id: A8Z522
gene_symbol: fosB
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:451516
  label: Staphylococcus aureus (strain USA300 / TCH1516)
description: >-
  fosB encodes a divalent-metal-dependent fosfomycin resistance enzyme in
  Staphylococcus aureus. FosB catalyzes thiol-dependent ring opening of
  fosfomycin, preferentially using bacillithiol in staphylococci, to form an
  inactive fosfomycin-thiol conjugate. This is mechanistically distinct from
  FosA glutathione transferases and FosX hydrolases.
existing_annotations:
- term:
    id: GO:0000287
    label: magnesium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: enables
  review:
    summary: Correct cofactor annotation, but secondary to the fosfomycin thiol-transferase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      UniProt and the FosB mechanism paper support divalent-metal dependence.
      The binding term should not be treated as the core function.
    supported_by:
    - reference_id: file:genes/STAAT/fosB/fosB-uniprot.txt
      supporting_text: "Name=Mg(2+)"
    - reference_id: PMID:23256780
      supporting_text: "FosB is a divalent-metal-dependent thiol-S-transferase implicated in fosfomycin"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Correct location for a soluble staphylococcal fosfomycin-inactivation enzyme.
    action: ACCEPT
    reason: The UniProt record carries cytoplasm as the subcellular-location-derived GO annotation.
    supported_by:
    - reference_id: file:genes/STAAT/fosB/fosB-uniprot.txt
      supporting_text: "DR   GO; GO:0005737; C:cytoplasm"
- term:
    id: GO:0016765
    label: transferase activity, transferring alkyl or aryl (other than methyl) groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Directionally correct core MF, but far less specific than the needed FosB/fosfomycin thiol-S-transferase term.
    action: ACCEPT
    reason: >-
      FosB catalyzes transfer/addition of a thiol cofactor to fosfomycin. GO lacks
      a suitable fosfomycin-specific bacillithiol/L-cysteine transferase term, so
      the broad transferase term is retained while a new term is proposed.
    supported_by:
    - reference_id: file:genes/STAAT/fosB/fosB-uniprot.txt
      supporting_text: "Metallothiol transferase which confers resistance to"
    - reference_id: PMID:23256780
      supporting_text: "SaFosB is the first to be characterized among a new class of enzyme"
- term:
    id: GO:0046677
    label: response to antibiotic
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Correct high-level antibiotic-response annotation for a fosfomycin-inactivation enzyme.
    action: ACCEPT
    reason: >-
      FosB is a bona fide antibiotic-inactivation resistance determinant, although
      the most useful curation gain is the specific molecular function.
    supported_by:
    - reference_id: file:genes/STAAT/fosB/fosB-uniprot.txt
      supporting_text: "DR   CARD; ARO:3004661; Saur_FosB; ARO:0001004; antibiotic inactivation."
    - reference_id: PMID:23256780
      supporting_text: "Disruption of BSH biosynthesis in S. aureus increases sensitivity to fosfomycin."
references:
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:genes/STAAT/fosB/fosB-uniprot.txt
  title: UniProt flat file for fosB (A8Z522)
  findings:
  - statement: UniProt names FosB as a metallothiol transferase that adds a thiol cofactor to fosfomycin.
    supporting_text: "catalyzing the addition of a thiol cofactor to"
- id: PMID:23256780
  title: "Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus."
  findings:
  - statement: SaFosB preferentially uses bacillithiol and produces a bacillithiol-fosfomycin product.
    supporting_text: "confirm that bacillithiol (BSH) is its preferred physiological thiol substrate"
- id: PMID:17986343
  title: Subtle genetic changes enhance virulence of methicillin resistant and sensitive Staphylococcus aureus.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Genome paper for the source strain; mechanism comes from UniProt/HAMAP and PMID:23256780.
  findings:
  - statement: Genome-sequence source for the USA300/TCH1516 entry, not primary evidence for FosB mechanism.
    supporting_text: "USA300-MRSA 2658 chromosomal open reading frames were predicted"
- id: file:projects/ANTIMICROBIAL_RESISTANCE/aro2go.sssom.yaml
  title: Curated ARO to GO mapping set for AMR gene families
  findings:
  - statement: The AMR mapping explicitly excludes FosB from glutathione transferase propagation.
    supporting_text: "The parent node also contains FosB (bacillithiol/L-cysteine thiol transferase, NOT"
core_functions:
- description: >-
    Divalent-metal-dependent fosfomycin thiol-S-transferase activity that opens
    the fosfomycin epoxide using bacillithiol as the preferred physiological
    thiol in S. aureus, producing inactive BS-fosfomycin and fosfomycin resistance.
  molecular_function:
    id: GO:0016765
    label: transferase activity, transferring alkyl or aryl (other than methyl) groups
  directly_involved_in:
  - id: GO:0046677
    label: response to antibiotic
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:23256780
    supporting_text: "NMR characterization of the reaction product (BS-fosfomycin)"
  - reference_id: file:genes/STAAT/fosB/fosB-uniprot.txt
    supporting_text: "L-cysteine is probably the physiological thiol donor."
proposed_new_terms:
- proposed_name: fosfomycin bacillithiol-S-transferase activity
  proposed_definition: >-
    Catalysis of the addition of bacillithiol or a related low-molecular-mass
    thiol to fosfomycin, opening the fosfomycin epoxide ring and forming an
    inactive fosfomycin-thiol conjugate.
  justification: >-
    FosB enzymes are not glutathione transferases, and propagation of a generic
    FosA/GST mapping would mis-annotate staphylococcal FosB. A FosB-specific GO
    term is needed to represent bacillithiol/L-cysteine-dependent fosfomycin
    inactivation.
  proposed_parent:
    id: GO:0016765
    label: transferase activity, transferring alkyl or aryl (other than methyl) groups
  proposed_mappings:
  - predicate: skos:exactMatch
    target_term:
      id: ARO:3004661
      label: Saur_FosB
  supported_by:
  - reference_id: PMID:23256780
    supporting_text: "SaFosB is a divalent-metal-dependent"
  - reference_id: file:projects/ANTIMICROBIAL_RESISTANCE/aro2go.sssom.yaml
    supporting_text: "The parent node also contains FosB (bacillithiol/L-cysteine thiol transferase, NOT"
suggested_questions:
- question: Should GO model FosB as a bacillithiol-specific term, a broader fosfomycin thiol-S-transferase term, or both?
  experts: []
suggested_experiments:
- description: >-
    Compare purified FosB activity with bacillithiol, L-cysteine, glutathione,
    and coenzyme A across representative FosB subfamilies to set the substrate
    scope for the GO term.
  experiment_type: in vitro enzyme assay