What is Diadenosine tetraphosphate, commonly known as Ap4A?

Ap4A, or Diadenosine tetraphosphate, is a molecule that is found in a wide variety of organisms, from bacteria to humans. It is characterized by two adenosine molecules linked together by a chain of four phosphates connected at the 5' positions.

What is the general significance of adenosine polyphosphates like Ap4A?

Adenosine polyphosphates, including Ap4A, are known to be capable of triggering various physiological responses within organisms. This suggests they play roles in cellular signaling or regulation.

What are the IUPAC and common names for Ap4A?

The IUPAC name for Ap4A is O1,O7-Di(5'-deoxyadenosin-5'-yl) tetrahydrogen tetraphosphate. It is also commonly referred to as Diadenosine tetraphosphate, 5',5'''-Diadenosine tetraphosphate, and Ap4A.

What is the chemical formula and molar mass of Ap4A?

The chemical formula for Ap4A is C20H28N10O19P4, and its molar mass is approximately 836.390 grams per mole.

How is Ap4A synthesized in eukaryotes through a non-canonical activity?

In eukaryotes, Ap4A can be generated by a non-canonical function of the enzyme Lysyl-tRNA synthetase (LysRS). This specific activity is triggered when LysRS is phosphorylated on serine 207 and subsequently detaches from the multi-synthetase complex (MSC).

What is the role of Ap4A as a signaling molecule in eukaryotes?

Ap4A functions as a second messenger in eukaryotic cells, participating in signaling pathways. It has been identified as a key component in the LysRS-Ap4A-MITF signaling pathway.

How does Ap4A interact with the MITF-HINT1 complex?

Ap4A binds to the histidine triad nucleotide-binding protein 1 (HINT1), which is part of an inhibitory complex with the Microphthalmia-associated transcription factor (MITF). This binding releases MITF, allowing it to increase the transcription of its target genes.

Beyond MITF, what other transcription factor does Ap4A positively regulate?

Ap4A also positively influences the activity of the transcription factor USF2. It achieves this through a molecular mechanism similar to the one it employs with MITF.

What role does Ap4A play in the function of dendritic cells (DCs)?

In dendritic cells (DCs), an increased intracellular concentration of Ap4A has been observed to enhance their motility and improve their ability to present antigens. This suggests Ap4A plays a role in immune cell function and communication.

How does Ap4A influence dendritic cell function at the molecular level?

The enhancement of dendritic cell motility and antigen presentation by Ap4A is associated with alterations in the small GTPases present within these cells. Small GTPases are proteins involved in regulating cell movement and signaling.

How was the role of Ap4A in dendritic cells discovered?

The role of Ap4A in dendritic cells was elucidated by studying mice that were deficient in the enzyme NUDT2. NUDT2 is known to act as a hydrolase for Ap4A, meaning it breaks down Ap4A, and its absence allowed researchers to observe the effects of elevated Ap4A levels.

What is the function of the enzyme NUDT2 in relation to Ap4A?

NUDT2 serves as a hydrolase for Ap4A, which means it is responsible for breaking down Ap4A molecules within the cell. This enzyme plays a crucial role in controlling the intracellular levels of Ap4A.

Can Ap4A induce cell death, and if so, how?

Yes, Ap4A has been shown to induce apoptosis, or programmed cell death, in several cell lines. The exact mechanism by which it triggers apoptosis is still unknown, but it has been noted that the degradation of Ap4A is necessary for this process, as hydrolysis-resistant versions of the molecule did not cause cell death.

What is the function of Ap4A in prokaryotes, such as E. coli?

In prokaryotes like E. coli, Ap4A functions as an alarmone. Alarmones are signaling molecules that are produced in response to cellular stress.

Under what conditions does the concentration of Ap4A increase in E. coli?

The intracellular concentration of Ap4A increases in E. coli specifically when the bacteria are subjected to heat stress. This indicates its role as a stress response molecule.

How can Ap4A be incorporated into RNA in prokaryotes?

Ap4A, along with other dinucleoside polyphosphates, can be incorporated into the 5' end of RNA molecules as a cap structure. This process involves the RNA polymerase enzyme.

What is the significance of Ap4A acting as a 5' RNA cap in bacteria?

When Ap4A is incorporated as a 5' cap on RNA molecules in bacteria, the intracellular levels of these capped RNAs increase during stress conditions. This suggests that the cap structure may provide increased stability to the RNA molecule.

What type of bacteria is Myxococcus xanthus, and what is its relevance to Ap4A synthesis?

Myxococcus xanthus is a type of Gram-negative bacteria. Its lysyl-tRNA synthetase enzyme, known as LysS, is capable of synthesizing diadenosine tetraphosphates (Ap4A) when adenosine triphosphate (ATP) is available.

How is Diadenosine pentaphosphate (Ap5A) related to Ap4A synthesis in Myxococcus xanthus?

In Myxococcus xanthus, Diadenosine pentaphosphate (Ap5A) can be synthesized from Ap4A and ATP, indicating a metabolic pathway where Ap4A serves as a precursor to Ap5A.

What is the chemical structure of Ap4A?

Ap4A consists of two adenosine molecules linked together. The linkage occurs between the 5' carbon of the ribose sugar on one adenosine and the 5' carbon of the ribose sugar on the other adenosine, with a chain of four phosphate groups connecting them.

What does the term ubiquitous mean in the context of Ap4A's presence?

When Ap4A is described as ubiquitous, it means it is found commonly or is present everywhere within the biological systems mentioned, ranging from simple organisms like bacteria to complex ones like humans.

What is a putative alarmone?

A putative alarmone is a molecule that is suspected or believed to function as an alarmone. Alarmones are signaling molecules produced by cells in response to various stresses, alerting other cells or triggering defense mechanisms.

What is the role of the multi-synthetase complex (MSC) in relation to LysRS and Ap4A?

The multi-synthetase complex (MSC) is a cellular structure to which Lysyl-tRNA synthetase (LysRS) normally binds. The dissociation of LysRS from the MSC, following phosphorylation, is a condition that activates its non-canonical synthesis of Ap4A.

What is the significance of Ap4A binding to HINT1?

Ap4A's binding to HINT1 is significant because HINT1 is part of an inhibitory complex with MITF. By binding to HINT1, Ap4A effectively releases MITF, thereby activating MITF's function in gene transcription.

What is the function of MITF in the context of Ap4A signaling?

MITF (Microphthalmia-associated transcription factor) is a transcription factor whose activity is regulated by Ap4A. When released from its inhibitor (HINT1) by Ap4A binding, MITF increases the transcription of its target genes.

What is the function of USF2 in cellular processes?

USF2 (Upstream Stimulatory Factor 2) is a transcription factor. The text indicates that Ap4A positively regulates its activity, suggesting USF2 is involved in gene regulation processes influenced by Ap4A.

What are small GTPases, and why is their alteration by Ap4A important in dendritic cells?

Small GTPases are a family of proteins that act as molecular switches, regulating various cellular processes including cell movement, signaling, and growth. Their alteration by Ap4A in dendritic cells is linked to improved cell motility and antigen presentation, which are crucial functions for immune surveillance.

What is the biological significance of Ap4A inducing apoptosis?

The induction of apoptosis by Ap4A suggests it can play a role in programmed cell death, a fundamental process for development, tissue homeostasis, and eliminating damaged or infected cells. The fact that its degradation is necessary implies a controlled or regulated cell death pathway.

What does it mean for Ap4A to be a substrate for RNA polymerase?

When Ap4A is a substrate for RNA polymerase, it means that the enzyme can use Ap4A in its biochemical reactions. In this context, RNA polymerase incorporates Ap4A into the 5' end of RNA molecules, particularly under stress conditions in bacteria.

What is the difference between Ap4A and Ap5A in terms of their synthesis?

Ap4A is synthesized by the enzyme LysS in Myxococcus xanthus from ATP. Ap5A, on the other hand, is synthesized from Ap4A and ATP in the same organism, indicating a sequential synthesis pathway.

What is the CAS Registry Number for Ap4A?

The CAS Registry Number for Diadenosine tetraphosphate (Ap4A) is 5542-28-9. This is a unique numerical identifier for chemical substances.

What does the InChI string represent for Ap4A?

The InChI (International Chemical Identifier) string for Ap4A is a standardized, unique textual identifier for chemical substances, used for information retrieval and unambiguous representation of molecular structures. The provided InChI string is InChI=1S/C20H28N10O19P4/c21-15-9-17(25-3-23-15)29(5-27-9)19-13(33)11(31)7(45-19)1-43-50(35,36)47-52(39,40)49-53(41,42)48-51(37,38)44-2-8-12(32)14(34)20(46-8)30-6-28-10-16(22)24-4-26-18(10)30/h3-8,11-14,19-20,31-34H,1-2H2,(H,35,36)(H,37,38)(H,39,40)(H,41,42)(H2,21,23,25)(H2,22,24,26)/t7-,8-,11-,12-,13-,14-,19-,20-/m1/s1.

What does the SMILES string represent for Ap4A?

The SMILES (Simplified Molecular Input Line Entry System) string for Ap4A is a chemical notation that represents its molecular structure in a linear text format. The SMILES string provided is C1=NC2=C(C(=N1)N)N=CN2[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)OC[C@@H]4[C@H]([C@H]([C@@H](O4)N5C=NC6=C5N=CN=C6N)O)O)O)O.

What is the significance of the standard state note in the infobox?

The note about materials being in their standard state (at 25°C and 100 kPa) indicates that the properties listed, such as molar mass, are typically reported under these specific, common laboratory conditions for consistency and comparability.

What is the relationship between LysRS phosphorylation and its Ap4A synthesis activity?

Phosphorylation of Lysyl-tRNA synthetase (LysRS) on serine 207 is a key event that activates its non-canonical synthesis of Ap4A. This phosphorylation also leads to LysRS dissociating from the multi-synthetase complex (MSC), further enabling this alternative function.

How does Ap4A contribute to the regulation of gene transcription in eukaryotes?

Ap4A contributes to gene transcription regulation by binding to HINT1, which is part of an inhibitory complex with the transcription factor MITF. This binding releases MITF, allowing it to promote the transcription of its target genes.

What is the potential impact of Ap4A on cellular stress responses?

Ap4A appears to be involved in cellular stress responses in both prokaryotes and eukaryotes. In bacteria like E. coli, its levels rise under heat stress, and it can stabilize RNA. In eukaryotes, it is involved in signaling pathways that may respond to cellular conditions.

What is the role of Ap4A in the context of RNA stability in bacteria?

In bacteria, Ap4A can be incorporated as a 5' cap onto RNA molecules. This capping process, facilitated by RNA polymerase, is associated with increased RNA stability, particularly under stress conditions.

What is the difference between Ap4A and other dinucleoside polyphosphates mentioned in the text?

The text mentions Ap4A alongside other dinucleoside polyphosphates, such as Ap5A. While Ap4A is composed of two adenosine units linked by four phosphates, Ap5A has five phosphates. The text also notes that Ap4A and other dinucleoside polyphosphates can act as 5' RNA caps in bacteria.

What is the significance of Ap4A's presence in both prokaryotes and eukaryotes?

Ap4A's presence in both prokaryotes (like bacteria) and eukaryotes (like humans) suggests it plays fundamental roles in cellular processes that are conserved across different domains of life. These roles appear to include stress response, signaling, and regulation of gene expression.

What is the primary function of the enzyme Lysyl-tRNA synthetase (LysRS) under normal conditions?

Under normal physiological conditions, Lysyl-tRNA synthetase (LysRS) is primarily involved in protein synthesis by attaching the amino acid lysine to its corresponding transfer RNA (tRNA). The text highlights its non-canonical activity in synthesizing Ap4A, implying this is a secondary or stress-related function.

What is the potential impact of Ap4A on cellular motility?

Ap4A has been shown to positively impact cellular motility, particularly in dendritic cells. This suggests it plays a role in regulating cell movement, which is important for various physiological processes including immune responses and tissue development.

What does the term alarmone signify regarding Ap4A's role in bacteria?

When Ap4A is referred to as an alarmone in bacteria like E. coli, it means it acts as a signaling molecule that is produced in response to cellular stress, such as heat shock. This alarm signal likely triggers adaptive mechanisms within the bacterial cell.

How does Ap4A's role in dendritic cells relate to immune function?

Ap4A's ability to improve dendritic cell motility and antigen presentation directly relates to immune function. Enhanced motility allows immune cells to patrol tissues more effectively, while improved antigen presentation is critical for initiating adaptive immune responses against pathogens.

What is the relationship between Ap4A and transcription factors like MITF and USF2?

Ap4A acts as a regulator for transcription factors MITF and USF2. It positively influences their activity, either by releasing MITF from an inhibitory complex or through similar mechanisms for USF2, ultimately affecting gene expression.

What is the significance of Ap4A's structure, specifically the tetraphosphate chain?

The tetraphosphate chain (four phosphate groups) is a key structural feature of Ap4A that links the two adenosine molecules. This chain is crucial for its chemical properties and its ability to interact with various cellular targets, influencing its function as a signaling molecule or substrate.

What does the term non-canonical activity imply for Lysyl-tRNA synthetase?

The term non-canonical activity for Lysyl-tRNA synthetase (LysRS) implies that it performs a function outside its primary, well-established role. In this case, its primary role is in protein synthesis, while its non-canonical activity is the synthesis of Ap4A.

What is the role of Ap4A in the context of the LysRS-Ap4A-MITF signaling pathway?

In the LysRS-Ap4A-MITF signaling pathway, Ap4A acts as a crucial link. It is synthesized by LysRS and then interacts with the HINT1-MITF complex, leading to the release of MITF and subsequent activation of gene transcription.

What is the CAS number for Ap4A?

The CAS Registry Number for Ap4A is 5542-28-9.

What is the chemical formula for Ap4A?

The chemical formula for Ap4A is C20H28N10O19P4.

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What is Ap4A?

Molecular Structure

Diadenosine tetraphosphate, commonly abbreviated as Ap4A, is a molecule composed of two adenosine units linked by a chain of four phosphate groups connected via a 5'-5' phosphodiester bond. This unique structure allows it to participate in various cellular processes.

Ubiquitous Presence

Ap4A is found across a wide range of organisms, from simple bacteria to complex multicellular life, including humans. Its presence in diverse biological systems underscores its fundamental importance in cellular physiology.

Physiological Roles

As a member of the adenosine polyphosphate family, Ap4A is recognized for its capacity to elicit multiple physiological effects. It is often described as a potential "alarmone," signaling cellular stress or changes in metabolic state.

Chemical Identifiers

Chemical Data

Detailed information regarding the chemical identity and properties of Ap4A is crucial for researchers and scientists. This includes systematic nomenclature, registry numbers, and structural data.

Ap4A
Names
[Image removed as per instructions - Wikimedia image link was present]
IUPAC name O¹,O⁷-Di(5′-deoxyadenosin-5′-yl) tetrahydrogen tetraphosphate
Systematic IUPAC name O¹,O⁷-Bis{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl} tetrahydrogen tetraphosphate
Other names Diadenosine tetraphosphate; 5',5'''-Diadenosine tetraphosphate; AppppA
Identifiers
Chemical nomenclature	5542-28-9
3D model (JSmol)	Interactive image
ChEBI	CHEBI:17422
ChEMBL	ChEMBL339385
ChemSpider	20402
KEGG	C01260
PubChem CID	21706
InChI InChI=1S/C20H28N10O19P4/c21-15-9-17(25-3-23-15)29(5-27-9)19-13(33)11(31)7(45-19)1-43-50(35,36)47-52(39,40)49-53(41,42)48-51(37,38)44-2-8-12(32)14(34)20(46-8)30-6-28-10-16(22)24-4-26-18(10)30/h3-8,11-14,19-20,31-34H,1-2H2,(H,35,36)(H,37,38)(H,39,40)(H,41,42)(H2,21,23,25)(H2,22,24,26)/t7-,8-,11-,12-,13-,14-,19-,20-/m1/s1 Key: YOAHKNVSNCMZGQ-XPWFQUROSA-N
SMILES C1=NC2=C(C(=N1)N)N=CN2[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)OC[C@@H]4[C@H]([C@H]([C@@H](O4)N5C=NC6=C5N=CN=C6N)O)O)O)O
Properties
Chemical formula	C₂₀H₂₈N₁₀O₁₉P₄
Molar mass	836.390 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Cellular Functions

Signaling Molecule

Ap4A acts as a signaling molecule, mediating various cellular responses. Its concentration often fluctuates in response to cellular stress, suggesting a role in communication pathways that regulate cell behavior and survival.

Gene Regulation

Ap4A has been implicated in the regulation of gene transcription. It can interact with specific transcription factors, influencing the expression of genes critical for cellular processes.

Stress Response

In prokaryotes, Ap4A functions as an alarmone, accumulating during periods of cellular stress such as heat shock. This accumulation signals a state of stress and can trigger adaptive responses, including increased RNA stability.

Role in Eukaryotes

Synthesis and Pathways

In eukaryotic cells, Ap4A can be synthesized by a non-canonical activity of Lysyl-tRNA synthetase (LysRS), particularly when LysRS is phosphorylated and dissociates from the multi-synthetase complex (MSC). This highlights a dual role for enzymes involved in protein synthesis.

MITF and USF2 Regulation

Ap4A plays a role in the LysRS-Ap4A-MITF signaling pathway. It binds to the inhibitory complex of Histidine Triad Nucleotide-Binding Protein 1 (HINT1) and the Microphthalmia-associated Transcription Factor (MITF), releasing MITF and promoting the transcription of its target genes. Ap4A also positively regulates the transcription factor USF2 via a similar mechanism.

Dendritic Cell Function

Research indicates Ap4A influences the function of dendritic cells (DCs). Increased intracellular Ap4A levels enhance DC motility and antigen presentation capabilities by modulating small GTPases within these cells. This effect was observed in mice deficient in NUDT2, an enzyme that degrades Ap4A.

Apoptosis Induction

Interestingly, Ap4A has also been shown to induce apoptosis (programmed cell death) in several cell lines. The precise mechanism remains under investigation, but it is known that hydrolysis-resistant analogues of Ap4A do not elicit this apoptotic effect, suggesting the molecule's intact form is required.

Role in Prokaryotes

Alarmone Function

In prokaryotes like E. coli, Ap4A serves as a critical alarmone. Its intracellular concentration rises significantly during stress conditions, such as heat shock, signaling a cellular distress state to the organism.

RNA Stabilization

Ap4A, along with other dinucleoside polyphosphates, can be incorporated into the 5' cap of RNA molecules. This capping process, facilitated by RNA polymerase, increases the stability of the RNA, particularly under stressful conditions where RNA integrity is compromised.

Synthesis in Bacteria

In bacteria such as Myxococcus xanthus, the enzyme Lysyl-tRNA synthetase (LysS) synthesizes Ap4A when adenosine triphosphate (ATP) is available. This enzyme can also synthesize diadenosine pentaphosphate (Ap5A) from Ap4A and ATP, indicating a cascade of polyphosphate synthesis.

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References

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Ap4A Unveiled

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What is Ap4A? ℹ️

🔗 Molecular Structure

🌍 Ubiquitous Presence

⚡ Physiological Roles

Chemical Identifiers 🔢

🔬 Chemical Data

Cellular Functions ⚙️

💡 Signaling Molecule

⬆️ Gene Regulation

🛡️ Stress Response

Role in Eukaryotes 👤

🛠️ Synthesis and Pathways

📜 MITF and USF2 Regulation

🦠 Dendritic Cell Function

💀 Apoptosis Induction

Role in Prokaryotes 🦠

🚨 Alarmone Function

📄 RNA Stabilization

🔬 Synthesis in Bacteria

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📜 Important Notice

Dive in with Flashcard Learning!

What is Ap4A?

Molecular Structure

Ubiquitous Presence

Physiological Roles

Chemical Identifiers

Chemical Data

Cellular Functions

Signaling Molecule

Gene Regulation

Stress Response

Role in Eukaryotes

Synthesis and Pathways

MITF and USF2 Regulation

Dendritic Cell Function

Apoptosis Induction

Role in Prokaryotes

Alarmone Function

RNA Stabilization

Synthesis in Bacteria

Teacher's Corner

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Test Your Knowledge!

Gamer's Corner

Discover other topics to study!

References

Feedback & Support

Disclaimer

Important Notice