pdsA (PdsA, DdPDE1, PDE1) is the major extracellular cyclic nucleotide phosphodiesterase of Dictyostelium discoideum. It is a secreted glycoprotein of the class II cyclic nucleotide phosphodiesterase family that is synthesized with a cleaved signal peptide and is released into the medium. Older biochemical preparations suggested a cell-surface-associated form, whereas imaging of functional tagged PdsA during chemotaxis localized its intracellular pool to the endoplasmic reticulum and did not detect plasma-membrane association. The enzyme hydrolyzes extracellular 3',5'-cyclic AMP to 5'-AMP with a preference for cAMP over cGMP, but has dual specificity and also hydrolyzes 3',5'-cyclic GMP. By degrading the extracellular cAMP chemoattractant, PdsA sharpens the spatial cAMP gradient and terminates and resets the propagating cAMP waves that guide chemotaxis and streaming during starvation-induced aggregation; cells lacking PdsA fail to aggregate. Its activity is negatively modulated by a secreted heat-stable glycoprotein inhibitor (PdiA), and this inhibition is relieved by reducing agents such as dithiothreitol. PdsA expression is developmentally controlled through multiple promoters, including a prestalk-specific promoter whose activity is required for later morphogenesis (slug formation and culmination).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0110034 negative regulation of adenylate cyclase-activating glucose-activated G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | UNDECIDED | Summary: The glucose-activated pathway specificity is a substantive concern, but the available evidence does not establish loss of the ancestral regulatory role. Reason: The PTHR28283 IBD at PTN002001416 derives from a glucose-signaling source context. The verified GO:0110034 definition requires that glucose-activated GPCR pathway; ordinary cAMP-receptor feedback alone does not establish it. The focused report claims the pathway is absent in Dictyostelium but explicitly lists this as an unresolved knowledge gap and did not examine the fungal primary source in full. PdsA being secreted and cAR1 being cAMP-activated do not by themselves exclude an additional nutrient-signaling contribution. PMID:19477920 tested ACA activation after 10 micromolar cAMP in cells prepared with exogenous PDE; it is not a glucose-pathway loss experiment. Withdraw the provisional REMOVE, retain uncertainty, and seek expert assessment of source pathway scope and target conservation. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002001416 Β· PTN002001416 UNRESOLVED The node is verified in PTHR28283. Glucose-versus-cAMP pathway specificity is unresolved; no target-specific loss is established by extracellular specialization or the report absence claim. Supporting Evidence: file:DICDI/pdsA/pdsA-hypotheses/extracellular-pde-and-camp-pathway-regulation/openscientist.md Is there any Dictyostelium glucose-sensing GPCRβadenylate cyclase pathway? PMID:19477920 Cells were stimulated with 10 ΞΌM cAMP. |
| GO:0141162 negative regulation of cAMP/PKA signal transduction | IBA GO_REF:0000033 | UNDECIDED | Summary: Extracellular PdsA and intracellular RegA degrade different cAMP pools, but that does not settle whether PdsA negatively regulates cAMP/PKA signaling through feedback. Reason: GO:0141162 covers any process reducing cAMP/PKA signaling; it does not require direct hydrolysis of the cAMP bound by PKA. PMID:17040207 demonstrates pool partition, and PMID:30790701/11390363 establish RegA control of PKA, but neither excludes an upstream PdsA role. PMID:23473502 demonstrates positive/negative feedback through extracellular cAMP clearance and synthesis. The focused report admits that no PdsA-specific intracellular-cAMP/PKA assay was found, so its refuted verdict goes beyond the evidence. The 2009 normal stimulated ACA machinery result likewise does not exclude feedback under native gradients. Keep the PTN002001416 inference unresolved pending a pathway-output assessment; do not assert either a proven PKA role or proven loss. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002001416 Β· PTN002001416 UNRESOLVED Different direct substrate pools do not refute a broader negative-regulation process. The report did not find a discriminating PdsA PKA-output assay; functional retention versus loss remains unsettled. Supporting Evidence: PMID:17040207 Intracellular cAMP is degraded by the DdPDE2, a class I enzyme regulated by histidine kinase/phospho-relay, and by the cAMP-/cGMP-stimulated class II DdPDE6. PMID:23473502 The observed precise regulation of PDE expression together with degradation of extracellular cAMP by PDE form a dual positive and negative feedback circuit file:DICDI/pdsA/pdsA-hypotheses/extracellular-pde-and-camp-pathway-regulation/openscientist.md no assay shows PdsA setting intracellular cAMP |
| GO:0047555 3',5'-cyclic-GMP phosphodiesterase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PdsA is a dual-specificity phosphodiesterase that hydrolyzes both cAMP and cGMP, so cGMP phosphodiesterase activity is a genuine molecular function, although cAMP is the preferred substrate. Reason: Direct biochemical characterization shows PdsA (DdPDE1) has dual cAMP/cGMP specificity, consistent with the assigned EC 3.1.4.35 (cGMP) activity. The IBA inference is corroborated by experimental evidence for this gene. Supporting Evidence: PMID:17040207 Both DdPDE1 and DdPDE7 are PDEs with dual cAMP/cGMP specificity, and are strongly inhibited by DTT and insensitive to IBMX. |
| GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity | IBA GO_REF:0000033 | ACCEPT | Summary: cAMP phosphodiesterase activity is the core, well-established molecular function of PdsA and is strongly supported by direct biochemical evidence. Reason: PdsA is the principal enzyme degrading extracellular cAMP in Dictyostelium; the IBA inference matches the experimentally determined activity. Supporting Evidence: PMID:17040207 Extracellular cAMP is degraded predominantly by the class II high-affinity enzyme DdPDE1 |
| GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of the core cAMP phosphodiesterase activity, consistent with direct experimental evidence. Reason: This is the central catalytic activity of PdsA and is experimentally confirmed. Supporting Evidence: PMID:17040207 Extracellular cAMP is degraded predominantly by the class II high-affinity enzyme DdPDE1 |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: PdsA is a secreted enzyme released into the extracellular medium, so extracellular region localization is correct. Reason: The protein carries a cleaved signal peptide and is secreted; extracellular localization is directly demonstrated by purification of active enzyme from culture supernatant. Supporting Evidence: PMID:17040207 both DdPDE1 and DdPDE7 are secreted into the medium and are attached to the cell surface |
| GO:0006198 cAMP catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Degradation of cAMP to AMP is the core biological process enabled by PdsA's phosphodiesterase activity. Reason: PdsA is the main enzyme catabolizing extracellular cAMP in Dictyostelium, making this process annotation directly appropriate. Supporting Evidence: PMID:17040207 DdPDE1 is the main PDE that degrades extracellular cAMP during cell aggregation and is thereby essential for shaping cAMP waves |
| GO:0008081 phosphoric diester hydrolase activity | IEA GO_REF:0000002 | MODIFY | Summary: This is a correct but overly general parent term for the specific cyclic-nucleotide phosphodiesterase activity of PdsA. Reason: Phosphoric diester hydrolase activity is a high-level parent. The experimentally established activity is more precisely 3',5'-cyclic-nucleotide phosphodiesterase activity (dual cAMP/cGMP), so a more specific term is preferred. Proposed replacements: 3',5'-cyclic-nucleotide phosphodiesterase activity Supporting Evidence: PMID:17040207 Both DdPDE1 and DdPDE7 are PDEs with dual cAMP/cGMP specificity, and are strongly inhibited by DTT and insensitive to IBMX. |
| GO:0009986 cell surface | IEA GO_REF:0000044 | UNDECIDED | Summary: Cell-surface association is supported by older biochemical fractionation but disputed by direct PdsA imaging during chemotaxis. Reason: The UniProt mapping reflects older surface-associated PDE assignments. The later primary study imaged functional PdsA constructs, detected the intracellular protein at the ER, and explicitly found no plasma-membrane colocalization. The historical surface association and the more recent negative localization result cannot be reconciled from the available evidence; retain the electronic assertion as unresolved. Supporting Evidence: PMID:19477920 We found no colocalization of PdsA-Myc with the plasma membrane (Figure 5C). |
| GO:0047555 3',5'-cyclic-GMP phosphodiesterase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of cGMP phosphodiesterase activity, consistent with the enzyme's demonstrated dual specificity. Reason: PdsA hydrolyzes cGMP in addition to cAMP, as shown biochemically. Supporting Evidence: PMID:17040207 Both DdPDE1 and DdPDE7 are PDEs with dual cAMP/cGMP specificity, and are strongly inhibited by DTT and insensitive to IBMX. |
| GO:0047555 3',5'-cyclic-GMP phosphodiesterase activity | IGI PMID:17040207 Seven Dictyostelium discoideum phosphodiesterases degrade th... | ACCEPT | Summary: Genetic interaction evidence supporting cGMP phosphodiesterase activity; the paper characterizes the contribution of PdsA (DdPDE1) to the degradation of cyclic nucleotide pools including cGMP. Reason: The Bader et al. analysis confirms PdsA as a dual-specificity enzyme contributing to cGMP as well as cAMP degradation. Supporting Evidence: PMID:17040207 Both DdPDE1 and DdPDE7 are PDEs with dual cAMP/cGMP specificity, and are strongly inhibited by DTT and insensitive to IBMX. |
| GO:0004114 3',5'-cyclic-nucleotide phosphodiesterase activity | IDA PMID:6302095 Purification and characterization of the extracellular cycli... | ACCEPT | Summary: Direct biochemical purification and characterization of the extracellular cyclic nucleotide phosphodiesterase demonstrates this activity for PdsA. Reason: The enzyme was purified from aggregation-phase culture supernatant and characterized as a cyclic nucleotide phosphodiesterase, directly supporting this molecular function. Supporting Evidence: PMID:6302095 Extracellular phosphodiesterase for adenosine 3':5'-monophosphate [EC 3.1.4.17] was purified from the supernatant of aggregation phase culture of Dictyostelium discoideum |
| GO:0005576 extracellular region | IDA PMID:6265455 The extracellular cyclic nucleotide phosphodiesterase of Dic... | ACCEPT | Summary: The active extracellular phosphodiesterase was purified from culture medium, directly demonstrating that PdsA is active in the extracellular region. Reason: Purification of the active secreted enzyme directly supports extracellular localization and activity. Supporting Evidence: PMID:6265455 Two forms of the extracellular cyclic nucleotide phosphodiesterase (EC 3.1.4.17) of Dictyostelium discoideum have been purified. |
| GO:0005783 endoplasmic reticulum | IDA PMID:19477920 The group migration of Dictyostelium cells is regulated by e... | ACCEPT | Summary: Endoplasmic reticulum localization from Garcia et al. 2009, whose cached full text directly reports that the intracellular pool of PdsA is in the ER, proposed as a storage/secretion compartment for this secreted phosphodiesterase. Verified against the cached publication. Reason: The full text of PMID:19477920 is cached and explicitly localizes the intracellular pool of PdsA to the endoplasmic reticulum, consistent with ER transit of a signal-peptide-bearing secreted protein. This is a genuine (non-core) intracellular localization of an otherwise extracellular enzyme. Supporting Evidence: PMID:19477920 the intracellular pool of PdsA is localized to the endoplasmic reticulum, which may provide a compartment for storage and secretion of PdsA |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IMP PMID:17040207 Seven Dictyostelium discoideum phosphodiesterases degrade th... | MODIFY | Summary: PdsA clears the extracellular cAMP ligand and resets an adenylate-cyclase-activating receptor loop. Reason: Live GO:0007193 requires a GPCR pathway transmitting a signal by inhibition of adenylyl cyclase. PdsA instead degrades the ligand of the cAMP-receptor pathway that activates ACA, negatively regulating its repeated activation. PMID:17040207 establishes extracellular cAMP turnover and PMID:23473502 describes the resulting feedback circuit. Replace with negative regulation of the activating GPCR pathway (GO:0106072), preserving the original experimental source. This is a directional correction of an existing process assertion, not a new pathway claim. Proposed replacements: negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:17040207 DdPDE1 is the main PDE that degrades extracellular cAMP during cell aggregation and is thereby essential for shaping cAMP waves PMID:23473502 For pulses to be relayed from cell to cell repetitively, secreted cAMP must be cleared and brought down to the subthreshold level. |
| GO:1900115 extracellular regulation of signal transduction | IMP PMID:17040207 Seven Dictyostelium discoideum phosphodiesterases degrade th... | ACCEPT | Summary: PdsA degrades extracellular cAMP, the diffusible chemotactic signal, thereby regulating signal transduction in the extracellular space. This term accurately captures the biological purpose of the enzyme. Reason: Extracellular cAMP degradation by PdsA shapes and resets the cAMP waves that coordinate chemotaxis, which is precisely extracellular regulation of signal transduction. Supporting Evidence: PMID:17040207 DdPDE1 is the main PDE that degrades extracellular cAMP during cell aggregation and is thereby essential for shaping cAMP waves |
| GO:0005515 protein binding | IPI PMID:230476 Binding of inhibitor alters kinetic and physical properties ... | REMOVE | Summary: PdsA forms a complex with the extracellular phosphodiesterase inhibitor PdiA. Reason: The interaction is experimentally supported, but generic protein binding provides no useful account of PdsA phosphodiesterase function. Remove the uninformative annotation without disputing inhibitor binding or inventing a separate molecular function. Supporting Evidence: PMID:230476 The second form is the result of a complex formed with a heat-stable inhibitor and has a Km in the millimolar range. |
| GO:0031153 slug development involved in sorocarp development | IMP PMID:7851634 The phosphodiesterase secreted by prestalk cells is necessar... | KEEP AS NON CORE | Summary: Prestalk-specific PDE expression is required for morphogenesis; blocking PDE activity in prestalk cells (via targeted inhibitor overexpression) blocks slug formation and culmination. This supports a role of PdsA in slug/sorocarp development, downstream of its enzymatic function. Reason: PdsA activity is required for the slug and later morphogenetic stages, but this is a developmental consequence of extracellular cAMP regulation rather than the core molecular function. Supporting Evidence: PMID:7851634 followed by a block in slug formation and an inability to culminate |
| GO:0072720 response to dithiothreitol | IDA PMID:230476 Binding of inhibitor alters kinetic and physical properties ... | KEEP AS NON CORE | Summary: Dithiothreitol strongly stimulates extracellular PDE activity by inactivating the heat-stable inhibitor bound to PdsA. This is an experimentally observed response but a peripheral property, not a core biological function. Reason: The response to DTT reflects relief of inhibitor-mediated suppression of the enzyme rather than a physiological signaling role; keep as non-core. Supporting Evidence: PMID:230476 Treating the enzyme-inhibitor complex with dithiothreitol stimulated enzyme activity 20- to 100-fold |
| GO:0051591 response to cAMP | IDA PMID:2162056 Conditions that alter intracellular cAMP levels affect expre... | KEEP AS NON CORE | Summary: Expression of the PDE gene is regulated by intracellular cAMP levels, so PdsA responds to cAMP at the level of gene expression. This is a regulatory response rather than a core molecular function. Reason: The response-to-cAMP annotation captures developmental/transcriptional regulation of the gene by cAMP, which is contextual rather than the enzyme's core evolved function. Supporting Evidence: PMID:2162056 the magnitude of PDE gene expression is negatively regulated by intracellular cAMP levels |
| GO:1903013 response to differentiation-inducing factor 1 | IDA PMID:2049870 Cyclic nucleotide phosphodiesterase of Dictyostelium discoid... | KEEP AS NON CORE | Summary: The prestalk-specific (2.2 kb) PDE transcript is induced by differentiation-inducing factor (DIF), so PdsA expression responds to DIF-1. This is a transcriptional/developmental response. Reason: DIF-1 induction of the prestalk PDE transcript is a developmental regulatory context, not the core molecular function of the enzyme. Supporting Evidence: PMID:2049870 is induced by differentiation-inducing factor |
| GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity | IDA PMID:6265455 The extracellular cyclic nucleotide phosphodiesterase of Dic... | ACCEPT | Summary: Direct purification and characterization of the extracellular cyclic nucleotide phosphodiesterase supports cAMP phosphodiesterase activity, the core molecular function of PdsA. Reason: The purified secreted enzyme hydrolyzes cAMP, directly supporting this activity. Supporting Evidence: PMID:6265455 Two forms of the extracellular cyclic nucleotide phosphodiesterase (EC 3.1.4.17) of Dictyostelium discoideum have been purified. |
| GO:0030552 cAMP binding | IDA PMID:2722797 The cyclic nucleotide specificity of eight cAMP-binding prot... | ACCEPT | Summary: PdsA binds cAMP as part of its established catalytic substrate recognition. Reason: PMID:2722797 directly analyzes cAMP-phosphodiesterase substrate contacts. The binding term does not require a separate regulatory receptor function, and participation in catalysis makes this a core biochemical property rather than an incidental interaction. A more specific phosphodiesterase annotation can coexist with this experimentally supported binding assertion. Supporting Evidence: PMID:2722797 binding of cAMP to phosphodiesterase involves only O3' and exocyclic oxygen |
| GO:0005886 plasma membrane | IDA NOT PMID:19477920 The group migration of Dictyostelium cells is regulated by e... | ACCEPT | Summary: The NOT plasma-membrane annotation is supported by direct imaging of functional tagged PdsA during chemotaxis. Reason: PMID:19477920 tests plasma-membrane colocalization with cAR1 and reports its absence; both N-terminal YFP and C-terminal Myc constructs rescue development. The authors explicitly conclude that PdsA is not associated with the plasma membrane during chemotaxis and propose ER contamination of older membrane fractions. This is direct negative localization evidence, not simply observation of an ER pool. Accept the NOT annotation in the tested chemotactic context while recording the older conflicting fractionation result. Supporting Evidence: PMID:19477920 We found no colocalization of PdsA-Myc with the plasma membrane (Figure 5C). PMID:19477920 our studies establish that PdsA is not associated with the plasma membrane during chemotaxis. |
| GO:0031152 aggregation involved in sorocarp development | IMP PMID:19477920 The group migration of Dictyostelium cells is regulated by e... | ACCEPT | Summary: PdsA is required for normal aggregation and streaming through extracellular cAMP degradation. Reason: The cited primary paper is available in the cache and directly examines pdsA-null cells. Together with independent extracellular PDE rescue experiments, it establishes that PdsA shapes the external cAMP field required for collective migration. Supporting Evidence: PMID:19477920 the group migration behavior of these cells is compromised even though their signaling machinery is intact. PMID:17040207 UK7 cells fail to aggregate, but can be rescued by adding exogenous PDE activity |
| GO:0031152 aggregation involved in sorocarp development | IEP PMID:25887420 Leaps and lulls in the developmental transcriptome of Dictyo... | ACCEPT | Summary: Developmental PdsA expression accompanies its experimentally established role in aggregation. Reason: The IEP observation is consistent with the independent loss-of-function and extracellular-PDE rescue evidence. Aggregation through extracellular cAMP-wave shaping is a principal biological role of PdsA, so retain the annotation as core consistently with the IMP rows. Supporting Evidence: PMID:17040207 UK7 cells fail to aggregate, but can be rescued by adding exogenous PDE activity |
| GO:0005886 plasma membrane | IDA PMID:9168471 Identification of detergent-resistant plasma membrane microd... | UNDECIDED | Summary: The older plasma-membrane fractionation result conflicts with later direct imaging of functional PdsA during chemotaxis. Reason: PMID:9168471 reports cell-surface phosphodiesterase in a CHAPS-resistant plasma-membrane preparation, but PMID:19477920 directly tested functional PdsA fusions, found no plasma-membrane colocalization and suggested ER contamination of earlier fractions. The conflicting experimental results should not be reconciled by inventing distinct pools. Retain the source record and leave the positive localization unresolved pending assessment of preparation identity, stage and specificity. Supporting Evidence: PMID:9168471 The cell surface phosphodiesterase (PDE) and a downstream effector of cAR1, adenylate cyclase (ACA), were specifically localized in these structures PMID:19477920 We presume that ER contamination in the plasma membrane fractions is responsible for the earlier findings. |
| GO:1902168 response to catechin | IDA PMID:23516620 The green tea catechin epigallocatechin gallate (EGCG) block... | KEEP AS NON CORE | Summary: The green tea catechin EGCG blocks Dictyostelium aggregation, streaming and cAMP-wave-dependent development. This is a peripheral pharmacological response context rather than a core function of PdsA. Reason: The response-to-catechin annotation reflects a small-molecule perturbation of the cAMP-signaling/development program in which PdsA participates; it is contextual and non-core. Supporting Evidence: PMID:23516620 In the presence of EGCG aggregation is delayed, cells do not stream and development is typically stalled at the loose aggregate stage. |
| GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity | IMP PMID:17040207 Seven Dictyostelium discoideum phosphodiesterases degrade th... | ACCEPT | Summary: Loss-of-function (pdsA-null, strain UK7) evidence confirms that PdsA is the main cAMP phosphodiesterase degrading extracellular cAMP. This is the core molecular function. Reason: The pdsA-null phenotype (loss of extracellular cAMP degradation, failure to aggregate) directly supports cAMP phosphodiesterase activity as the central function of the gene. Supporting Evidence: PMID:17040207 DdPDE1 is the main PDE that degrades extracellular cAMP during cell aggregation and is thereby essential for shaping cAMP waves |
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