Cyclic Nucleotides and PDE in Malaria
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Questions and Answers

Which cyclic nucleotide is produced by purine nucleotide cyclases using ATP?

  • cAMP (correct)
  • cGMP
  • cCMP
  • cUMP

What is the primary role of cyclic nucleotide phosphodiesterases (PDEs)?

  • Synthesize cAMP and cGMP
  • Regulate ATP and GTP levels
  • Activate PKA and PKG
  • Hydrolyze cyclic nucleotides (correct)

Which of the following PDEs in P.falciparum is suggested to be essential for asexual blood stage development?

  • PDEδ
  • PDEα
  • PDEβ (correct)
  • PDEγ

How many phosphodiesterases are encoded in the P.falciparum genome?

<p>Four (C)</p> Signup and view all the answers

Which enzyme is known to be associated with the hydrolysis of cGMP?

<p>PDEδ (A), PDEα (B), PDEγ (C)</p> Signup and view all the answers

What is the effect of cyclic nucleotide levels reaching a concentration threshold in the cell?

<p>Activate cyclic nucleotide-dependent protein kinases (B)</p> Signup and view all the answers

What has been observed regarding the PDEβ enzyme in previous studies?

<p>It has been indicated as essential based on low growth rates. (A)</p> Signup and view all the answers

What primarily regulates cyclic nucleotide levels in the cell?

<p>The balance of cyclases and phosphodiesterases (A)</p> Signup and view all the answers

What is the primary role of PfPDEβ in blood stage malaria parasites?

<p>Regulating cAMP levels (B)</p> Signup and view all the answers

What effect does ablation of PfPDEβ have on PKA activity?

<p>Causes hyperactivity of PKA (B)</p> Signup and view all the answers

How does the localization of PfPDEβ from apical to peripheral locations impact its function?

<p>It regulates local cyclic nucleotide levels (D)</p> Signup and view all the answers

Which phosphorylation sites are shown to have dependence on PKA in P.falciparum?

<p>MyoA S19 and AMA1 S610 (A)</p> Signup and view all the answers

What consequence does dysregulated phosphorylation due to hyperactivity of PKA lead to?

<p>Loss of merozoite invasive capacity (C)</p> Signup and view all the answers

Which of the following licensed drugs targets human phosphodiesterases?

<p>Roflumilast (B)</p> Signup and view all the answers

What potential future work is suggested regarding PDEβ function in malaria parasites?

<p>Understanding the dynamics of its function (A)</p> Signup and view all the answers

What is the differentiation of hydrolysis that requires further understanding in relation to PDEβ?

<p>Hydrolysis of cAMP and cGMP (D)</p> Signup and view all the answers

What is the relationship between PDEβ disruption and cAMP levels in malaria parasites?

<p>PDEβ disruption leads to increased cAMP levels. (B)</p> Signup and view all the answers

Which of the following roles does cAMP signalling play in malaria parasites as suggested by the phosphoproteomic analysis?

<p>Involvement in chromatin organization. (C)</p> Signup and view all the answers

What effect does PDEβ knockout have on blood stage replication in malaria parasites?

<p>It causes dysregulation of key events. (B)</p> Signup and view all the answers

Which other cyclic nucleotide is mentioned alongside cAMP in the context of PDEβ?

<p>Both cAMP and cGMP. (A)</p> Signup and view all the answers

Which cellular process is NOT directly associated with cAMP signalling in the context of malaria parasites?

<p>Glycolysis modulation. (A)</p> Signup and view all the answers

Which of the following could potentially be a target for the development of new antimalarial drugs?

<p>PDEβ regulation mechanisms. (C)</p> Signup and view all the answers

Which component is important for the malaria parasite's invasion of erythrocytes?

<p>EBA175. (A)</p> Signup and view all the answers

Which pathway does NOT get hyperactivated as a result of elevated cAMP levels?

<p>Calcium signaling. (C)</p> Signup and view all the answers

Flashcards

PDEβ

An enzyme in malaria parasites that breaks down cAMP and cGMP, leading to increased cAMP levels and hyperactivation of PKA.

cAMP

Cyclic adenosine monophosphate, a molecule that acts as a signaling molecule in cells.

cGMP

Cyclic guanosine monophosphate, another signaling molecule in cells.

PKA

Protein kinase A, an enzyme activated by cAMP that phosphorylates proteins, affecting their activity.

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Phosphoproteomic analysis

A technique used to study the phosphorylation of proteins on a large scale, providing insights into cellular processes.

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Chromatin organization

The way DNA is packaged within the nucleus, affecting gene expression.

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Erythrocyte invasion

The process by which malaria parasites enter red blood cells to multiply.

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Anti-malarial drugs

Medicines used to treat malaria infections.

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Cyclic Nucleotides

Cyclic nucleotides, like cAMP and cGMP, are important signaling molecules in cells. They are involved in a wide range of cellular processes, such as cell growth, metabolism, and even parasite development.

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cAMP and cGMP synthesis

cAMP and cGMP are synthesized from ATP and GTP respectively by the enzyme Purine Nucleotide Cyclase (PNC).

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cAMP and cGMP breakdown

Cyclic Nucleotide Phosphodiesterases (PDEs) break down cAMP and cGMP by hydrolysis. They act as the 'off switch' for these signaling molecules.

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PDEα, PDEγ, PDEδ

These PDEs are found in the parasite Plasmodium falciparum. While they are involved in cGMP hydrolysis, they are not essential for the parasite's survival in the blood stage.

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PKA and PKG

Protein Kinase A (PKA) and Protein Kinase G (PKG) are activated by cAMP and cGMP respectively. They act as downstream effectors in the signaling pathways.

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PlasmoGEM

A project aimed at creating a comprehensive set of gene knockouts in the malaria parasite Plasmodium berghei. This project helps understand essential genes and pathways.

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Transposon mutagenesis

A method used to study the function of genes by inserting a transposon (jumping gene) into the DNA. This can disrupt the gene's function, allowing scientists to study its role.

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Merozoite Invasion

The process by which a malaria parasite enters a new red blood cell, a crucial step in its lifecycle.

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How does PfPDEβ affect malaria parasite development?

PfPDEβ controls cAMP levels, which in turn regulate PKA activity. This affects parasite development, particularly during the crucial stage of invading new red blood cells.

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What happens when PfPDEβ is removed?

Without PfPDEβ, the malaria parasite's PKA becomes overactive. This causes problems with parasite growth and invasion, sometimes even leading to parasite death.

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Why is PfPDEβ a potential target for new malaria drugs?

PfPDEβ is essential for the malaria parasite's survival, making it an attractive target for drugs that could block its function and prevent parasite development.

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Study Notes

Phosphodiesterase Beta Regulation of cAMP Signaling in Malaria

  • Phosphodiesterase β (PDEβ) is a major regulator of malaria parasite differentiation
  • PDEβ hydrolyzes both cyclic GMP (cGMP) and cyclic AMP (cAMP)
  • PDEβ is essential for blood stage viability in Plasmodium falciparum
  • Disruption of PDEβ leads to a significant reduction in erythrocyte invasion and rapid death of merozoites
  • This effect stems from elevated cAMP levels and hyperactivation of the cAMP-dependent protein kinase (PKA)
  • Phosphoproteomic analysis of PDEβ-null parasites reveals a >2-fold increase in phosphorylation at over 200 phosphosites, with more than half conforming to PKA substrate consensus sequences
  • PDEβ likely plays a crucial role in regulating the correct temporal activation of PKA for erythrocyte invasion, while suppressing untimely PKA activation during early intra-erythrocytic development

PDEβ Localization and Function

  • PfPDEβ is a dual-specific PDE that translocates to a likely apical location in merozoites, then to the peripheral membrane as development proceeds
  • PfPDEβ expression increases during the latter half of the 48-hour asexual blood-stage cycle, peaking in mature schizonts
  • It likely translocates from the endoplasmic reticulum (ER) to an apical location, followed by release to the plasma membrane of merozoites

PDEβ Essentiality for Viability

  • A conditional knockout approach using rapamycin-inducible Cre recombinase was used to disrupt PfPDEβ
  • Disruption of PDEβ caused severe reduction in erythrocyte invasion and rapid post-invasion parasite death
  • This correlated with reduced cyclic AMP (cAMP) hydrolyzing activity and a 3-fold increase in intracellular cAMP levels
  • Successful invasion, although observed in some cases, was followed by rapid and significant loss of PDEβ-null parasites, preceding normal ring stage development, within 2 cycles

Impact on PKA Activity and Invasion Processes

  • Dysregulation of PKA activity due to elevated intra-parasite cAMP levels has profound effects on downstream processes critical for invasion
  • Phosphorylation of PKA substrates, such as myosin A (MyoA, at site S19), is significantly increased in PDEβ-null parasites, suggesting elevated PKA activity.
  • MyoA S19 phosphorylation appears to be PKG-independent in PfPDEβ-null schizonts.
  • Premature PKA activation potentially leading to premature proteolytic shedding of apical membrane protein AMA1, which plays a role in host cell invasion,
  • This is because inhibition of PKA in wild type parasites partially rescued the BIPPO treated schizont morphology, and this is not observed with PKG inhibitors.

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Description

This quiz focuses on the role of cyclic nucleotides and phosphodiesterases in malaria parasites, particularly Plasmodium falciparum. It includes questions about enzyme production, regulation, and the effects of dysregulated phosphorylation related to malaria's blood stage development.

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