acaA

id: Q03100
gene_symbol: acaA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: Adenylate cyclase A (ACA, encoded by acaA) is the aggregation-stage
  adenylyl cyclase of Dictyostelium discoideum, a multi-pass transmembrane enzyme
  of the class-4 adenylyl cyclase/guanylyl cyclase family that catalyzes the
  Mg2+-dependent conversion of ATP to 3',5'-cyclic AMP (cAMP). It is the enzyme
  responsible for cAMP synthesis during the aggregation phase of development,
  generating the oscillatory extracellular cAMP waves that act as the
  chemoattractant driving chemotactic cell aggregation (the cAMP relay). ACA
  activity is controlled downstream of the cAMP receptor cAR1 through
  heterotrimeric G proteins and the cytosolic regulator CRAC, with additional
  input from PI3K, RasG/RasC, Rap1 and TORC2 signaling. In polarized, chemotaxing
  cells ACA is enriched in the plasma membrane at the rear (uropod/trailing edge);
  ACA protein and its mRNA are carried on ACA-containing intracellular vesicles to
  the back of cells, where localized translation and vesicle secretion (as
  multivesicular bodies) relay the cAMP signal head-to-tail to trailing cells to
  enable stream formation. Beyond aggregation, ACA-derived cAMP acts through PKA
  during later development, including at the organizing tip where it mediates
  c-di-GMP-induced stalk cell differentiation. Loss of ACA abolishes cAMP
  synthesis and aggregation and impairs suppression of lateral pseudopods during
  chemotaxis. ACA is distinct from the germination/spore adenylyl cyclase ACG and
  the culmination adenylyl cyclase ACR/ACB.
existing_annotations:
- term:
    id: GO:0004016
    label: adenylate cyclase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of adenylate cyclase activity is correct and
      strongly corroborated by direct enzymatic assays on ACA. This is the core
      molecular function of the gene product.
    action: ACCEPT
    reason: ACA is a bona fide adenylyl cyclase (EC 4.6.1.1) responsible for cAMP
      synthesis during aggregation; the IBA inference agrees with multiple direct
      experimental annotations.
    supported_by:
    - reference_id: PMID:1348970
      supporting_text: has little detectable adenylyl cyclase activity and fails
        to aggregate
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ACA is a multi-pass plasma membrane enzyme and functions at the
      plasma membrane, as confirmed by direct biochemical fractionation.
    action: ACCEPT
    reason: ACA is an integral plasma membrane protein enriched in plasma membrane
      microdomains; the phylogenetic localization inference is well supported.
    supported_by:
    - reference_id: PMID:9168471
      supporting_text: adenylate cyclase (ACA), were specifically localized in
        these structures
- term:
    id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ACA is activated downstream of the cAMP receptor cAR1 via
      heterotrimeric G proteins, placing it centrally in this signaling pathway.
    action: ACCEPT
    reason: ACA activation is receptor- and G protein-regulated and it synthesizes
      the cAMP that relays the chemotactic signal; this is a core biological
      process.
    supported_by:
    - reference_id: PMID:16267269
      supporting_text: which synthesizes the chemoattractant cAMP, is essential to
        relay the signal to
- term:
    id: GO:0006171
    label: cAMP biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ACA synthesizes cAMP; cAMP biosynthetic process is a core biological
      process for this enzyme.
    action: ACCEPT
    reason: Directly supported by the catalytic activity (ATP to cAMP) and by loss
      of cAMP synthesis in aca- mutants.
    supported_by:
    - reference_id: PMID:1348970
      supporting_text: has little detectable adenylyl cyclase activity and fails
        to aggregate
- term:
    id: GO:0001931
    label: uropod
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: In polarized cells ACA becomes highly enriched at the uropod; this
      localization is directly documented.
    action: ACCEPT
    reason: UniProt subcellular-location mapping to uropod is confirmed by
      experimental localization of ACA to the uropod of aggregating cells.
    supported_by:
    - reference_id: PMID:26315268
      supporting_text: The localization of adenylyl cyclase A (ACA) to uropod of
        cells is required for the stream formation
- term:
    id: GO:0004016
    label: adenylate cyclase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated RHEA/EC mapping to adenylate cyclase activity, consistent
      with the experimentally established catalytic activity.
    action: ACCEPT
    reason: EC 4.6.1.1 mapping is correct; ACA catalyzes ATP to 3',5'-cyclic AMP.
    supported_by:
    - reference_id: PMID:1348970
      supporting_text: has little detectable adenylyl cyclase activity and fails
        to aggregate
- term:
    id: GO:0009190
    label: cyclic nucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Correct but general parent of cAMP biosynthetic process. The specific
      child (cAMP biosynthetic process) better captures ACA function.
    action: KEEP_AS_NON_CORE
    reason: InterPro2GO inference is accurate but non-specific; the more
      informative term cAMP biosynthetic process is already annotated.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Correct but general. ACA is a membrane protein, but plasma membrane
      and uropod membrane are the informative, well-supported locations.
    action: KEEP_AS_NON_CORE
    reason: Generic membrane is subsumed by the more specific plasma membrane
      and uropod membrane annotations.
- term:
    id: GO:0016849
    label: phosphorus-oxygen lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Correct but general parent of adenylate cyclase activity. Adenylyl
      cyclases are phosphorus-oxygen lyases (EC 4.6.1.-), but the specific term is
      more informative.
    action: KEEP_AS_NON_CORE
    reason: InterPro2GO parent-level MF term; the specific child adenylate cyclase
      activity (GO:0004016) is the informative function.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: General signaling term. ACA does participate in signal transduction
      (cAMP relay) but more specific pathway terms are annotated.
    action: KEEP_AS_NON_CORE
    reason: Broad InterPro2GO term subsumed by the specific adenylate
      cyclase-activating GPCR signaling annotations.
- term:
    id: GO:0060359
    label: response to ammonium ion
  evidence_type: IDA
  original_reference_id: PMID:41406008
  qualifier: acts_upstream_of_or_within
  review:
    summary: ACA-derived cAMP feeds a cascade in which extracellular cAMP is
      converted to adenosine and then to ammonia during tip organizer
      development. This is a peripheral, developmentally contextual role.
    action: KEEP_AS_NON_CORE
    reason: ACA supplies the cAMP upstream of the adenosine/ammonia cascade; the
      link is indirect and not a core function.
    supported_by:
    - reference_id: PMID:41406008
      supporting_text: the consecutive transformation of extracellular cAMP to
        adenosine, and adenosine to ammonia
- term:
    id: GO:1903561
    label: extracellular vesicle
  evidence_type: IDA
  original_reference_id: PMID:19047467
  qualifier: located_in
  review:
    summary: Migrating cells shed ACA-containing vesicles, consistent with an
      extracellular-vesicle localization documented by direct imaging.
    action: ACCEPT
    reason: ACA is found on secreted vesicles that relay the chemoattractant to
      trailing cells, a well-supported part of the ACA trafficking story.
    supported_by:
    - reference_id: PMID:19047467
      supporting_text: leave behind ACA-containing vesicles
- term:
    id: GO:0046686
    label: response to cadmium ion
  evidence_type: HEP
  original_reference_id: PMID:39874878
  qualifier: acts_upstream_of_or_within
  review:
    summary: This annotation derives from a high-throughput transcriptomic study
      of cadmium tolerance in which acaA appears among differentially expressed
      genes. It reflects a general stress transcriptional response, not a specific
      ACA function.
    action: MARK_AS_OVER_ANNOTATED
    reason: HEP evidence from a genome-wide expression screen; there is no
      indication that ACA has a dedicated role in cadmium response beyond being a
      regulated developmental gene.
    supported_by:
    - reference_id: PMID:39874878
      supporting_text: key genes involved in metal transport, detoxification, and
        stress response
- term:
    id: GO:0004016
    label: adenylate cyclase activity
  evidence_type: IDA
  original_reference_id: PMID:18180289
  qualifier: enables
  review:
    summary: Direct assay of the adenylyl cyclase activation pathway supports ACA
      adenylate cyclase activity in the context of Ras/Rap1 signaling.
    action: ACCEPT
    reason: Experimental support for ACA catalytic activity; core molecular
      function.
    supported_by:
    - reference_id: PMID:18180289
      supporting_text: the adenylyl cyclase activation pathway in the rasC
- term:
    id: GO:1902351
    label: response to imidacloprid
  evidence_type: IEP
  original_reference_id: PMID:36716868
  qualifier: acts_upstream_of_or_within
  review:
    summary: Derived from a transcriptome study of imidacloprid effects on
      Dictyostelium; acaA appears as an expression-regulated gene. This is a
      general environmental stress response rather than a specific ACA function.
    action: MARK_AS_OVER_ANNOTATED
    reason: IEP annotation from a broad toxicant-response expression profile; not
      indicative of a dedicated ACA role in imidacloprid response.
    supported_by:
    - reference_id: PMID:36716868
      supporting_text: imidacloprid affected
- term:
    id: GO:0031254
    label: cell trailing edge
  evidence_type: IDA
  original_reference_id: PMID:16267269
  qualifier: located_in
  review:
    summary: ACA is asymmetrically localized to the rear (trailing edge) of
      polarized chemotaxing cells, where it relays cAMP to following cells.
    action: ACCEPT
    reason: Rear/trailing-edge enrichment of ACA is a well-documented and
      functionally important localization.
    supported_by:
    - reference_id: PMID:19047467
      supporting_text: the asymmetrical distribution of adenylyl cyclase (ACA) at
        the back of Dictyostelium discoideum cells
- term:
    id: GO:0031254
    label: cell trailing edge
  evidence_type: IDA
  original_reference_id: PMID:29618632
  qualifier: is_active_in
  review:
    summary: ACA protein is locally translated and active at the back of
      chemotaxing cells, supporting trailing-edge activity.
    action: ACCEPT
    reason: Live-cell imaging shows ACA mRNA transport and local translation at
      the cell rear, confirming trailing-edge localization and activity.
    supported_by:
    - reference_id: PMID:29618632
      supporting_text: local translation of ACA-YFP occurs at the back of cells
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: located_in
  review:
    summary: Review-based assertion of plasma membrane localization, consistent
      with ACA being an integral plasma membrane cyclase.
    action: ACCEPT
    reason: Plasma membrane localization is well established from primary
      biochemical evidence.
    supported_by:
    - reference_id: PMID:9168471
      supporting_text: adenylate cyclase (ACA), were specifically localized in
        these structures
- term:
    id: GO:0140582
    label: adenylate cyclase-activating G protein-coupled cAMP receptor signaling
      pathway
  evidence_type: IMP
  original_reference_id: PMID:28302905
  qualifier: involved_in
  review:
    summary: ACA-mediated intracellular cAMP production lies at the heart of this
      cAMP receptor signaling pathway, which is modulated by PKA via
      RasG/Rap1/TORC2.
    action: ACCEPT
    reason: Mutant analysis places ACA-mediated cAMP production centrally in the
      cAR1/G-protein/cAMP signaling network; core biological process.
    supported_by:
    - reference_id: PMID:28302905
      supporting_text: these pathways control the ACA-mediated production of
        intracellular cAMP
- term:
    id: GO:0031259
    label: uropod membrane
  evidence_type: IDA
  original_reference_id: PMID:26315268
  qualifier: is_active_in
  review:
    summary: ACA is enriched and active at the uropod membrane of polarized cells,
      a localization required for stream formation.
    action: ACCEPT
    reason: Directly demonstrated uropod-membrane localization of ACA that is
      required for streaming.
    supported_by:
    - reference_id: PMID:26315268
      supporting_text: The localization of adenylyl cyclase A (ACA) to uropod of
        cells is required for the stream formation
- term:
    id: GO:0031271
    label: lateral pseudopodium assembly
  evidence_type: IMP
  original_reference_id: PMID:15821137
  qualifier: acts_upstream_of_or_within
  review:
    summary: Intracellular cAMP from ACA is required to suppress lateral
      pseudopods during chemotaxis; aca- cells fail to suppress them.
    action: ACCEPT
    reason: Mutant phenotype directly implicates ACA-derived cAMP in the control
      of lateral pseudopod formation.
    supported_by:
    - reference_id: PMID:15821137
      supporting_text: defective in suppressing lateral pseudopods in response to
        a spatial gradient of cAMP
- term:
    id: GO:0031259
    label: uropod membrane
  evidence_type: IDA
  original_reference_id: PMID:19047467
  qualifier: located_in
  review:
    summary: ACA accumulates at the rear/uropod membrane via vesicular
      trafficking, consistent with its head-to-tail signal relay role.
    action: ACCEPT
    reason: Directly documented rear/uropod localization of ACA-containing
      structures.
    supported_by:
    - reference_id: PMID:19047467
      supporting_text: the asymmetrical distribution of adenylyl cyclase (ACA) at
        the back of Dictyostelium discoideum cells
- term:
    id: GO:0031152
    label: aggregation involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:1348970
  qualifier: involved_in
  review:
    summary: aca- mutants fail to aggregate, establishing ACA as essential for the
      aggregation stage of Dictyostelium development. This is a core process.
    action: ACCEPT
    reason: Classic gene-disruption phenotype (no cAMP synthesis and failure to
      aggregate); central developmental role.
    supported_by:
    - reference_id: PMID:1348970
      supporting_text: has little detectable adenylyl cyclase activity and fails
        to aggregate
- term:
    id: GO:0140582
    label: adenylate cyclase-activating G protein-coupled cAMP receptor signaling
      pathway
  evidence_type: IMP
  original_reference_id: PMID:20670432
  qualifier: involved_in
  review:
    summary: This annotation comes from a study of the Kelch-domain regulator KeaA
      showing that cAMP production and detection after stress requires KeaA; the
      link to ACA in this pathway is indirect.
    action: KEEP_AS_NON_CORE
    reason: Supports ACA involvement in cAMP signaling in a stress/development
      context but via an indirect (KeaA-focused) genetic experiment.
    supported_by:
    - reference_id: PMID:20670432
      supporting_text: keaA is necessary for the production and detection of cAMP
- term:
    id: GO:0010225
    label: response to UV-C
  evidence_type: IDA
  original_reference_id: PMID:25858552
  qualifier: acts_upstream_of_or_within
  review:
    summary: aca is one of several developmentally regulated genes whose
      expression was profiled by RT-PCR after UV-C exposure; it is used here as a
      developmental marker rather than a functional effector of UV response.
    action: MARK_AS_OVER_ANNOTATED
    reason: Annotation reflects aca expression change in a marker-gene panel, not
      a dedicated role of ACA in the UV-C response.
    supported_by:
    - reference_id: PMID:25858552
      supporting_text: yakA, car1, aca, csA, regA
- term:
    id: GO:0031285
    label: regulation of sorocarp stalk cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:28057864
  qualifier: acts_upstream_of_or_within
  review:
    summary: Tip-expressed ACA produces the cAMP that, via PKA, induces stalk gene
      expression downstream of c-di-GMP at the organizer. ACA is required for
      c-di-GMP-induced stalk formation.
    action: ACCEPT
    reason: Genetic and pharmacological evidence shows ACA is required for
      c-di-GMP-induced stalk gene transcription, a genuine later-development role.
    supported_by:
    - reference_id: PMID:28057864
      supporting_text: the more widely expressed DgcA activates tip-expressed ACA,
        which then acts on PKA to induce stalk genes
- term:
    id: GO:0061939
    label: c-di-GMP signaling
  evidence_type: IMP
  original_reference_id: PMID:28057864
  qualifier: acts_upstream_of_or_within
  review:
    summary: ACA acts as a downstream effector within the c-di-GMP signaling
      pathway (DgcA activates ACA, which acts on PKA). Its role is as an
      intermediary rather than a core c-di-GMP signaling component.
    action: KEEP_AS_NON_CORE
    reason: ACA is downstream of the diguanylate cyclase DgcA in transmitting the
      c-di-GMP signal; a real but non-core, context-specific role.
    supported_by:
    - reference_id: PMID:28057864
      supporting_text: the more widely expressed DgcA activates tip-expressed ACA,
        which then acts on PKA to induce stalk genes
- term:
    id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:1348970
  qualifier: acts_upstream_of_or_within
  review:
    summary: aca- disruption abolishes receptor/G protein-regulated adenylyl
      cyclase activity, confirming ACA's role in this signaling pathway.
    action: ACCEPT
    reason: Restoration of receptor- and guanine nucleotide-regulated adenylyl
      cyclase activity by ACA expression confirms pathway involvement.
    supported_by:
    - reference_id: PMID:1348970
      supporting_text: ACA expression restores receptor and guanine
        nucleotide-regulated adenylyl cyclase activity
- term:
    id: GO:0010042
    label: response to manganese ion
  evidence_type: IDA
  original_reference_id: PMID:108168
  qualifier: involved_in
  review:
    summary: Manganese directly stimulates adenylyl cyclase activity and can
      overcome Ca2+ inhibition, reflecting divalent-cation regulation of the
      enzyme rather than a developmental process per se.
    action: KEEP_AS_NON_CORE
    reason: Reflects genuine biochemical regulation of ACA activity by Mn2+, but
      is a peripheral/regulatory property, not a core evolved function.
    supported_by:
    - reference_id: PMID:108168
      supporting_text: was shown to directly stimulate adenyl cyclase
- term:
    id: GO:0005771
    label: multivesicular body
  evidence_type: IDA
  original_reference_id: PMID:19047467
  qualifier: located_in
  review:
    summary: ACA-containing vesicles are secreted as multivesicular bodies during
      collective migration, supporting this localization.
    action: ACCEPT
    reason: Directly imaged ACA in multivesicular-body structures shed by
      migrating cells.
    supported_by:
    - reference_id: PMID:19047467
      supporting_text: likely secreted as multivesicular bodies
- term:
    id: GO:0071944
    label: cell periphery
  evidence_type: IDA
  original_reference_id: PMID:19047467
  qualifier: located_in
  review:
    summary: General peripheral localization; the informative locations (plasma
      membrane, uropod membrane, trailing edge) are separately annotated.
    action: KEEP_AS_NON_CORE
    reason: Broad cell periphery term subsumed by more specific plasma
      membrane/uropod annotations.
    supported_by:
    - reference_id: PMID:19047467
      supporting_text: the asymmetrical distribution of adenylyl cyclase (ACA) at
        the back of Dictyostelium discoideum cells
- term:
    id: GO:0097708
    label: intracellular vesicle
  evidence_type: IDA
  original_reference_id: PMID:19047467
  qualifier: located_in
  review:
    summary: ACA is carried on intracellular vesicles that traffic to the cell
      rear, a well-supported part of the ACA relay mechanism.
    action: ACCEPT
    reason: Directly documented association of ACA with intracellular vesicular
      structures.
    supported_by:
    - reference_id: PMID:26315268
      supporting_text: ACA-YFP is mainly associated with intracellular vesicular
        structures
- term:
    id: GO:0004016
    label: adenylate cyclase activity
  evidence_type: IMP
  original_reference_id: PMID:1348970
  qualifier: enables
  review:
    summary: Gene disruption abolishes detectable adenylyl cyclase activity,
      directly attributing the activity to ACA.
    action: ACCEPT
    reason: Loss-of-function evidence for ACA adenylate cyclase activity; core
      molecular function.
    supported_by:
    - reference_id: PMID:1348970
      supporting_text: has little detectable adenylyl cyclase activity and fails
        to aggregate
- term:
    id: GO:0010447
    label: response to acidic pH
  evidence_type: IDA
  original_reference_id: PMID:7883072
  qualifier: involved_in
  review:
    summary: Weak acids that lower cytosolic pH inhibit ACA activity, reflecting
      the pH dependence of the enzyme rather than a dedicated developmental
      process.
    action: KEEP_AS_NON_CORE
    reason: Captures biochemical pH-sensitivity of ACA activity; a
      regulatory/peripheral property, not a core function.
    supported_by:
    - reference_id: PMID:7883072
      supporting_text: weak acids inhibit both ACA and ACG permanently
- term:
    id: GO:1904643
    label: response to curcumin
  evidence_type: IDA
  original_reference_id: PMID:26449461
  qualifier: involved_in
  review:
    summary: Curcumin suppresses YakA-pathway developmental genes and delays
      development; any effect on acaA is part of a broad developmental/stress
      response rather than a specific ACA function.
    action: KEEP_AS_NON_CORE
    reason: Peripheral chemical-response annotation reflecting curcumin's general
      effects on the developmental program.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IDA
  original_reference_id: PMID:26315268
  qualifier: located_in
  review:
    summary: ACA associates with cytoplasmic (intracellular) vesicles that are
      trafficked to the plasma membrane at the cell rear.
    action: ACCEPT
    reason: Directly documented ACA localization to vesicular structures during
      trafficking.
    supported_by:
    - reference_id: PMID:26315268
      supporting_text: ACA-YFP is mainly associated with intracellular vesicular
        structures
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:9168471
  qualifier: located_in
  review:
    summary: ACA is directly localized to plasma membrane microdomains (CHIFF)
      enriched in signal transduction proteins.
    action: ACCEPT
    reason: Primary biochemical evidence for plasma membrane localization of ACA;
      core localization.
    supported_by:
    - reference_id: PMID:9168471
      supporting_text: adenylate cyclase (ACA), were specifically localized in
        these structures
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23473502
  qualifier: acts_upstream_of_or_within
  review:
    summary: ACA-generated cAMP oscillations drive developmental gene expression
      (for example of cAMP-relay components). The connection to gene expression is
      indirect, via the cAMP signal.
    action: KEEP_AS_NON_CORE
    reason: Downstream, indirect effect of ACA-derived cAMP on developmental gene
      expression; not a core molecular function.
- term:
    id: GO:0031000
    label: response to caffeine
  evidence_type: IDA
  original_reference_id: PMID:22928977
  qualifier: involved_in
  review:
    summary: Caffeine (an adenosine antagonist) lowers AcaA levels and cAMP,
      contributing to multiple-tip formation; this reflects modulation of ACA by
      caffeine rather than a dedicated ACA function.
    action: KEEP_AS_NON_CORE
    reason: Reflects caffeine-induced reduction of ACA levels affecting the cAMP
      gradient; a peripheral chemical-response context.
    supported_by:
    - reference_id: PMID:22928977
      supporting_text: Caffeine decreases adenyl cyclase-A (AcaA) levels
- term:
    id: GO:1902168
    label: response to catechin
  evidence_type: IDA
  original_reference_id: PMID:23516620
  qualifier: involved_in
  review:
    summary: EGCG (a green-tea catechin) blocks Dictyostelium motility,
      chemotaxis and development; any ACA involvement is part of a broad effect on
      the cAMP-driven developmental program.
    action: KEEP_AS_NON_CORE
    reason: Peripheral chemical-response annotation; not a core ACA function.
- term:
    id: GO:0004016
    label: adenylate cyclase activity
  evidence_type: IDA
  original_reference_id: PMID:8619862
  qualifier: enables
  review:
    summary: Loss of adenylyl cyclase activation upon G protein inhibition
      supports ACA adenylate cyclase activity within the G protein pathway.
    action: ACCEPT
    reason: Experimental support linking ACA adenylate cyclase activity to G
      protein activation; core molecular function.
    supported_by:
    - reference_id: PMID:8619862
      supporting_text: a loss of adenylyl cyclase activation
- term:
    id: GO:0030435
    label: sporulation resulting in formation of a cellular spore
  evidence_type: IGI
  original_reference_id: PMID:9582274
  qualifier: acts_upstream_of_or_within
  review:
    summary: Genetic interaction with the phosphorelay component RdeA implicates
      ACA/cAMP-PKA signaling in the timing of development and sporulation. This is
      a later-development, non-core role.
    action: KEEP_AS_NON_CORE
    reason: Supports a role for ACA-derived cAMP signaling in developmental
      timing/sporulation through the RdeA phosphorelay, but peripheral to the core
      aggregation function.
    supported_by:
    - reference_id: PMID:9582274
      supporting_text: RdeA is part of a multistep phosphorelay system that
        modulates the rate of development
- term:
    id: GO:0007015
    label: actin filament organization
  evidence_type: IMP
  original_reference_id: PMID:15821137
  qualifier: acts_upstream_of_or_within
  review:
    summary: aca- cells show altered pseudopod behavior and cell shape during
      chemotaxis; effects on actin organization are indirect consequences of lost
      intracellular cAMP signaling.
    action: KEEP_AS_NON_CORE
    reason: Indirect, downstream effect of ACA on the actin cytoskeleton via
      cAMP-regulated chemotactic behavior; not a core function.
    supported_by:
    - reference_id: PMID:15821137
      supporting_text: adenylyl cyclase play an intracellular role in the
        chemotactic response
- term:
    id: GO:0008360
    label: regulation of cell shape
  evidence_type: IMP
  original_reference_id: PMID:15821137
  qualifier: acts_upstream_of_or_within
  review:
    summary: Loss of ACA impairs polarity and shape control during chemotaxis;
      this is an indirect consequence of disrupted intracellular cAMP signaling.
    action: KEEP_AS_NON_CORE
    reason: Downstream phenotypic effect of ACA loss on cell shape; peripheral to
      the core catalytic/relay function.
    supported_by:
    - reference_id: PMID:15821137
      supporting_text: adenylyl cyclase play an intracellular role in the
        chemotactic response
- term:
    id: GO:0050920
    label: regulation of chemotaxis
  evidence_type: IMP
  original_reference_id: PMID:15821137
  qualifier: acts_upstream_of_or_within
  review:
    summary: Intracellular cAMP produced by ACA is required for normal chemotactic
      behavior (suppression of lateral pseudopods, chemotaxis in natural cAMP
      waves).
    action: KEEP_AS_NON_CORE
    reason: ACA-derived cAMP regulates chemotactic responsiveness; an important
      but downstream/regulatory role rather than the core catalytic function.
    supported_by:
    - reference_id: PMID:15821137
      supporting_text: adenylyl cyclase play an intracellular role in the
        chemotactic response
- term:
    id: GO:0004016
    label: adenylate cyclase activity
  evidence_type: IDA
  original_reference_id: PMID:10556070
  qualifier: enables
  review:
    summary: Direct experimental annotation of ACA adenylate cyclase activity by
      dictyBase curators. Adenylate cyclase activity is firmly established for
      this gene product.
    action: ACCEPT
    reason: Core molecular function, corroborated by numerous direct assays; defer
      to the experimental curation.
- term:
    id: GO:0004016
    label: adenylate cyclase activity
  evidence_type: IDA
  original_reference_id: PMID:15507682
  qualifier: enables
  review:
    summary: Direct experimental annotation of ACA adenylate cyclase activity by
      dictyBase curators.
    action: ACCEPT
    reason: Core molecular function of ACA; consistent with all other direct
      enzymatic evidence.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10556070
  title: An adenylyl cyclase that functions during late development of Dictyostelium.
  findings: []
- id: PMID:108168
  title: The effect of divalent cations on aggregation of Dictyostelium discoideum.
  findings:
  - statement: Manganese ions directly stimulate adenylyl cyclase and can overcome
      Ca2+ inhibition of the enzyme.
    supporting_text: was shown to directly stimulate adenyl cyclase
- id: PMID:1348970
  title: Structurally distinct and stage-specific adenylyl cyclase genes play different
    roles in Dictyostelium development.
  findings:
  - statement: aca- disruption mutants have little detectable adenylyl cyclase
      activity and fail to aggregate, showing cAMP is required for cell-cell
      communication.
    supporting_text: has little detectable adenylyl cyclase activity and fails to
      aggregate
  - statement: ACA expression restores receptor- and guanine nucleotide-regulated
      adenylyl cyclase activity.
    supporting_text: ACA expression restores receptor and guanine
      nucleotide-regulated adenylyl cyclase activity
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational paper cloning ACA and demonstrating its requirement
      for cAMP synthesis and aggregation; abstract-only in cache but claims verified
      against the abstract.
- id: PMID:15473840
  title: Chemoattractant signaling in dictyostelium discoideum.
  findings: []
- id: PMID:15507682
  title: A rapid and efficient method to generate multiple gene disruptions in Dictyostelium
    discoideum using a single selectable marker and the Cre-loxP system.
  findings: []
- id: PMID:15821137
  title: Intracellular role of adenylyl cyclase in regulation of lateral pseudopod
    formation during Dictyostelium chemotaxis.
  findings:
  - statement: aca- cells are defective in suppressing lateral pseudopods in
      response to spatial and temporal cAMP gradients.
    supporting_text: defective in suppressing lateral pseudopods in response to a
      spatial gradient of cAMP
  - statement: Intracellular cAMP, and hence adenylyl cyclase, plays an
      intracellular role in the chemotactic response.
    supporting_text: adenylyl cyclase play an intracellular role in the chemotactic
      response
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the intracellular (cAMP/PKA circuit) role of ACA in
      lateral pseudopod suppression and chemotaxis.
- id: PMID:16267269
  title: Phosphoinositide 3-kinase activity controls the chemoattractant-mediated
    activation and adaptation of adenylyl cyclase.
  findings:
  - statement: ACA synthesizes the chemoattractant cAMP and is essential to relay
      the signal to neighboring cells; PI3K controls ACA activation and adaptation.
    supporting_text: which synthesizes the chemoattractant cAMP, is essential to
      relay the signal to
- id: PMID:18180289
  title: Rap1 activation in response to cAMP occurs downstream of ras activation during
    Dictyostelium aggregation.
  findings:
  - statement: The adenylyl cyclase activation pathway operates downstream of RasG
      and RasC during aggregation.
    supporting_text: the adenylyl cyclase activation pathway in the rasC
- id: PMID:19047467
  title: Collective cell migration requires vesicular trafficking for chemoattractant
    delivery at the trailing edge.
  findings:
  - statement: ACA is asymmetrically distributed at the back of cells via vesicular
      trafficking, an essential determinant of head-to-tail migration.
    supporting_text: the asymmetrical distribution of adenylyl cyclase (ACA) at the
      back of Dictyostelium discoideum cells
  - statement: Migrating cells leave behind ACA-containing vesicles, likely secreted
      as multivesicular bodies.
    supporting_text: likely secreted as multivesicular bodies
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key paper establishing ACA vesicular trafficking and rear-of-cell
      accumulation underlying the cAMP relay.
- id: PMID:20670432
  title: KeaA, a Dictyostelium Kelch-domain protein that regulates the response to
    stress and development.
  findings:
  - statement: KeaA is required for the production and detection of cAMP following
      stress.
    supporting_text: keaA is necessary for the production and detection of cAMP
- id: PMID:22928977
  title: Regulation of multiple tip formation by caffeine in cellular slime molds.
  findings:
  - statement: Caffeine decreases AcaA levels, lowering cAMP synthesis and altering
      the cAMP gradient during multiple-tip formation.
    supporting_text: Caffeine decreases adenyl cyclase-A (AcaA) levels
- id: PMID:23473502
  title: 'Robustness of self-organizing chemoattractant field arising from precise
    pulse induction of its breakdown enzyme: a single-cell level analysis of PDE expression
    in Dictyostelium.'
  findings: []
- id: PMID:23516620
  title: The green tea catechin epigallocatechin gallate (EGCG) blocks cell motility,
    chemotaxis and development in Dictyostelium discoideum.
  findings: []
- id: PMID:25858552
  title: Response of Dictyostelium discoideum to UV-C and involvement of poly (ADP-ribose)
    polymerase.
  findings:
  - statement: aca is among the developmentally regulated genes profiled by RT-PCR
      after UV-C exposure.
    supporting_text: yakA, car1, aca, csA, regA
- id: PMID:26315268
  title: Adenylyl cyclase localization to the uropod of aggregating Dictyostelium
    cells requires RacC.
  findings:
  - statement: ACA localization to the uropod is required for stream formation and
      depends on RacC-mediated vesicle trafficking.
    supporting_text: The localization of adenylyl cyclase A (ACA) to uropod of cells
      is required for the stream formation
  - statement: ACA-YFP is mainly associated with intracellular vesicular structures
      that traffic toward the plasma membrane.
    supporting_text: ACA-YFP is mainly associated with intracellular vesicular
      structures
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Demonstrates RacC-dependent trafficking of ACA vesicles to the
      uropod required for streaming.
- id: PMID:26449461
  title: 'Curcumin inhibits development and cell adhesion in Dictyostelium discoideum:
    Implications for YakA signaling and GST enzyme function.'
  findings: []
- id: PMID:28057864
  title: Adenylate cyclase A acting on PKA mediates induction of stalk formation by
    cyclic diguanylate at the Dictyostelium organizer.
  findings:
  - statement: DgcA-derived c-di-GMP activates tip-expressed ACA, which acts on PKA
      to induce stalk genes.
    supporting_text: the more widely expressed DgcA activates tip-expressed ACA,
      which then acts on PKA to induce stalk genes
  - statement: ACA produces the cAMP pulses coordinating morphogenetic cell movement
      and is highly expressed at the organizing tip.
    supporting_text: ACA produces the cAMP pulses that coordinate Dictyostelium
      morphogenetic cell movement and is highly expressed at the organizing tip
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes a later-development role for ACA at the organizer,
      transducing c-di-GMP to PKA for stalk cell differentiation.
- id: PMID:28302905
  title: Protein kinase A regulates the Ras, Rap1 and TORC2 pathways in response to
    the chemoattractant cAMP in Dictyostelium.
  findings:
  - statement: RasG, Rap1 and TORC2 pathways control ACA-mediated production of
      intracellular cAMP, upstream of PKA.
    supporting_text: these pathways control the ACA-mediated production of
      intracellular cAMP
- id: PMID:29618632
  title: Adenylyl cyclase A mRNA localized at the back of cells is actively translated
    in live chemotaxing Dictyostelium.
  findings:
  - statement: ACA mRNA is transported to the back of polarized cells and locally
      translated there to relay cAMP signals during chemotaxis.
    supporting_text: local translation of ACA-YFP occurs at the back of cells
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Shows localized translation of ACA at the cell rear as part of the
      relay mechanism.
- id: PMID:36716868
  title: The neonicotinoid insecticide imidacloprid has unexpected effects on the
    growth and development of soil amoebae.
  findings:
  - statement: Imidacloprid affects Dictyostelium growth and development and alters
      expression of key genes; acaA appears as an expression-regulated gene.
    supporting_text: imidacloprid affected
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Broad toxicant transcriptome study; acaA response is a general
      stress/developmental readout, not a specific ACA function.
- id: PMID:39874878
  title: Exploring the mechanisms of cadmium tolerance and bioaccumulation in a soil
    amoeba.
  findings:
  - statement: Cadmium exposure alters expression of genes involved in metal
      transport, detoxification and stress response in Dictyostelium.
    supporting_text: key genes involved in metal transport, detoxification, and
      stress response
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput expression screen; acaA is a differentially
      expressed gene rather than a dedicated cadmium-response effector.
- id: PMID:41406008
  title: Extracellular adenosine deamination primes tip organizer development in Dictyostelium.
  findings:
  - statement: The consecutive transformation of extracellular cAMP to adenosine and
      adenosine to ammonia is integral to Dictyostelium development.
    supporting_text: the consecutive transformation of extracellular cAMP to
      adenosine, and adenosine to ammonia
- id: PMID:7883072
  title: Regulation of Dictyostelium adenylylcyclases by morphogen-induced modulation
    of cytosolic pH or Ca2+ levels.
  findings:
  - statement: Weak acids that lower cytosolic pH permanently inhibit both ACA and
      ACG, reflecting the pH dependence of the enzymes.
    supporting_text: weak acids inhibit both ACA and ACG permanently
- id: PMID:8619862
  title: Tetrahydropterins interfere with the G protein pathway in Dictyostelium discoideum.
  findings:
  - statement: Inhibition of G protein activation is accompanied by a loss of
      adenylyl cyclase activation.
    supporting_text: a loss of adenylyl cyclase activation
- id: PMID:9168471
  title: 'Identification of detergent-resistant plasma membrane microdomains in dictyostelium:
    enrichment of signal transduction proteins.'
  findings:
  - statement: ACA, a downstream effector of cAR1, is specifically localized to
      plasma membrane microdomains (CHIFF).
    supporting_text: adenylate cyclase (ACA), were specifically localized in these
      structures
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Biochemical evidence for ACA plasma membrane localization in
      signaling microdomains.
- id: PMID:9582274
  title: Evidence that the RdeA protein is a component of a multistep phosphorelay
    modulating rate of development in Dictyostelium.
  findings:
  - statement: RdeA is part of a multistep phosphorelay that modulates the rate of
      Dictyostelium development.
    supporting_text: RdeA is part of a multistep phosphorelay system that modulates
      the rate of development
core_functions:
- description: ACA catalyzes the Mg2+-dependent synthesis of 3',5'-cyclic AMP from
    ATP (EC 4.6.1.1) as the aggregation-stage adenylyl cyclase, and is the enzyme
    responsible for cAMP production during Dictyostelium aggregation. It acts as an
    integral plasma membrane enzyme that becomes enriched at the rear (uropod and
    trailing edge) of polarized cells.
  molecular_function:
    id: GO:0004016
    label: adenylate cyclase activity
  directly_involved_in:
  - id: GO:0006171
    label: cAMP biosynthetic process
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0031259
    label: uropod membrane
  - id: GO:0031254
    label: cell trailing edge
  supported_by:
  - reference_id: PMID:1348970
    supporting_text: has little detectable adenylyl cyclase activity and fails to
      aggregate
  - reference_id: PMID:9168471
    supporting_text: adenylate cyclase (ACA), were specifically localized in these
      structures
- description: Through localized synthesis and vesicular delivery of cAMP at the
    cell rear, ACA relays the extracellular cAMP chemoattractant to neighboring
    cells, driving chemotactic aggregation (the cAMP relay). ACA activity is
    controlled downstream of the cAR1 receptor via G proteins/CRAC and
    PI3K/Ras/Rap1/TORC2, and its cAMP output also acts through PKA at the
    organizing tip in later development.
  molecular_function:
    id: GO:0004016
    label: adenylate cyclase activity
  directly_involved_in:
  - id: GO:0031152
    label: aggregation involved in sorocarp development
  - id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  locations:
  - id: GO:0031254
    label: cell trailing edge
  supported_by:
  - reference_id: PMID:29618632
    supporting_text: local translation of ACA-YFP occurs at the back of cells
  - reference_id: PMID:28057864
    supporting_text: ACA produces the cAMP pulses that coordinate Dictyostelium
      morphogenetic cell movement and is highly expressed at the organizing tip