PANK4

# yaml-language-server: $schema=../../../src/ai_gene_review/schema/gene_review.yaml
id: Q9NVE7
gene_symbol: PANK4
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'PANK4 is a two-domain cytoplasmic enzyme of the pantothenate kinase family. Its N-terminal
  type II pantothenate-kinase-like domain is catalytically degenerate: PANK4 has no pantothenate kinase
  activity and is a ''pseudo-pantothenate kinase''. Its functional activity resides in the C-terminal
  damage-control (DUF89) domain, a metal-dependent (Mg2+/Mn2+) phosphatase that dephosphorylates 4''-phosphopantetheine
  and related metabolites (e.g. pantetheine-phosphate sulfonate). Through this 4''-phosphopantetheine
  phosphatase activity PANK4 participates in coenzyme-A pathway homeostasis / metabolite repair. It is
  widely expressed, with high levels in muscle, and forms homodimers. PANK4 thus illustrates a domain-swap
  pseudoenzyme: a dead ancestral catalytic domain alongside a retained, distinct enzymatic activity.'
existing_annotations:
- term:
    id: GO:0004594
    label: pantothenate kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  negated: true
  review:
    summary: 'NOT (negated): PANK4 does NOT have pantothenate kinase activity. Although it belongs to
      the type II pantothenate kinase family, its kinase domain is degenerate; PANK4 is a ''pseudo-pantothenate
      kinase''.'
    action: ACCEPT
    reason: Correct, well-supported negation (IMP, PMID:30927326 'pseudo-pantothenate kinase'). The CAUTION
      flags the degenerate PanK domain. Retain.
    supported_by: &id002
    - reference_id: PMID:30927326
      supporting_text: Human pantothenate kinase 4 is a pseudo-pantothenate kinase
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Nucleus (IBA, is_active_in). UniProt records PANK4 as cytoplasmic; the nuclear assignment
      is a phylogenetic inference not corroborated by the curated subcellular location.
    action: KEEP_AS_NON_CORE
    reason: Likely over-propagated by IBA. PANK4 is reported cytoplasmic (UniProt); keep as non-core pending
      direct evidence rather than asserting it as a core location.
    supported_by:
    - reference_id: file:human/PANK4/PANK4-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Cytosol (IBA), consistent with the curated cytoplasmic localization.
    action: ACCEPT
    reason: Correct core localization.
    supported_by:
    - reference_id: file:human/PANK4/PANK4-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0016791
    label: phosphatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: 'Phosphatase activity: PANK4''s C-terminal damage-control (DUF89) domain is a metal-dependent
      phosphatase that dephosphorylates 4''-phosphopantetheine (and related metabolites), a metabolite-repair
      / CoA-pathway regulatory activity.'
    action: ACCEPT
    reason: Core molecular function with direct experimental support (EXP, PMID:27322068; UniProt RecName
      '4'-phosphopantetheine phosphatase'). This is the protein's real activity, distinct from the dead
      PanK domain.
    supported_by: &id001
    - reference_id: file:human/PANK4/PANK4-uniprot.txt
      supporting_text: Phosphatase which shows a preference for 4'-
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP binding (IEA) from the (degenerate) pantothenate-kinase domain signature.
    action: KEEP_AS_NON_CORE
    reason: Plausible nucleotide binding by the kinase-like fold, but not the demonstrated catalytic activity
      (which is metal-dependent phosphatase). Non-core.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasm (IEA).
    action: ACCEPT
    reason: Correct, matches UniProt.
    supported_by:
    - reference_id: file:human/PANK4/PANK4-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0015937
    label: coenzyme A biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: 'Coenzyme A biosynthetic process (IEA): PANK4''s 4''-phosphopantetheine phosphatase activity
      acts on a CoA-pathway intermediate (metabolite repair / regulation).'
    action: KEEP_AS_NON_CORE
    reason: Correct pathway association via the phosphatase activity, but PANK4 modulates rather than
      performs core CoA biosynthesis; non-core.
- term:
    id: GO:0015939
    label: pantothenate metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-199220
  qualifier: involved_in
  review:
    summary: Pantothenate metabolic process (TAS), pathway context (CoA/pantothenate).
    action: KEEP_AS_NON_CORE
    reason: Pathway-level association; non-core.
- term:
    id: GO:0016791
    label: phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:27322068
  qualifier: enables
  review:
    summary: 'Phosphatase activity: PANK4''s C-terminal damage-control (DUF89) domain is a metal-dependent
      phosphatase that dephosphorylates 4''-phosphopantetheine (and related metabolites), a metabolite-repair
      / CoA-pathway regulatory activity.'
    action: ACCEPT
    reason: Core molecular function with direct experimental support (EXP, PMID:27322068; UniProt RecName
      '4'-phosphopantetheine phosphatase'). This is the protein's real activity, distinct from the dead
      PanK domain.
    supported_by: *id001
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Cytoplasm (ISS).
    action: ACCEPT
    reason: Consistent core localization.
    supported_by:
    - reference_id: file:human/PANK4/PANK4-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0004594
    label: pantothenate kinase activity
  evidence_type: IMP
  original_reference_id: PMID:30927326
  qualifier: enables
  negated: true
  review:
    summary: 'NOT (negated): PANK4 does NOT have pantothenate kinase activity. Although it belongs to
      the type II pantothenate kinase family, its kinase domain is degenerate; PANK4 is a ''pseudo-pantothenate
      kinase''.'
    action: ACCEPT
    reason: Correct, well-supported negation (IMP, PMID:30927326 'pseudo-pantothenate kinase'). The CAUTION
      flags the degenerate PanK domain. Retain.
    supported_by: *id002
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9837419
  qualifier: located_in
  review:
    summary: Cytosol (TAS).
    action: ACCEPT
    reason: Consistent core localization.
references:
- id: GO_REF:0000002
  title: GO annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified annotations to orthologs by curator judgment (ISS)
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: GO annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: PMID:27322068
  title: A family of metal-dependent phosphatases implicated in metabolite damage-control.
  findings:
  - statement: PANK4 belongs to a family of metal-dependent phosphatases implicated in metabolite damage-control;
      it dephosphorylates 4'-phosphopantetheine.
    supporting_text: A family of metal-dependent phosphatases implicated in metabolite damage-control
  reference_review: &id003
    relevance: HIGH
    correctness: VERIFIED
- id: PMID:30927326
  title: Human pantothenate kinase 4 is a pseudo-pantothenate kinase.
  findings:
  - statement: Human PANK4 is a pseudo-pantothenate kinase (no PanK activity).
    supporting_text: Human pantothenate kinase 4 is a pseudo-pantothenate kinase
  reference_review: *id003
- id: Reactome:R-HSA-199220
  title: Pantothenate and CoA biosynthesis
  findings: []
- id: Reactome:R-HSA-9837419
  title: Metabolism / cytosolic reaction (PANK4)
  findings: []
- id: file:human/PANK4/PANK4-uniprot.txt
  title: UniProt entry Q9NVE7 (PANK4)
  findings:
  - statement: PANK4 is a phosphatase preferring 4'-phosphopantetheine; its PanK domain is degenerate.
    supporting_text: Phosphatase which shows a preference for 4'-
aliases:
- Pantothenate kinase 4
- Pseudo-pantothenate kinase
- 4'-phosphopantetheine phosphatase
core_functions:
- description: Metal-dependent 4'-phosphopantetheine phosphatase (damage-control/metabolite-repair enzyme)
    acting in coenzyme-A pathway homeostasis. The ancestral pantothenate-kinase domain is catalytically
    dead.
  molecular_function:
    id: GO:0016791
    label: phosphatase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:27322068
    supporting_text: A family of metal-dependent phosphatases implicated in metabolite damage-control
  - reference_id: file:human/PANK4/PANK4-uniprot.txt
    supporting_text: Phosphatase which shows a preference for 4'-
suggested_questions:
- question: What is the precise physiological substrate spectrum of PANK4's phosphatase activity, and
    does it regulate CoA levels in vivo (e.g. in muscle)?
suggested_experiments:
- hypothesis: PANK4 phosphatase activity regulates intracellular CoA/4'-phosphopantetheine pools.
  description: Measure 4'-phosphopantetheine and CoA levels in PANK4-knockout vs wild-type cells/tissues,
    with rescue by phosphatase-dead PANK4.