dmtA

id: Q8T638
gene_symbol: dmtA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: Des-methyl-DIF-1 methyltransferase A (DmtA) is a soluble,
  S-adenosyl-L-methionine-dependent O-methyltransferase of the cation-independent
  COMT subfamily that catalyzes the final step of DIF-1
  (differentiation-inducing factor 1) biosynthesis in Dictyostelium discoideum.
  DIF-1 is a chlorinated alkyl phenone polyketide morphogen. Its biosynthesis
  begins with assembly of the C12 polyketide (2,4,6-trihydroxyphenyl)-1-hexan-1-one
  (THPH) by the polyketide synthase StlB, which is dichlorinated by the
  flavin-dependent halogenase ChlA to give des-methyl-DIF-1 (dichloro-THPH); DmtA
  then O-methylates des-methyl-DIF-1 to yield mature DIF-1. DIF-1 is a diffusible
  signal that induces prestalk-O (pstO) cell differentiation and specifies the
  anterior-like cells that form the basal disc and much of the lower cup of the
  fruiting body. dmtA is maximally expressed in prespore cells around the
  first-finger/slug stage, is induced by cyclic-AMP, and is repressed by DIF-1.
  Loss of DmtA blocks DIF-1 production and causes accumulation of the biosynthetic
  intermediate des-methyl-DIF-1.
existing_annotations:
- term:
    id: GO:0008171
    label: O-methyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of O-methyltransferase activity is correct.
      DmtA is a functionally characterized O-methyltransferase that transfers a
      methyl group to a hydroxyl of its dichloro-THPH substrate.
    action: ACCEPT
    reason: The general MF term is accurate and consistent with the experimentally
      characterized activity, though the specific reaction is better captured by
      GO:0106268.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
- term:
    id: GO:0008757
    label: S-adenosylmethionine-dependent methyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DmtA uses S-adenosyl-L-methionine as the methyl donor, so this
      SAM-dependent methyltransferase grouping term is correct.
    action: ACCEPT
    reason: Directly supported by enzymology showing the methyltransferase uses
      SAM as co-substrate; consistent with the class I-like SAM-binding
      methyltransferase superfamily assignment.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
- term:
    id: GO:0032259
    label: methylation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This is a very general biological-process grouping term. DmtA does
      carry out methylation, but the specific and informative process is DIF-1
      biosynthesis via O-methylation of des-methyl-DIF-1.
    action: KEEP_AS_NON_CORE
    reason: The term is correct but too general to represent the core function;
      the specific DIF-1 biosynthetic process (GO:0031148) is the informative
      annotation.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: Conversion requires both chlorination and methylation of
        THPH, and enzymatic activities able to do this exist in cell lysates
- term:
    id: GO:0008168
    label: methyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Correct but general parent term for methyltransferase activity,
      subsumed by the more specific O-methyltransferase and dichloro-THPH
      methyltransferase annotations.
    action: ACCEPT
    reason: Accurate grouping term consistent with the experimentally established
      methyltransferase activity; retained as an accurate but non-specific parent.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
- term:
    id: GO:0008171
    label: O-methyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO inference of O-methyltransferase activity from the
      COMT-like domain signature. This is correct for DmtA.
    action: ACCEPT
    reason: The domain-based inference agrees with the experimentally determined
      O-methyltransferase activity of DmtA.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
- term:
    id: GO:0046983
    label: protein dimerization activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: This InterPro2GO annotation derives from the COMT dimerisation domain
      (PF08100) present in the protein. Many cation-independent COMT-family
      O-methyltransferases function as homodimers, so dimerization is plausible on
      structural grounds, but there is no direct experimental evidence that DmtA
      dimerizes and this is not an informative functional annotation.
    action: KEEP_AS_NON_CORE
    reason: The dimerization inference is a domain-based structural prediction, not
      experimentally verified for DmtA, and does not describe the gene's catalytic
      or biological function. Retained as non-core rather than removed because the
      dimerisation domain is genuinely present and functionally plausible for the
      COMT family.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
- term:
    id: GO:0106268
    label: 3,5-dichloro-THPH methyl transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: This Rhea-based term captures the precise reaction catalyzed by DmtA -
      O-methylation of (3,5-dichloro-2,4,6-trihydroxyphenyl)hexan-1-one
      (des-methyl-DIF-1) using SAM to yield DIF-1. This is the core molecular
      function.
    action: ACCEPT
    reason: This is the specific, biochemically demonstrated catalytic activity of
      DmtA and represents its core molecular function.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
- term:
    id: GO:0106268
    label: 3,5-dichloro-THPH methyl transferase activity
  evidence_type: EXP
  original_reference_id: PMID:9446571
  qualifier: enables
  review:
    summary: Experimental evidence from enzymological characterization of the
      DIF-1 methyltransferase activity in Dictyostelium lysates, showing SAM-dependent
      O-methylation of dichloro-THPH with strong substrate preference. This is the
      core catalytic function of DmtA.
    action: ACCEPT
    reason: Direct experimental characterization of the methyltransferase catalyzing
      the final step of DIF-1 biosynthesis; the defining core function of the gene.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
    - reference_id: PMID:9446571
      supporting_text: Conversion requires both chlorination and methylation of
        THPH, and enzymatic activities able to do this exist in cell lysates
- term:
    id: GO:0010623
    label: programmed cell death involved in cell development
  evidence_type: IMP
  original_reference_id: PMID:28055008
  qualifier: involved_in
  review:
    summary: In this study the DmtA-null (DIF-1-deficient) strain was used as a
      tool to test whether endogenous DIF-1 is required for developmental cell
      death. Vacuolar developmental cell death and its early hallmarks were
      induced in DmtA-null cells by an exogenous second signal (DIF-1 or
      c-di-GMP), and initial priming did not require endogenous DIF-1. Thus DmtA
      itself is not directly required for the death program; the connection to
      cell death is indirect, via the DIF-1 morphogen it produces.
    action: KEEP_AS_NON_CORE
    reason: The annotation reflects a downstream developmental role of the
      DmtA-produced DIF-1 signal rather than a core molecular or biosynthetic
      function of the protein. DmtA-null cells still undergo developmental cell
      death when supplied exogenous DIF-1, so this is a non-core developmental
      context.
    supported_by:
    - reference_id: PMID:28055008
      supporting_text: DH1.DmtA- mutant cells (Figure 2) unable to synthesize DIF-1
- term:
    id: GO:0031149
    label: sorocarp stalk cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:18402932
  qualifier: acts_upstream_of_or_within
  review:
    summary: The dmtA-null mutant, blocked in the last step of DIF-1 synthesis,
      shows delayed tip formation and fewer prestalk-O cells, and (like other
      DIF-1 pathway mutants) a defective basal disc, consistent with a role of
      DmtA-produced DIF-1 in prestalk/stalk cell differentiation. This is a
      downstream developmental consequence of DIF-1 production.
    action: KEEP_AS_NON_CORE
    reason: Correct developmental phenotype attributable to loss of the DIF-1
      signal made by DmtA, but this is a downstream morphogenetic role rather than
      the core catalytic function of the gene product.
    supported_by:
    - reference_id: PMID:18402932
      supporting_text: The dmtA(-) methyltransferase mutant, blocked in the last
        step of DIF-1 synthesis, resembles the stlB(-) mutant but has delayed tip
        formation and fewer prestalk-O cells
- term:
    id: GO:0031288
    label: sorocarp morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:18402932
  qualifier: acts_upstream_of_or_within
  review:
    summary: Loss of DmtA (and hence DIF-1) produces fruiting-body morphogenesis
      defects shared with other DIF-1 signaling mutants, including near-absence of
      the basal disc. This is a downstream developmental role of the DIF-1 signal.
    action: KEEP_AS_NON_CORE
    reason: The morphogenesis phenotype is a valid developmental consequence of
      loss of DmtA-produced DIF-1, but is downstream of and non-core relative to
      the enzyme's biosynthetic function.
    supported_by:
    - reference_id: PMID:18402932
      supporting_text: This is a common feature of DIF-1 signaling mutants also
        found in dmtA, dimA, and mybE strains
    - reference_id: PMID:18402932
      supporting_text: DIF-1 is required for slug migration and specifies the
        anterior-like cells forming the basal disc
- term:
    id: GO:0030435
    label: sporulation resulting in formation of a cellular spore
  evidence_type: IMP
  original_reference_id: PMID:11163223
  qualifier: acts_upstream_of_or_within
  review:
    summary: This IMP annotation derives from characterization of the DIF-1
      biosynthesis mutant during multicellular development. The cached record for
      this reference is abstract-only and the abstract focuses on prestalk (pstO)
      cell induction rather than sporulation, so the specific sporulation
      phenotype cannot be independently verified here; the curator annotation is
      from the full text. This is at most a downstream developmental role of the
      DIF-1 pathway, not a core function.
    action: KEEP_AS_NON_CORE
    reason: Retained as a non-core developmental annotation, deferring to the
      curator's reading of the full text; DmtA's core function is DIF-1
      biosynthesis, and any effect on spore formation is downstream and indirect.
- term:
    id: GO:0031154
    label: culmination involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:11163223
  qualifier: acts_upstream_of_or_within
  review:
    summary: DIF-1 pathway loss affects late multicellular development including
      culmination; the related study of the DIF-1 synthesis (PKS) mutant notes
      that the basal-disc defect may cause culmination to initiate along the
      substratum. This is a downstream developmental role of the DIF-1 signal
      produced by DmtA rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: A valid downstream developmental context attributable to loss of the
      DIF-1 morphogen, but non-core relative to the enzyme's biosynthetic activity.
    supported_by:
    - reference_id: PMID:18402932
      supporting_text: which perhaps in consequence initiates culmination along
        the substratum
- term:
    id: GO:0031148
    label: DIF-1 biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11163223
  qualifier: involved_in
  review:
    summary: DmtA catalyzes the final O-methylation step of DIF-1 biosynthesis, so
      it is directly involved in the DIF-1 biosynthetic process. Construction of a
      mutant blocked in DIF-1 biosynthesis established this pathway role. This is a
      core biological-process annotation.
    action: ACCEPT
    reason: DmtA performs the terminal methylation reaction of the DIF-1
      biosynthetic pathway; this is a core annotation directly supported by
      enzymology and mutant analysis.
    supported_by:
    - reference_id: PMID:11163223
      supporting_text: a mutant blocked in the biosynthesis of DIF-1, a chlorinated
        signal molecule proposed to induce differentiation of both major prestalk
        cell types
    - reference_id: PMID:18402932
      supporting_text: and then methylated to produce DIF-1, with methylation
        catalyzed by the DmtA methyl transferase
- term:
    id: GO:0045595
    label: regulation of cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:11163223
  qualifier: acts_upstream_of_or_within
  review:
    summary: By producing the DIF-1 morphogen, DmtA acts upstream of prestalk/stalk
      cell differentiation. The DIF-1 biosynthesis mutant fails to make pstO cells,
      which are restored by exogenous DIF-1. This is a general downstream
      developmental-regulatory role rather than a core function.
    action: KEEP_AS_NON_CORE
    reason: The gene influences cell differentiation only indirectly, through the
      DIF-1 signal it synthesizes; the term is general and downstream, so it is
      retained as non-core.
    supported_by:
    - reference_id: PMID:11163223
      supporting_text: Normal pstO cell differentiation and their patterning in the
        slug are restored by development on a uniform concentration of DIF-1
- term:
    id: GO:0008171
    label: O-methyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:11163223
  qualifier: enables
  review:
    summary: Direct-assay annotation of O-methyltransferase activity for DmtA,
      consistent with the enzymological characterization of the DIF-1
      methyltransferase. Correct core-level molecular function (specific reaction
      captured by GO:0106268).
    action: ACCEPT
    reason: Agrees with the experimentally established O-methyltransferase activity
      of DmtA on the des-methyl-DIF-1 substrate.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
- term:
    id: GO:0008757
    label: S-adenosylmethionine-dependent methyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:11163223
  qualifier: enables
  review:
    summary: Direct-assay annotation that DmtA is a SAM-dependent methyltransferase,
      consistent with the demonstration that the DIF-1 methyltransferase uses
      S-adenosyl-L-methionine as co-substrate.
    action: ACCEPT
    reason: Correct molecular function supported by enzymology showing SAM
      dependence of the methyltransferase.
    supported_by:
    - reference_id: PMID:9446571
      supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
        as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
        strongly prefers this substrate to close analogues
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:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11163223
  title: The role of DIF-1 signaling in Dictyostelium development.
  findings:
  - statement: A mutant blocked in DIF-1 biosynthesis lacks pstO cells, identifying
      DIF-1 as the pstO inducer and establishing the developmental role of the
      DIF-1 pathway.
    supporting_text: a mutant blocked in the biosynthesis of DIF-1, a chlorinated
      signal molecule proposed to induce differentiation of both major prestalk
      cell types
  - statement: pstO cell differentiation is restored by exogenous DIF-1, showing
      DIF-1 acts as the diffusible pstO inducer.
    supporting_text: Normal pstO cell differentiation and their patterning in the
      slug are restored by development on a uniform concentration of DIF-1
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified abstract (full text not cached). Thompson & Kay
      2000 constructed the DIF-1 biosynthesis mutant and established DIF-1 as the
      pstO inducer; underpins the dmtA developmental annotations.
- id: PMID:18402932
  title: DIF-1 induces the basal disc of the Dictyostelium fruiting body.
  findings:
  - statement: The dmtA-null methyltransferase mutant, blocked in the last step of
      DIF-1 synthesis, has delayed tip formation and fewer prestalk-O cells.
    supporting_text: The dmtA(-) methyltransferase mutant, blocked in the last step
      of DIF-1 synthesis, resembles the stlB(-) mutant but has delayed tip
      formation and fewer prestalk-O cells
  - statement: DIF-1 biosynthesis is completed by O-methylation catalyzed by the
      DmtA methyltransferase.
    supporting_text: and then methylated to produce DIF-1, with methylation
      catalyzed by the DmtA methyl transferase
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text (PMC2726288) available and read; directly describes the
      dmtA-null phenotype and DmtA's role in the terminal methylation step of DIF-1
      biosynthesis.
- id: PMID:28055008
  title: Early nucleolar disorganization in Dictyostelium cell death.
  findings:
  - statement: DmtA-null cells, which cannot synthesize DIF-1, were used to show
      that developmental cell death can be induced by exogenous DIF-1 independently
      of endogenous DIF-1.
    supporting_text: DH1.DmtA- mutant cells (Figure 2) unable to synthesize DIF-1
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available. DmtA-null strain used only as a
      DIF-1-deficient tool; the gene is not directly required for the death program,
      supporting a non-core assignment of the programmed-cell-death annotation.
- id: PMID:9446571
  title: The biosynthesis of differentiation-inducing factor, a chlorinated signal
    molecule regulating Dictyostelium development.
  findings:
  - statement: The DIF-1 methyltransferase is soluble, SAM-dependent, and strongly
      prefers dichloro-THPH (des-methyl-DIF-1) as substrate.
    supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
      as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
      strongly prefers this substrate to close analogues
  - statement: DIF-1 biosynthesis from the THPH polyketide requires both
      chlorination and methylation steps.
    supporting_text: Conversion requires both chlorination and methylation of THPH,
      and enzymatic activities able to do this exist in cell lysates
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified abstract (full text not cached). Kay 1998
      biochemically characterized the DIF-1 methyltransferase (the DmtA activity),
      the primary evidence for the core catalytic function.
core_functions:
- description: DmtA catalyzes the final, S-adenosyl-L-methionine-dependent
    O-methylation step of DIF-1 biosynthesis, converting des-methyl-DIF-1
    (3,5-dichloro-THPH) to the chlorinated polyketide morphogen DIF-1. This
    terminal methylation completes production of the diffusible signal that induces
    prestalk-O cell differentiation during Dictyostelium development.
  molecular_function:
    id: GO:0106268
    label: 3,5-dichloro-THPH methyl transferase activity
  directly_involved_in:
  - id: GO:0031148
    label: DIF-1 biosynthetic process
  supported_by:
  - reference_id: PMID:9446571
    supporting_text: The methyltransferase is soluble, uses S-adenosyl-L-methionine
      as a co-substrate, has a Km for dichloro-THPH of about 1.1 microM, and
      strongly prefers this substrate to close analogues
  - reference_id: PMID:18402932
    supporting_text: and then methylated to produce DIF-1, with methylation
      catalyzed by the DmtA methyl transferase