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Adenosine diphosphate
Adenosine diphosphate
Adenosine diphosphate
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Adenosine diphosphate
Skeletal formula of ADP
Skeletal formula of ADP
Ball-and-stick model of ADP (shown here as a 3- ion)
Ball-and-stick model of ADP (shown here as a 3- ion)
Names
IUPAC name
Adenosine 5′-(trihydrogen diphosphate)
Systematic IUPAC name
[(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl trihydrogen diphosphate
Other names
Adenosine 5′-diphosphate; Adenosine 5′-pyrophosphate; Adenosine pyrophosphate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.356 Edit this at Wikidata
EC Number
  • 218-249-0
KEGG
RTECS number
  • AU7467000
UNII
  • InChI=1S/C10H15N5O10P2/c11-8-5-9(13-2-12-8)15(3-14-5)10-7(17)6(16)4(24-10)1-23-27(21,22)25-26(18,19)20/h2-4,6-7,10,16-17H,1H2,(H,21,22)(H2,11,12,13)(H2,18,19,20)/t4-,6-,7-,10-/m1/s1 checkY
    Key: XTWYTFMLZFPYCI-KQYNXXCUSA-N checkY
  • InChI=1/C10H15N5O10P2/c11-8-5-9(13-2-12-8)15(3-14-5)10-7(17)6(16)4(24-10)1-23-27(21,22)25-26(18,19)20/h2-4,6-7,10,16-17H,1H2,(H,21,22)(H2,11,12,13)(H2,18,19,20)/t4-,6-,7-,10-/m1/s1
    Key: XTWYTFMLZFPYCI-KQYNXXCUBP
  • O=P(O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n2cnc1c(ncnc12)N)[C@H](O)[C@@H]3O
  • c1nc(c2c(n1)n(cn2)[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(O)OP(=O)(O)O)O)O)N
Properties
C10H15N5O10P2
Molar mass 427.201 g/mol
Density 2.49 g/mL
log P −2.640
Hazards
Safety data sheet (SDS) MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbone attached to adenine and two phosphate groups bonded to the 5 carbon atom of ribose. The diphosphate group of ADP is attached to the 5’ carbon of the sugar backbone, while the adenine attaches to the 1’ carbon.[1]

ADP can be interconverted to adenosine triphosphate (ATP) and adenosine monophosphate (AMP). ATP contains one more phosphate group than ADP, while AMP contains one fewer phosphate group. Energy transfer used by all living things is a result of dephosphorylation of ATP by enzymes known as ATPases. The cleavage of a phosphate group from ATP results in the coupling of energy to metabolic reactions and a by-product of ADP.[1] ATP is continually reformed from lower-energy species ADP and AMP. The biosynthesis of ATP is achieved throughout processes such as substrate-level phosphorylation, oxidative phosphorylation, and photophosphorylation, all of which facilitate the addition of a phosphate group to ADP.

Bioenergetics

[edit]

ADP cycling supplies the energy needed to do work in a biological system, the thermodynamic process of transferring energy from one source to another. There are two types of energy: potential energy and kinetic energy. Potential energy can be thought of as stored energy, or usable energy that is available to do work. Kinetic energy is the energy of an object as a result of its motion. The significance of ATP is in its ability to store potential energy within the phosphate bonds. The energy stored between these bonds can then be transferred to do work. For example, the transfer of energy from ATP to the protein myosin causes a conformational change when connecting to actin during muscle contraction.[1]

The cycle of synthesis and degradation of ATP; 1 and 2 represent output and input of energy, respectively.

It takes multiple reactions between myosin and actin to effectively produce one muscle contraction, and, therefore, the availability of large amounts of ATP is required to produce each muscle contraction. For this reason, biological processes have evolved to produce efficient ways to replenish the potential energy of ATP from ADP.[2]

Breaking one of ATP's phosphorus bonds generates approximately 30.5 kilojoules per mole of ATP (7.3 kcal).[3] ADP can be converted, or powered back to ATP through the process of releasing the chemical energy available in food; in humans, this is constantly performed via aerobic respiration in the mitochondria.[2] Plants use photosynthetic pathways to convert and store energy from sunlight, also conversion of ADP to ATP.[3] Animals use the energy released in the breakdown of glucose and other molecules to convert ADP to ATP, which can then be used to fuel necessary growth and cell maintenance.[2]

Cellular respiration

[edit]

Catabolism

[edit]

The ten-step catabolic pathway of glycolysis is the initial phase of free-energy release in the breakdown of glucose and can be split into two phases, the preparatory phase and payoff phase. ADP and phosphate are needed as precursors to synthesize ATP in the payoff reactions of the TCA cycle and oxidative phosphorylation mechanism.[4] During the payoff phase of glycolysis, the enzymes phosphoglycerate kinase and pyruvate kinase facilitate the addition of a phosphate group to ADP by way of substrate-level phosphorylation.[5]

Glycolysis overview

Glycolysis

[edit]
Main article: glycolysis

Glycolysis is performed by all living organisms and consists of 10 steps. The net reaction for the overall process of glycolysis is:[6]

Glucose + 2 NAD+ + 2 Pi + 2 ADP → 2 pyruvate + 2 ATP + 2 NADH + 2 H2O

Steps 1 and 3 require the input of energy derived from the hydrolysis of ATP to ADP and Pi (inorganic phosphate), whereas steps 7 and 10 require the input of ADP, each yielding ATP.[7] The enzymes necessary to break down glucose are found in the cytoplasm, the viscous fluid that fills living cells, where the glycolytic reactions take place.[1]

Citric acid cycle

[edit]
Main article: citric acid cycle

The citric acid cycle, also known as the Krebs cycle or the TCA (tricarboxylic acid) cycle is an 8-step process that takes the pyruvate generated by glycolysis and generates 4 NADH, FADH2, and GTP, which is further converted to ATP.[8] It is only in step 5, where GTP is generated, by succinyl-CoA synthetase, and then converted to ATP, that ADP is used (GTP + ADP → GDP + ATP).[9]

Oxidative phosphorylation

[edit]
Main article: oxidative phosphorylation

Oxidative phosphorylation produces 26 of the 30 equivalents of ATP generated in cellular respiration by transferring electrons from NADH or FADH2 to O2 through electron carriers.[10] The energy released when electrons are passed from higher-energy NADH or FADH2 to the lower-energy O2 is required to phosphorylate ADP and once again generate ATP.[11] It is this energy coupling and phosphorylation of ADP to ATP that gives the electron transport chain the name oxidative phosphorylation.[1]

ATP-Synthase

Mitochondrial ATP synthase complex

[edit]
Main article: ATP synthase

During the initial phases of glycolysis and the TCA cycle, cofactors such as NAD+ donate and accept electrons[12] that aid in the electron transport chain's ability to produce a proton gradient across the inner mitochondrial membrane.[13] The ATP synthase complex exists within the mitochondrial membrane (FO portion) and protrudes into the matrix (F1 portion). The energy derived as a result of the chemical gradient is then used to synthesize ATP by coupling the reaction of inorganic phosphate to ADP in the active site of the ATP synthase enzyme; the equation for this can be written as ADP + Pi → ATP.[citation needed]

Blood platelet activation

[edit]

Under normal conditions, small disk-shape platelets circulate in the blood freely and without interaction with one another. ADP is stored in dense bodies inside blood platelets and is released upon platelet activation. ADP interacts with a family of ADP receptors found on platelets (P2Y1, P2Y12, and P2X1), which leads to platelet activation.[14]

  • P2Y1 receptors initiate platelet aggregation and shape change as a result of interactions with ADP.
  • P2Y12 receptors further amplify the response to ADP and draw forth the completion of aggregation.

ADP in the blood is converted to adenosine by the action of ecto-ADPases, inhibiting further platelet activation via adenosine receptors.[citation needed]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Adenosine diphosphate

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from Grokipedia
Adenosine diphosphate (ADP) is a fundamental diphosphate in cellular , consisting of the base linked to a sugar and two groups attached via a high-energy phosphoanhydride bond. Formed primarily through the of (ATP), ADP releases approximately 7.3 kcal/mol of free energy, which powers essential cellular processes such as , , and . In energy , ADP acts as both a product of ATP breakdown and a substrate for ATP resynthesis via in mitochondria or substrate-level phosphorylation in and the , maintaining the cell's through the ATP-ADP cycle. Beyond energy transfer, ADP functions as a critical signaling molecule, particularly in , where it is released from activated platelets' dense granules to amplify platelet aggregation. Binding to G-protein-coupled P2Y1 and receptors on the platelet surface, ADP induces shape change, calcium mobilization, and expression of the , enabling fibrinogen-mediated platelet clumping and formation of a stable hemostatic plug at sites of vascular injury. This role underscores ADP's involvement in , where dysregulated signaling can contribute to pathological clot formation, making P2Y12 antagonists like clopidogrel key therapeutics in management. Additionally, as a human metabolite, ADP participates in broader purinergic signaling pathways, influencing processes from to , though its primary physiological impact centers on energy dynamics and .

Structure and properties

Chemical structure

Adenosine diphosphate (ADP) has the molecular formula C₁₀H₁₅N₅O₁₀P₂ and a of 427.20 g/mol. Structurally, ADP comprises an base—a derivative with an amino group at the 6-position—attached via an N-glycosidic bond to the anomeric C1' carbon of a β-D- sugar moiety, forming the . The exists in a cyclic form, characterized by a five-membered ring with hydroxyl groups at the 2' and 3' positions. At the 5' carbon of the , a chain of two groups is esterified, connected by a high-energy phosphoanhydride bond between the α- and β-phosphates, resulting in a linear diphosphate extension. In standard representations, the of ADP is depicted with the base oriented above the ring, the sugar shown in its with the 5'-OH replaced by the -O-PO₂-OPO₃²⁻ diphosphate chain extending outward; this linear arrangement contrasts with the cyclic , highlighting the molecule's nucleoside-diphosphate architecture. ADP differs structurally from related nucleotides by the number of groups in its chain: (AMP) possesses a single esterified to the 5' carbon of (formula C₁₀H₁₄N₅O₇P), while (ATP) features three phosphates linked by two phosphoanhydride bonds (formula C₁₀H₁₆N₅O₁₃P₃).

Physical and chemical properties

Adenosine diphosphate (ADP) appears as a white to off-white crystalline powder at room temperature. It exhibits solubility in water up to approximately 50 mg/mL at room temperature for salt forms such as the lithium salt, with the disodium salt showing higher solubility around 100 mg/mL under certain conditions; solubility in organic solvents such as DMSO and methanol is limited unless heated. The phosphate groups of ADP have pKa values of approximately 0.9 (first phosphate ionization), 6.5 (α-phosphate), and 7.5 (β-phosphate), influencing its ionization states and reactivity in aqueous environments. Chemically, ADP shows characteristic UV absorption at 259 nm with a molar extinction coefficient of 15,400 M⁻¹ cm⁻¹, attributable to the nucleobase. The phosphoanhydride linkage between the two groups confers reactivity, enabling to (AMP) and inorganic under acidic conditions or by phosphatases, though the molecule remains stable at neutral . ADP's stability is compromised by enzymatic via phosphatases, which cleave the terminal ; it is not typically degraded by nucleases due to its monomeric nature. To prevent degradation, ADP is stored as a dry powder at -20°C or in neutral aqueous solutions at low temperatures, where it maintains integrity for months under frozen conditions but only days at 4°C.

Biosynthesis and metabolism

Synthesis pathways

De novo synthesis of adenine nucleotides occurs via the purine biosynthetic pathway. Phosphoribosyl pyrophosphate (PRPP) reacts with to initiate ring assembly, leading to inosine monophosphate (IMP) through a series of 10 enzymatic steps. IMP is aminated to adenylosuccinate by adenylosuccinate synthetase, then cleaved to AMP by adenylosuccinate lyase. AMP is then phosphorylated to ADP by or . Adenosine diphosphate (ADP) is synthesized in cells through de novo purine biosynthesis leading to AMP, salvage pathways, and interconversion of existing adenine nucleotides to maintain cellular . The key enzyme (AK) catalyzes the reversible transfer of a from ATP to AMP, producing two molecules of ADP according to the reaction AMP + ATP ⇌ 2 ADP. This equilibrium reaction is crucial for buffering fluctuations in adenine nucleotide pools, ensuring rapid ADP availability when cellular energy demands increase. Multiple isoforms of AK exist, including cytosolic AK1 and mitochondrial AK2, each localized to specific compartments to support localized energy transfer; for instance, AK1 predominates in muscle and tissues, while AK2 is essential in mitochondria for support. AK activity is tightly regulated by the cellular energy charge, with inhibition at high ATP/AMP ratios to prevent excessive ADP accumulation, thereby linking synthesis directly to ATP levels. Nucleoside diphosphate kinase (NDPK) also contributes to ADP synthesis by catalyzing the transfer of a γ-phosphate from ATP to other nucleoside diphosphates, including ADP itself in equilibrium reactions such as ATP + GDP ⇌ ADP + GTP, though its primary role is in phosphorylating non-adenine NDPs to NTPs while generating ADP as a byproduct. NDPK isoforms, such as NDPK-A (NM23-H1) and NDPK-B (NM23-H2), are ubiquitously expressed and maintain nucleotide balance across cellular compartments, with NDPK-D localized to mitochondria to facilitate ADP regeneration near ATP synthase. This enzyme's broad substrate specificity ensures efficient phosphate shuttling, but for adenine-specific synthesis, it complements rather than supplants AK. In the salvage pathway, ADP is produced by recycling free purine bases or nucleosides, conserving cellular resources and preventing loss of adenine moieties. Adenosine is phosphorylated to AMP by adenosine kinase (ADK), followed by conversion to ADP via AK or other kinases. Similarly, free adenine is salvaged by adenine phosphoribosyltransferase (APRT), which combines it with 5-phosphoribosyl-1-pyrophosphate (PRPP) to form AMP, subsequently phosphorylated to ADP. This pathway is particularly active in tissues with high nucleotide turnover, such as erythrocytes, where ADK efficiently recaptures adenosine to sustain adenine nucleotide pools. For industrial and commercial production, ADP is manufactured enzymatically using engineered microorganisms or through chemical phosphorylation of AMP. Microbial fermentation with bacteria like or expressing high levels of kinases converts to ADP and ATP, yielding up to 15 g/L of ADP under optimized conditions. Chemical methods involve reacting AMP with (POCl₃) in controlled conditions to add the second group, followed by purification, though enzymatic routes are preferred for higher purity in biochemical applications. These processes support research and pharmaceutical needs, emphasizing scalability and cost-effectiveness.

Degradation and regulation

Adenosine diphosphate (ADP) is degraded primarily through to (AMP), a process catalyzed by ecto-nucleotidases such as ecto-ATP diphosphohydrolases (E-NTPDases, including CD39) and ecto-5'-nucleotidase (CD73). These membrane-bound enzymes sequentially hydrolyze extracellular ADP to AMP, releasing inorganic phosphate and contributing to the termination of purinergic signaling while generating as a downstream product. Intracellularly, similar nucleotidase activities, including cytosolic 5'-nucleotidases, facilitate ADP breakdown, helping to maintain pool balance and prevent excessive accumulation under stress conditions. This is energy-releasing and plays a key role in cellular by modulating levels. ADP can also be converted back to adenosine triphosphate (ATP) through mechanisms that serve as regulatory feedback to restore energy balance, such as the in mitochondria during or the reaction in the phosphagen system. In the latter, donates a phosphate group to ADP (PCr + ADP → Cr + ATP), buffering fluctuations in the ATP/ADP ratio and providing rapid ATP regeneration during transient energy demands. These conversions are tightly regulated to prevent futile cycling, with ADP levels acting as a signal to activate ATP production pathways when the ATP/ADP ratio falls below equilibrium thresholds. Regulatory mechanisms for ADP degradation and interconversion involve allosteric modulation of enzymes like adenylate kinase, which catalyzes the reversible reaction 2 ADP ⇌ ATP + AMP to equilibrate nucleotide pools. High ATP/ADP ratios lead to product inhibition of adenylate kinase by ATP and AMP binding, slowing the forward reaction and stabilizing high-energy states. A central concept in this regulation is the adenylate energy charge (AEC), defined as ATP+0.5ADPATP+ADP+AMP\frac{\text{ATP} + 0.5 \text{ADP}}{\text{ATP} + \text{ADP} + \text{AMP}}, which ranges from 0 to 1 and acts as a metabolic sensor; values above 0.8 promote biosynthetic pathways, while declines below 0.5 trigger catabolic responses and stress signaling. This framework, originally proposed by Atkinson, ensures that ADP levels feedback to adjust enzymatic activities and maintain cellular energy homeostasis. Pathological dysregulation of ADP degradation occurs during ischemia, where reduced oxygen supply impairs ATP synthesis, leading to ADP accumulation as ATP hydrolysis outpaces resynthesis. This elevates the ADP/ATP ratio, exacerbating mitochondrial dysfunction, calcium overload, and , which can culminate in cellular damage and if prolonged. In myocardial ischemia, for instance, ADP levels rise significantly within minutes, correlating with energetic collapse and contributing to upon restoration of blood flow.

Role in energy transfer

ATP-ADP cycle

The ATP-ADP cycle represents the central mechanism for energy exchange in cells, where adenosine triphosphate (ATP) serves as the primary energy currency. During hydrolysis, ATP is cleaved into adenosine diphosphate (ADP) and inorganic phosphate (Pi), releasing approximately 30.5 kJ/mol of free energy under standard biochemical conditions (1 M concentrations, 25°C, pH 7). This exergonic reaction powers a wide array of endergonic cellular processes, such as muscle contraction, active transport, and biosynthesis. Conversely, the reverse phosphorylation of ADP to ATP is endergonic and requires energy input, typically from catabolic pathways, to store energy in the high-energy phosphoanhydride bond of ATP. The core reaction of the cycle is reversible and can be expressed as: ATP+H2O⇌ADP+Pi+H+\text{ATP} + \text{H}_2\text{O} \rightleftharpoons \text{ADP} + \text{P}_\text{i} + \text{H}^+ with a standard free energy change (ΔG°') of -30.5 kJ/mol at pH 7, favoring under physiological conditions. This equilibrium is shifted dynamically based on cellular concentrations of ATP, ADP, and Pi, maintaining a high ATP/ADP ratio essential for efficient energy transfer. In eukaryotic cells, predominantly occurs in the , where it fuels general metabolic activities and mechanical work. Resynthesis of ATP from ADP, however, primarily takes place in the mitochondria via oxidative processes, with ADP imported into the matrix and newly formed ATP exported to the through specific carriers like the . This compartmentalization ensures a steady supply of ATP to cytosolic demands while coupling energy production to mitochondrial function. A key aspect of the cycle involves phosphate group transfer in coupled reactions, where ADP functions as the primary acceptor for phosphoryl groups from high-energy intermediates. This directly regenerates ATP, linking exergonic reactions (e.g., oxidation of fuels) to ATP production without requiring a proton gradient, thereby enhancing the efficiency of in cellular metabolism.

Bioenergetics principles

Adenosine diphosphate (ADP) plays a central role in cellular through the and formation of high-energy phosphoanhydride bonds, which differ markedly from those in (ATP). The phosphoanhydride bonds in ATP store significant , with the terminal bond exhibiting a standard free energy change (ΔG°) of approximately -30.5 kJ/mol upon to ADP and inorganic phosphate (Pi), whereas ADP possesses only one such bond, rendering it a lower-energy that serves as a substrate for capture. In physiological conditions, however, the actual ΔG for ATP is more negative, typically ranging from -50 to -60 kJ/mol, due to non-equilibrium concentrations of ATP, ADP, and Pi in the and mitochondria, which amplify the available for coupled reactions. The efficiency of energy transfer involving ADP and ATP in oxidative systems, such as mitochondrial respiration, achieves approximately 40-60%, reflecting the thermodynamic coupling between electron transport and ATP synthesis. This efficiency arises from the proton motive force generated across the , where ADP by harnesses the of protons (ΔμH⁺) to drive the reaction ADP + Pi → ATP, converting into energy with minimal dissipation as . In this process, ADP availability modulates the proton motive force by stimulating proton influx through , thereby linking substrate oxidation to energy demand and preventing excessive proton accumulation that could uncouple respiration. As the universal energy currency of the cell, the ADP/ATP ratio tightly regulates metabolic flux, particularly through respiratory control, where elevated ADP levels signal energy depletion and accelerate mitochondrial respiration to restore ATP. High ADP concentrations lower the ATP/ADP ratio, allosterically activating respiratory complexes and enhancing oxygen consumption, while high ATP/ADP ratios exert inhibitory feedback to match energy production to utilization. This dynamic equilibrium ensures efficient across cellular processes. The foundational understanding of ADP's bioenergetic role traces back to Karl Lohmann's 1929 discovery of ATP (and by extension ADP) as a key muscle energy compound, isolated from rabbit extracts. Later, Peter Mitchell's 1961 chemiosmotic theory revolutionized the field by elucidating how ADP is powered by transmembrane proton gradients, earning him the 1978 and establishing the mechanistic basis for in respiration and .

Participation in metabolic pathways

Glycolysis

In glycolysis, the cytosolic metabolic pathway that converts glucose to pyruvate, ADP plays a central role as the phosphate acceptor in , enabling the direct synthesis of ATP without the involvement of an . This process occurs in the payoff phase of , where high-energy phosphate compounds transfer their groups to ADP, regenerating ATP to support cellular energy demands. The ATP-ADP cycle is thus integral to maintaining during this anaerobic breakdown of glucose. Two critical reactions highlight ADP's involvement. In the seventh step, catalyzes the reversible transfer of a from $1,3-bisphosphoglycerate to ADP, producing $3-phosphoglycerate and ATP: 1,3-bisphosphoglycerate+ADP→3-phosphoglycerate+ATP1,3\text{-bisphosphoglycerate} + \text{ADP} \to 3\text{-phosphoglycerate} + \text{ATP} This yields two ATP molecules per glucose (one per glyceraldehyde-3-phosphate). In the tenth and final step, facilitates the irreversible transfer from phosphoenolpyruvate (PEP) to ADP, forming pyruvate and ATP: phosphoenolpyruvate+ADP→pyruvate+ATP\text{phosphoenolpyruvate} + \text{ADP} \to \text{pyruvate} + \text{ATP} This produces another two ATP per glucose. Overall, these substrate-level phosphorylations generate four ATP, but after subtracting the two ATP invested in the preparatory phase, the net yield is two ATP per glucose molecule. ADP levels also contribute to the regulation of glycolysis. Elevated ADP signals a low charge—defined as (ATP+0.5×ADP)/(ATP+ADP+AMP)(\text{ATP} + 0.5 \times \text{ADP}) / (\text{ATP} + \text{ADP} + \text{AMP})—which indirectly activates phosphofructokinase-1 (PFK-1), the pathway's primary regulatory enzyme, by favoring AMP production via and counteracting ATP inhibition. This allosteric activation accelerates the committed step of fructose-6-phosphate to fructose-1,6-bisphosphate, enhancing glycolytic flux when energy is depleted. In anaerobic conditions, such as during strenuous exercise in , glycolysis serves as the sole ATP-generating pathway, with ADP phosphorylation crucial for rapid energy production through lactate fermentation. Here, pyruvate is reduced to lactate to regenerate NAD+^+ for continued , sustaining a net yield of two ATP per glucose despite oxygen limitation and preventing ADP accumulation that could otherwise halt the process.

Citric acid cycle

The , occurring in the of eukaryotic cells, represents a core aerobic pathway for the oxidation of derived from carbohydrates, fats, and proteins, and it is evolutionarily conserved in both eukaryotes and prokaryotes. In this cycle, adenosine diphosphate (ADP) serves as a key acceptor in , directly contributing to energy conservation while the pathway generates reducing equivalents for subsequent respiratory processes. The cycle's enzymes facilitate the complete oxidation of one molecule to two molecules of , producing three NADH, one FADH₂, and one bond equivalent per turn. A pivotal step involving ADP is the conversion of succinyl-CoA to succinate, catalyzed by the succinyl-CoA synthetase (also known as succinate thiokinase). This reaction proceeds as follows: [Succinyl-CoA](/page/Succinyl-CoA)+ADP+Pi→succinate+CoA+ATP\text{[Succinyl-CoA](/page/Succinyl-CoA)} + \text{ADP} + \text{P}_\text{i} \rightarrow \text{succinate} + \text{CoA} + \text{ATP} This directly generates ATP from ADP and inorganic phosphate (P_i), harnessing the high-energy thioester bond of without requiring the . In some organisms, including certain prokaryotes and alternative isoforms in eukaryotes, the enzyme utilizes GDP to produce GTP instead, but this GTP is rapidly converted to ATP through the action of (GTP + ADP ⇌ GDP + ATP), ensuring functional equivalence in energy transfer. Per complete turn of the , the succinyl-CoA synthetase step yields one molecule of ATP (or GTP equivalent), representing the sole direct produced by the cycle itself. The pathway also generates NADH and FADH₂ at multiple dehydrogenation steps (isocitrate to α-ketoglutarate, α-ketoglutarate to , and succinate to fumarate), which donate electrons to the for . ADP concentrations further integrate the cycle with cellular energy status by allosterically activating , the enzyme converting isocitrate to α-ketoglutarate; elevated ADP signals low energy charge, enhancing flux through the cycle to boost ATP production. This regulatory mechanism ensures the responds dynamically to metabolic demands, linking carbon oxidation to bioenergetic needs.

Oxidative phosphorylation

Oxidative phosphorylation represents the primary stage of aerobic respiration where ADP is phosphorylated to ATP using energy derived from the in the . The process relies on reducing equivalents, such as NADH and FADH₂, generated from upstream metabolic pathways like the , which donate electrons to the chain, establishing a proton across the membrane. This , known as the proton motive force, drives ATP synthesis through . The core of this mechanism is the F₀F₁-ATP synthase complex, a rotary embedded in the . The F₀ subunit forms a proton channel that allows protons to flow back into , generating torque that rotates a central rotor within the F₁ subunit, which catalyzes the of ADP to ATP. Specifically, the reaction ADP + Pᵢ → ATP occurs at the catalytic sites of the F₁ β-subunits through a binding change mechanism, where conformational changes induced by rotation facilitate substrate binding, , and product release. This rotary enables the to synthesize up to 100-300 ATP molecules per second under optimal conditions. ADP enters the via the adenine nucleotide translocase (ANT), an that exchanges cytosolic ADP for matrix ATP, ensuring a continuous supply of substrate for . The overall yield from complete glucose oxidation via is approximately 28-30 ATP molecules per glucose molecule, accounting for the efficiency of the proton gradient and transport costs. Respiratory control regulates the rate of electron transport and ATP synthesis based on cellular demand, primarily through the ADP/ATP ratio. A high ADP/ATP ratio signals need, stimulating state 3 respiration where electron transport accelerates to maintain the proton gradient and support rapid ATP production; conversely, a low ratio leads to state 4 respiration, where the gradient builds up and respiration slows due to backpressure. This acceptor control by ADP ensures efficient coupling of oxidation to . Key inhibitors highlight the mechanistic dependencies: binds to the F₀ subunit of , blocking proton translocation and halting ATP synthesis while preserving the proton gradient, which inhibits electron transport. Uncouplers, such as , dissipate the proton gradient by shuttling protons across the membrane independently of , allowing unchecked electron transport and heat production without ADP phosphorylation.

Other biological functions

Platelet activation

Adenosine diphosphate (ADP) plays a pivotal role in platelet activation as an extracellular signaling molecule released from dense granules within platelets. These granules store ADP along with ATP and serotonin, and upon platelet activation by strong agonists such as or , ADP is rapidly secreted in an autocrine and paracrine manner to amplify the hemostatic response. This release occurs through of dense granules triggered by calcium-dependent mechanisms initiated by the primary agonists. ADP exerts its effects on platelets primarily through two G-protein-coupled receptors: P2Y1 and . The P2Y1 receptor, coupled to Gαq, activates , leading to the production of 1,4,5-trisphosphate (IP3) and subsequent of intracellular calcium stores, which induces platelet shape change from discoid to spherical and initiates reversible aggregation. In contrast, the P2Y12 receptor, coupled to Gαi2, inhibits to reduce cyclic AMP levels, thereby disinhibiting platelet activation pathways; it also activates (PI3K), promoting granule secretion and stabilizing aggregation by enhancing fibrinogen binding to the αIIbβ3 . Together, these receptors coordinate ADP-induced calcium release, further dense granule secretion, and potentiation of (TXA2) effects, where ADP amplifies TXA2-mediated signaling to sustain irreversible platelet aggregation and formation. In clinical contexts, ADP signaling via is a key target for antiplatelet therapy to prevent pathological , such as in and . Drugs like clopidogrel act as irreversible antagonists of the receptor by binding to its extracellular loops, thereby inhibiting ADP-induced platelet aggregation and reducing the risk of thrombotic events in patients with . Dysregulated ADP-mediated platelet activation contributes to excessive clotting in conditions like arterial , where blockade has demonstrated efficacy in stabilizing plaques and limiting growth.

Extracellular signaling

Extracellular (ADP) functions as a key signaling in purinergic pathways, primarily activating P2Y receptors on the surface of various cell types. Purinergic receptors are divided into P2X (ionotropic, ligand-gated ion channels mediating rapid calcium influx and fast cellular responses) and P2Y (metabotropic, G protein-coupled receptors eliciting slower, second-messenger-dependent effects). ADP predominantly targets P2Y subtypes, including P2Y1 (Gq-coupled, promoting activation and calcium mobilization), P2Y12 (Gi-coupled, inhibiting ), and P2Y13 (Gi-coupled, similarly modulating cAMP levels), with affinities varying from nanomolar to micromolar (e.g., EC50 ≈ 8 μM for P2Y1, ≈ 60 nM for P2Y12). These interactions enable ADP to coordinate intercellular communication in diverse tissues, distinct from its well-known role in platelet activation. In non-hematopoietic cells, ADP drives through endothelial P2Y1 receptors, where it stimulates and release, enhancing vascular relaxation and blood flow regulation. For instance, ADP-induced endothelial via P2Y1 supports hyperemia in response to neural activity, as seen in somatosensory cortex models. In the , extracellular ADP modulates by acting on P2Y receptors in neurons and ; it inhibits N-type calcium channels in dorsal root ganglia for effects and influences sodium currents and dynamics in central synapses, contributing to mechanosensory transduction and . Additionally, ADP promotes microglial and astrocyte-neuron interactions via P2Y12 and P2Y13, aiding and response to injury. In immune contexts, ADP activates on neutrophils and , facilitating and release to amplify inflammatory responses without directly triggering platelet aggregation. Physiologically, ADP signaling supports by recruiting inflammatory cells through P2Y-mediated and activation at injury sites, balancing and tissue repair. In , Gi-coupled P2Y receptors (e.g., ) dampen inflammatory by opposing Gq-coupled P2Y1 effects on sensory neurons, integrating pro- and anti-nociceptive signals to fine-tune sensitivity. These effects are concentration-dependent: nanomolar levels (10-100 nM) elicit precise signaling via P2Y receptors, while micromolar concentrations (≥1 μM) may lead to through secondary calcium overload or with P2X channels, though ADP is less toxic than ATP. Recent research highlights ADP's role in non-platelet , such as P2Y12-driven microglial migration in neuroinflammatory disorders, and emerging links to endothelial migration in tumor , though microbiome-host interactions remain underexplored for ADP specifically.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Adenosine-diphosphate
  2. https://www.ncbi.nlm.nih.gov/books/NBK553175/
  3. https://www.ncbi.nlm.nih.gov/books/NBK482478/
  4. https://pubchem.ncbi.nlm.nih.gov/compound/6022
  5. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5741946.htm
  6. https://www.sigmaaldrich.com/US/en/product/sigma/a2754
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