase activity on substrates such as proteins or membrane lipids are a common form of signal transduction. Phosphorylation of a protein by a kinase can activate or inhibit the target's activity, these proteins may themselves be kinases, and form part of a signal transduction cascade such as the mitogen-activated protein kinase cascade.[22]
ATP is also used by adenylate cyclase and is transformed to the second messenger molecule cyclic AMP, which is involved in triggering calcium signals by the release of calcium from intracellular stores.[23] This form of signal transduction is particularly important in brain function, although it is involved in the regulation of a multitude of other cellular processes.[24]
[edit] Deoxyribonucleotide synthesis In all known organisms, the deoxyribonucleotides that make up DNA are synthesized by the action of ribonucleotide reductase (RNR) enzymes on their corresponding ribonucleotides.[25] This enzyme reduces the 2' hydroxyl group on the ribose sugar to deoxyribose, forming a deoxyribonucleotide (denoted dATP). All ribonucleotide reductase enzymes use a common sulfhydryl radical mechanism reliant on reactive cysteine residues that oxidize to form disulfide bonds in the course of the reaction.[25] RNR enzymes are recycled by reaction with thioredoxin or glutaredoxin.[12]
The regulation of RNR and related enzymes maintains a balance of dNTPs relative to each other and relative to NTPs in the cell. Very low dNTP concentration inhibits DNA synthesis and DNA repair and is lethal to the cell, while an abnormal ratio of dNTPs is mutagenic due to the increased likelihood of misincorporating a dNTP during DNA synthesis.[12] Regulation of or differential specificity of RNR has been proposed as a mechanism for alterations in the relative sizes of intracellular dNTP pools under cellular stress such as hypoxia.[26]
Binding to proteins
Some proteins that bind ATP do so in a characteristic protein fold known as the Rossmann fold, which is a general nucleotide-binding structural domain that can also bind the cofactor NAD.[27] The most common ATP-binding proteins, known as kinases, share a small number of common folds; the protein kinases, the largest kinase superfamily, all share common structural features specialized for ATP binding and phosphate transfer.[28]
ATP in complexes with proteins generally requires the presence of a divalent cation, almost always magnesium, which binds to the ATP phosphate groups. The presence of magnesium greatly decreases the dissociation constant of ATP from its protein binding partner without affecting the ability of the enzyme to catalyze its reaction once the ATP has bound.[29] The presence of magnesium ions can serve as a mechanism for kinase regulation.[30]
[edit] ATP analogs Biochemistry laboratories often use in vitro studies to explore ATP-dependent molecular processes. Enzyme inhibitors of ATP-dependent enzymes such as kinases are needed to examine the binding sites and transition states involved in ATP-dependent reactions. ATP analogs are also used in X-ray crystallography to determine a protein structure in complex with ATP, often together with other substrates. Most useful ATP analogs cannot be hydrolyzed as ATP would be; instead they trap the enzyme in a structure closely related to the ATP-bound state. Adenosine 5'-(gamma-thiotriphosphate) is an extremely common ATP analog in which one of the gamma-phosphate oxygens is replaced by a sulfur atom; this molecule is hydrolyzed at a dramatically slower rate than ATP itself and functions as an inhibitor of ATP-dependent processes. In crystallographic studies, hydrolysis transition states are modeled by the bound vanadate ion. However, caution is warranted in interpreting the results of experiments using ATP analogs, since some enzymes can hydrolyze them at appreciable rates at high concentration.[31]
[edit] See also Adenosine diphosphate (ADP) Adenosine monophosphate (AMP) Cyclic adenosine monophosphate (cAMP) ATPases ATP hydrolysis Citric acid cycle (also called the Krebs cycle or TCA cycle) Phosphagen Nucleotide exchange factor Mitochondria Photophosphorylation
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-------------------- Do unto others as you would have them do unto you. Remember Iam not a Doctor Just someone struggling like you with Tick Borne Diseases.
quote:Consider decreasing the dose in patients on dipyridamole (Persantine) and diazepam (Valium) because adenosine potentiates the effects of these drugs.
Borrelia patients like benzos, i do
I am also interested in adrenaline, cause people with Th1 diseases (Marshall Protocol) seem to have problems receiving adrenaline in dental procedures in anesthetics. They have local or systemic reactions.
And other common stimulant, nicotine releases adrenaline
quote:Nicotine acts on the nicotinic acetylcholine receptors. In small concentrations it increases the activity of these receptors, among other things leading to an increased flow of adrenaline (epinephrine), a stimulating hormone. The release of adrenaline causes an increase in heart rate, blood pressure and respiration, as well as higher glucose levels in the blood.
by wikipedia
It is a nice adrenaline combination :)Nicotine releases it and caffeine prolongs its actions.
And we know stress shuts down immune system.
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