id: Q53H12
gene_symbol: AGK
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: AGK encodes a mitochondrial acylglycerol kinase with dual roles in lipid metabolism and mitochondrial protein import. Its catalytic activity phosphorylates monoacylglycerol and diacylglycerol to generate lysophosphatidic acid and phosphatidic acid. Independently of lipid kinase activity, AGK is a metazoan TIM22 complex subunit at the mitochondrial inner membrane/intermembrane-space interface, where it supports import and assembly of carrier-type multipass inner-membrane proteins. Biallelic AGK variants cause Sengers syndrome, linking defects in mitochondrial lipid metabolism and TIM22-dependent protein biogenesis to congenital cataracts, cardiomyopathy, skeletal myopathy, and lactic acidosis.
alternative_products:
- name: '1'
  id: Q53H12-1
- name: '2'
  id: Q53H12-2
  sequence_note: VSP_020925, VSP_020926
existing_annotations:
- term:
    id: GO:0001729
    label: ceramide kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Direct human evidence does not support ceramide kinase activity for AGK.
    action: REMOVE
    reason: The strongest accessible human enzymology detected AGK activity toward monoacylglycerols and diacylglycerols, while explicitly reporting no significant ceramide or sphingosine phosphorylation. The ceramide kinase annotation is therefore not supported for native human AGK.
    additional_reference_ids:
    - PMID:15939762
    - PMID:16269826
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Significant phosphorylated products were only detected with monoacylglycerols and diacylglycerols as substrates, but not with any other lipid tested, including ceramide and sphingosine
    - reference_id: PMID:16269826
      supporting_text: No evidence for phosphorylation of ceramide by the recently described multiple lipid kinase was found
- term:
    id: GO:0004143
    label: ATP-dependent diacylglycerol kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic propagation of ATP-dependent diacylglycerol kinase activity is supported by direct human enzymology.
    action: ACCEPT
    reason: AGK directly phosphorylates diacylglycerol to phosphatidic acid in the human study and UniProt records EC 2.7.1.107 for this activity.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Mitochondrial active localization is consistent with direct localization and TIM22-complex evidence.
    action: ACCEPT
    reason: 'The core AGK functions occur in mitochondria: the original lipid-kinase paper localized AGK to mitochondria and later TIM22 studies place AGK at the mitochondrial inner membrane/intermembrane-space face.'
    additional_reference_ids:
    - PMID:15939762
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Plasma-membrane activity is not supported for native human AGK.
    action: REMOVE
    reason: The accessible AGK literature supports mitochondrial localization. The ceramide-kinase paper instead describes HsCERK plasma-membrane localization and distinguishes it from the multiple lipid kinase, so propagation of plasma membrane activity to AGK is unsafe.
    additional_reference_ids:
    - PMID:15939762
    - PMID:16269826
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Significant phosphorylated products were only detected with monoacylglycerols and diacylglycerols as substrates, but not with any other lipid tested, including ceramide and sphingosine
    - reference_id: PMID:16269826
      supporting_text: No evidence for phosphorylation of ceramide by the recently described multiple lipid kinase was found
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Ceramide biosynthetic process is not supported for human AGK.
    action: REMOVE
    reason: Human AGK is better supported as an acylglycerol kinase and TIM22 subunit. The accessible enzymology does not support ceramide phosphorylation, so a ceramide biosynthesis process annotation overstates the evidence.
    additional_reference_ids:
    - PMID:15939762
    - PMID:16269826
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Significant phosphorylated products were only detected with monoacylglycerols and diacylglycerols as substrates, but not with any other lipid tested, including ceramide and sphingosine
    - reference_id: PMID:16269826
      supporting_text: No evidence for phosphorylation of ceramide by the recently described multiple lipid kinase was found
- term:
    id: GO:0047620
    label: acylglycerol kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Acylglycerol kinase activity is a core AGK molecular function.
    action: ACCEPT
    reason: This is the defining lipid-kinase activity of AGK and is directly supported by the human JCB study.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Sphingosine biosynthetic process is not supported for human AGK.
    action: REMOVE
    reason: AGK was identified while searching for sphingosine-kinase relatives, but the direct study reported no significant sphingosine phosphorylation. There is no basis here for a sphingosine biosynthesis process annotation.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Significant phosphorylated products were only detected with monoacylglycerols and diacylglycerols as substrates, but not with any other lipid tested, including ceramide and sphingosine
    - reference_id: PMID:16269826
      supporting_text: No evidence for phosphorylation of ceramide by the recently described multiple lipid kinase was found
- term:
    id: GO:0001729
    label: ceramide kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated ceramide kinase activity is contradicted by accessible human evidence.
    action: REMOVE
    reason: The IEA transfer appears to follow orthology/Rhea logic, but direct human evidence and the ceramide-kinase follow-up do not support ceramide kinase activity for native AGK.
    additional_reference_ids:
    - PMID:15939762
    - PMID:16269826
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Significant phosphorylated products were only detected with monoacylglycerols and diacylglycerols as substrates, but not with any other lipid tested, including ceramide and sphingosine
    - reference_id: PMID:16269826
      supporting_text: No evidence for phosphorylation of ceramide by the recently described multiple lipid kinase was found
- term:
    id: GO:0004143
    label: ATP-dependent diacylglycerol kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated diacylglycerol kinase activity is supported by direct human evidence.
    action: ACCEPT
    reason: The IEA call is consistent with the human biochemical characterization and UniProt catalytic-activity record.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Mitochondrial inner-membrane localization is well supported.
    action: ACCEPT
    reason: Multiple direct AGK/TIM22 studies and UniProt place AGK at the mitochondrial inner membrane.
    additional_reference_ids:
    - PMID:15939762
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion inner membrane
    - reference_id: PMID:28712724
      supporting_text: TIM22 complex in the mitochondrial inner membrane
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Mitochondrial intermembrane-space localization is well supported.
    action: ACCEPT
    reason: UniProt and the TIM22 literature place AGK in the intermembrane-space side of the inner membrane, matching this localization annotation.
    additional_reference_ids:
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion intermembrane space
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Localizes in the mitochondrion intermembrane space, where it associates with the inner membrane
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic kinase activity is correct but too broad for AGK.
    action: MODIFY
    reason: AGK is a lipid kinase, and the existing review contains the more informative acylglycerol and diacylglycerol kinase terms. The generic kinase term should be replaced by these specific activities.
    proposed_replacement_terms:
    - id: GO:0047620
      label: acylglycerol kinase activity
    - id: GO:0004143
      label: ATP-dependent diacylglycerol kinase activity
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0047620
    label: acylglycerol kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated acylglycerol kinase activity is supported by direct human evidence.
    action: ACCEPT
    reason: This IEA agrees with the experimentally characterized AGK activity.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: The HCCS interaction row is a generic protein-binding annotation from a proteome-scale interactome dataset.
    action: MARK_AS_OVER_ANNOTATED
    reason: The paper is useful as an interaction resource, but generic protein binding is discouraged and does not define AGK molecular function. AGK-specific core functions are lipid kinase activity and TIM22 complex participation.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: BioPlex 2.0 contains more than 29,000 previously unknown co-associations
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: The HTT interaction row is a generic protein-binding annotation from a neurodegeneration interactome map.
    action: MARK_AS_OVER_ANNOTATED
    reason: This high-throughput interaction context does not establish an AGK-specific molecular function. It should not be retained as a core GO MF annotation.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: This network reveals interconnectivity across diseases and links many known ND-causing proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: The HCCS interaction row is a generic protein-binding annotation from BioPlex-style AP-MS.
    action: MARK_AS_OVER_ANNOTATED
    reason: The evidence supports a broad interaction network resource, not a distinctive AGK function. Generic protein binding should not be treated as core.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37009826
  qualifier: enables
  review:
    summary: The SMIM26 interaction is biologically interesting but generic protein binding is not an informative AGK molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: PMID:37009826 supports a cancer-context SMIM26-AGK interaction, but native AGK curation should focus on lipid kinase and TIM22 import-complex functions rather than a generic binding term.
    supported_by:
    - reference_id: PMID:37009826
      supporting_text: SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK)
- term:
    id: GO:0001727
    label: lipid kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Lipid kinase activity is true but less specific than the supported AGK activities.
    action: MODIFY
    reason: The annotation should be refined to acylglycerol kinase and ATP-dependent diacylglycerol kinase activity, which are directly supported for human AGK.
    proposed_replacement_terms:
    - id: GO:0047620
      label: acylglycerol kinase activity
    - id: GO:0004143
      label: ATP-dependent diacylglycerol kinase activity
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Generic membrane localization is correct but too broad for AGK.
    action: MODIFY
    reason: AGK is specifically supported at the mitochondrial inner membrane and intermembrane-space side of that membrane. The broad membrane term loses the biologically important mitochondrial context.
    proposed_replacement_terms:
    - id: GO:0005743
      label: mitochondrial inner membrane
    - id: GO:0005758
      label: mitochondrial intermembrane space
    additional_reference_ids:
    - PMID:15939762
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion inner membrane
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion intermembrane space
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Localizes in the mitochondrion intermembrane space, where it associates with the inner membrane
- term:
    id: GO:0046486
    label: glycerolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: Glycerolipid metabolic process is a supported non-PN process context for AGK lipid kinase activity.
    action: ACCEPT
    reason: AGK phosphorylates monoacylglycerol and diacylglycerol to generate glycerolipid phosphate products, so this broad process annotation is directionally correct.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:32901109
  qualifier: located_in
  review:
    summary: The TIM22 cryo-EM/ComplexPortal row supports mitochondrial inner-membrane localization.
    action: ACCEPT
    reason: The human TIM22 structure includes AGK as part of the mitochondrial inner-membrane translocase complex, matching this localization.
    additional_reference_ids:
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:32901109
      supporting_text: Cryo-EM structure of the human mitochondrial translocase TIM22 complex
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IPI
  original_reference_id: PMID:32901109
  qualifier: part_of
  review:
    summary: AGK is a supported TIM22 complex subunit.
    action: ACCEPT
    reason: This is the main PN-relevant AGK role and is supported by independent TIM22 studies plus structural/ComplexPortal curation.
    additional_reference_ids:
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:32901109
      supporting_text: Cryo-EM structure of the human mitochondrial translocase TIM22 complex
    - reference_id: PMID:28712724
      supporting_text: we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane
    - reference_id: PMID:28712724
      supporting_text: AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins
    - reference_id: PMID:28712726
      supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
    - reference_id: PMID:28712726
      supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:32901109
  qualifier: involved_in
  review:
    summary: AGK participates in protein insertion into the mitochondrial inner membrane through TIM22.
    action: ACCEPT
    reason: The specific inner-membrane insertion process is more appropriate than the broad PN protein-transport candidate because AGK functions in the TIM22 carrier-import route.
    additional_reference_ids:
    - PMID:28712724
    - PMID:28712726
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supported_by:
    - reference_id: file:human/AGK/AGK-notes.md
      supporting_text: The strongest PN-relevant role is the TIM22 import-complex role, not a generic protein-transport assertion.
    - reference_id: PMID:28712726
      supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
    - reference_id: PMID:28712726
      supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA mitochondrial localization is consistent with AGK biology.
    action: ACCEPT
    reason: Independent localization and TIM22 data support AGK as a mitochondrial protein.
    additional_reference_ids:
    - PMID:15939762
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5696074
  qualifier: located_in
  review:
    summary: Mitochondrial outer membrane is likely the wrong mitochondrial membrane compartment for native AGK.
    action: MODIFY
    reason: Reactome captures AGK lipid-kinase chemistry, but direct AGK/TIM22 evidence places native AGK at the inner membrane/intermembrane-space face rather than the mitochondrial outer membrane.
    proposed_replacement_terms:
    - id: GO:0005743
      label: mitochondrial inner membrane
    - id: GO:0005758
      label: mitochondrial intermembrane space
    additional_reference_ids:
    - PMID:15939762
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion inner membrane
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion intermembrane space
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Localizes in the mitochondrion intermembrane space, where it associates with the inner membrane
- term:
    id: GO:0001729
    label: ceramide kinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Orthology-based ceramide kinase activity is not supported for native human AGK.
    action: REMOVE
    reason: The accessible human evidence does not support AGK as a ceramide kinase and instead directly supports acylglycerol/diacylglycerol kinase activity.
    additional_reference_ids:
    - PMID:15939762
    - PMID:16269826
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Significant phosphorylated products were only detected with monoacylglycerols and diacylglycerols as substrates, but not with any other lipid tested, including ceramide and sphingosine
    - reference_id: PMID:16269826
      supporting_text: No evidence for phosphorylation of ceramide by the recently described multiple lipid kinase was found
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteome evidence is consistent with AGK localization.
    action: ACCEPT
    reason: This HTP localization agrees with direct AGK and TIM22 complex evidence.
    additional_reference_ids:
    - PMID:15939762
    - PMID:28712724
    - PMID:28712726
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: We defined a human mitochondrial high-confidence proteome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802927
  qualifier: located_in
  review:
    summary: This Reactome cytosol row reflects BRAF/RAF fusion biology, not native AGK.
    action: REMOVE
    reason: The seeded Reactome event is titled for BRAF and RAF fusion mutant dimers. It should not be propagated to native AGK localization, which is mitochondrial.
    supported_by:
    - reference_id: file:human/AGK/AGK-notes.md
      supporting_text: Several Reactome-derived cytosol rows in the seeded GOA are attached to BRAF/RAF fusion events rather than native AGK biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802932
  qualifier: located_in
  review:
    summary: This Reactome cytosol row reflects BRAF/RAF fusion biology, not native AGK.
    action: REMOVE
    reason: The seeded Reactome event is titled for dissociation of a BRAF/RAF fusion complex. It should not be used as native AGK cytosol evidence.
    supported_by:
    - reference_id: file:human/AGK/AGK-notes.md
      supporting_text: Several Reactome-derived cytosol rows in the seeded GOA are attached to BRAF/RAF fusion events rather than native AGK biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802933
  qualifier: located_in
  review:
    summary: This Reactome cytosol row reflects BRAF/RAF fusion biology, not native AGK.
    action: REMOVE
    reason: The seeded Reactome event is titled for p-BRAF and RAF fusion dimers phosphorylating MAP2Ks, not for native AGK function or localization.
    supported_by:
    - reference_id: file:human/AGK/AGK-notes.md
      supporting_text: Several Reactome-derived cytosol rows in the seeded GOA are attached to BRAF/RAF fusion events rather than native AGK biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802934
  qualifier: located_in
  review:
    summary: This Reactome cytosol row reflects BRAF/RAF fusion biology, not native AGK.
    action: REMOVE
    reason: The seeded Reactome event is titled for p-BRAF and RAF fusion dimers binding MAP2Ks and MAPKs, not for native AGK function or localization.
    supported_by:
    - reference_id: file:human/AGK/AGK-notes.md
      supporting_text: Several Reactome-derived cytosol rows in the seeded GOA are attached to BRAF/RAF fusion events rather than native AGK biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802935
  qualifier: located_in
  review:
    summary: This Reactome cytosol row reflects BRAF/RAF fusion biology, not native AGK.
    action: REMOVE
    reason: The seeded Reactome event is titled for MAPKs phosphorylated downstream of BRAF and RAF fusion dimers, not for native AGK function or localization.
    supported_by:
    - reference_id: file:human/AGK/AGK-notes.md
      supporting_text: Several Reactome-derived cytosol rows in the seeded GOA are attached to BRAF/RAF fusion events rather than native AGK biology.
- term:
    id: GO:0004143
    label: ATP-dependent diacylglycerol kinase activity
  evidence_type: IDA
  original_reference_id: PMID:15939762
  qualifier: enables
  review:
    summary: Direct human evidence supports ATP-dependent diacylglycerol kinase activity.
    action: ACCEPT
    reason: PMID:15939762 directly characterized AGK phosphorylation of diacylglycerol to phosphatidic acid.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:15939762
  qualifier: located_in
  review:
    summary: Direct human evidence supports mitochondrial membrane localization.
    action: ACCEPT
    reason: PMID:15939762 localized AGK to mitochondria and subcellular fractions enriched for mitochondrial AGK activity.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0047620
    label: acylglycerol kinase activity
  evidence_type: IDA
  original_reference_id: PMID:15939762
  qualifier: enables
  review:
    summary: Direct human evidence supports acylglycerol kinase activity.
    action: ACCEPT
    reason: PMID:15939762 directly characterized AGK phosphorylation of monoacylglycerol to LPA.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:15939762
      supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:16269826
  qualifier: located_in
  review:
    summary: PMID:16269826 supports mitochondrial localization context but not ceramide kinase activity.
    action: ACCEPT
    reason: The paper distinguishes HsCERK from the recently described multiple lipid kinase and notes that the latter kinase is mitochondrial. For AGK, this supports mitochondrial membrane localization while arguing against ceramide kinase transfer.
    additional_reference_ids:
    - PMID:15939762
    supported_by:
    - reference_id: PMID:16269826
      supporting_text: The latter kinase is localized in the mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28712724
  qualifier: located_in
  review:
    summary: PMID:28712724 supports AGK mitochondrial inner-membrane localization.
    action: ACCEPT
    reason: This paper identifies AGK as a TIM22 complex constituent at the mitochondrial inner membrane.
    supported_by:
    - reference_id: PMID:28712724
      supporting_text: we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane
    - reference_id: PMID:28712724
      supporting_text: AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28712726
  qualifier: located_in
  review:
    summary: PMID:28712726 supports AGK mitochondrial inner-membrane localization.
    action: ACCEPT
    reason: This paper identifies AGK as a human TIM22 protein import complex subunit.
    supported_by:
    - reference_id: PMID:28712726
      supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
    - reference_id: PMID:28712726
      supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IDA
  original_reference_id: PMID:28712724
  qualifier: located_in
  review:
    summary: PMID:28712724 supports AGK intermembrane-space/inner-membrane association.
    action: ACCEPT
    reason: The TIM22 study places AGK at the mitochondrial inner membrane/intermembrane-space side of the complex.
    supported_by:
    - reference_id: PMID:28712724
      supporting_text: we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane
    - reference_id: PMID:28712724
      supporting_text: AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion intermembrane space
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Localizes in the mitochondrion intermembrane space, where it associates with the inner membrane
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IDA
  original_reference_id: PMID:28712726
  qualifier: located_in
  review:
    summary: PMID:28712726 supports AGK intermembrane-space/inner-membrane association.
    action: ACCEPT
    reason: The human TIM22 study supports AGK as a mitochondrial import-complex subunit at the inner membrane.
    supported_by:
    - reference_id: PMID:28712726
      supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
    - reference_id: PMID:28712726
      supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Mitochondrion intermembrane space
    - reference_id: file:human/AGK/AGK-uniprot.txt
      supporting_text: Localizes in the mitochondrion intermembrane space, where it associates with the inner membrane
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IDA
  original_reference_id: PMID:28712724
  qualifier: part_of
  review:
    summary: PMID:28712724 directly supports AGK as part of the TIM22 complex.
    action: ACCEPT
    reason: AGK assembles with TIMM22 and TIMM29 and supports import of multi-spanning membrane proteins.
    supported_by:
    - reference_id: PMID:28712724
      supporting_text: we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane
    - reference_id: PMID:28712724
      supporting_text: AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IDA
  original_reference_id: PMID:28712726
  qualifier: part_of
  review:
    summary: PMID:28712726 directly supports AGK as part of the human TIM22 complex.
    action: ACCEPT
    reason: AGK maintains TIM22 complex integrity and facilitates carrier import and assembly.
    supported_by:
    - reference_id: PMID:28712726
      supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
    - reference_id: PMID:28712726
      supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28712724
  qualifier: involved_in
  review:
    summary: PMID:28712724 supports AGK involvement in protein insertion into the mitochondrial inner membrane.
    action: ACCEPT
    reason: The paper ties AGK-containing TIM22 to import of multi-spanning inner-membrane proteins, matching this process annotation.
    supported_by:
    - reference_id: PMID:28712724
      supporting_text: we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane
    - reference_id: PMID:28712724
      supporting_text: AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28712726
  qualifier: involved_in
  review:
    summary: PMID:28712726 supports AGK involvement in protein insertion into the mitochondrial inner membrane.
    action: ACCEPT
    reason: The paper directly links AGK to TIM22-dependent import and assembly of mitochondrial carrier proteins.
    supported_by:
    - reference_id: PMID:28712726
      supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
    - reference_id: PMID:28712726
      supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15939762
  title: A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells.
  findings:
  - statement: Human AGK phosphorylates monoacylglycerol and diacylglycerol to generate LPA and PA.
    supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
  - statement: The same study did not support ceramide or sphingosine as AGK substrates.
    supporting_text: Significant phosphorylated products were only detected with monoacylglycerols and diacylglycerols as substrates, but not with any other lipid tested, including ceramide and sphingosine
  - statement: AGK localizes to mitochondria in microscopy and fractionation assays.
    supporting_text: Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria
- id: PMID:16269826
  title: 'Further characterization of mammalian ceramide kinase: substrate delivery and (stereo)specificity, tissue distribution, and subcellular localization studies.'
  findings:
  - statement: This ceramide kinase study argues against assigning ceramide kinase activity to the multiple lipid kinase now curated as AGK.
    supporting_text: No evidence for phosphorylation of ceramide by the recently described multiple lipid kinase was found
  - statement: The study notes that the multiple lipid kinase is mitochondrial.
    supporting_text: The latter kinase is localized in the mitochondria
- id: PMID:22284826
  title: Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome.
  full_text_unavailable: true
  findings:
  - statement: Biallelic loss-of-function AGK variants cause Sengers syndrome (congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, lactic acidosis), and AGK loss decreases the adenine nucleotide translocator in the inner mitochondrial membrane in muscle.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:28712724
  title: Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria.
  findings:
  - statement: AGK is a constituent of the TIM22 complex in the mitochondrial inner membrane.
    supporting_text: we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane
  - statement: AGK supports import of a subset of multi-spanning mitochondrial membrane proteins.
    supporting_text: AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins
- id: PMID:28712726
  title: Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex.
  findings:
  - statement: AGK is a human TIM22 protein import complex subunit.
    supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
  - statement: AGK supports TIM22 integrity and carrier-protein import independently of kinase activity.
    supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33476211
  title: The TIM22 complex mediates the import of sideroflexins and is required for efficient mitochondrial one-carbon metabolism.
  full_text_unavailable: true
  findings:
  - statement: AGK-containing TIM22 imports sideroflexin (SFXN) proteins as a novel substrate class beyond SLC25 carriers, and AGK loss impairs SFXN biogenesis, linking AGK deficiency to dysregulated mitochondrial one-carbon metabolism.
- id: PMID:32901109
  title: Cryo-EM structure of the human mitochondrial translocase TIM22 complex.
  findings:
  - statement: Structural/ComplexPortal evidence supports AGK as part of the human TIM22 complex.
    supporting_text: Cryo-EM structure of the human mitochondrial translocase TIM22 complex
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:37655851
  title: Mitochondrial phospholipid metabolism in health and disease.
  full_text_unavailable: true
  findings:
  - statement: AGK-mediated phosphorylation of diacylglycerol to phosphatidic acid in the inner mitochondrial membrane is an intramitochondrial PA-generating route that feeds downstream phospholipid synthesis, including cardiolipin biogenesis.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings:
  - statement: High-confidence mitochondrial proteomics supports AGK mitochondrial localization in the broader mitochondrial proteome resource.
    supporting_text: We defined a human mitochondrial high-confidence proteome
- id: PMID:37009826
  title: LINC00493-encoded microprotein SMIM26 exerts anti-metastatic activity in renal cell carcinoma.
  findings:
  - statement: SMIM26 interacts with AGK in a renal-cell carcinoma context.
    supporting_text: SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK)
- id: Reactome:R-HSA-5696074
  title: AGK:Mg2+ phosphorylates MAG, DAG
  findings: []
- id: Reactome:R-HSA-6802927
  title: BRAF and RAF fusion mutant dimers are phosphorylated
  findings: []
- id: Reactome:R-HSA-6802932
  title: Dissociation of BRAF/RAF fusion complex
  findings: []
- id: Reactome:R-HSA-6802933
  title: p-BRAF and RAF fusion dimers phosphorylate MAP2Ks
  findings: []
- id: Reactome:R-HSA-6802934
  title: p-BRAF and RAF fusion dimers bind MAP2Ks and MAPKs
  findings: []
- id: Reactome:R-HSA-6802935
  title: MAPKs are phosphorylated downstream of BRAF and RAF fusion dimers
  findings: []
- id: file:human/AGK/AGK-uniprot.txt
  title: UniProt record for human AGK
  findings:
  - statement: UniProt summarizes AGK lipid kinase and TIM22 complex roles.
    supporting_text: Independently of its lipid kinase activity, acts as a component of the TIM22 complex
- id: file:human/AGK/AGK-notes.md
  title: Manual AGK Proteostasis PN review notes
  findings:
  - statement: Manual fallback notes document the failed Falcon/fallback provider run and the conservative PN projection decision.
    supporting_text: The strongest PN-relevant role is the TIM22 import-complex role, not a generic protein-transport assertion.
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
  title: Proteostasis PN projected annotations report
  findings:
  - statement: PN projection reports broad protein transport for AGK as new to GOA while TIM22 complex is already exactly represented.
    supporting_text: AGK
aliases:
- MULK
tags:
- proteostasis
core_functions:
- description: Mitochondrial lipid kinase activity that phosphorylates monoacylglycerol and diacylglycerol, producing lysophosphatidic acid and phosphatidic acid in glycerolipid metabolism.
  molecular_function:
    id: GO:0047620
    label: acylglycerol kinase activity
  directly_involved_in:
  - id: GO:0046486
    label: glycerolipid metabolic process
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: PMID:15939762
    supporting_text: AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively
  - reference_id: file:human/AGK/AGK-uniprot.txt
    supporting_text: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively
- description: Kinase-independent contribution to the TIM22 mitochondrial inner-membrane import complex, supporting insertion/import and assembly of carrier-type multipass inner-membrane proteins.
  contributes_to_molecular_function:
    id: GO:0008320
    label: protein transmembrane transporter activity
  directly_involved_in:
  - id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  - id: GO:0005758
    label: mitochondrial intermembrane space
  in_complex:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  supported_by:
  - reference_id: PMID:28712724
    supporting_text: we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane
  - reference_id: PMID:28712724
    supporting_text: AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins
  - reference_id: PMID:28712726
    supporting_text: we identified AGK as a subunit of the mitochondrial TIM22 protein import complex
  - reference_id: PMID:28712726
    supporting_text: AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins
proposed_new_terms: []
suggested_questions:
- question: Does native human AGK have physiologically relevant ceramide kinase activity under any mitochondrial membrane context, or are current ceramide-related annotations orthology/context artifacts?
  experts:
  - Bektas M
  - Van Veldhoven PP
  - Stojanovski D
- question: Which AGK surfaces mediate TIM22 complex stabilization independently of the catalytic site, and how do Sengers syndrome variants separate lipid-kinase and import-complex defects?
  experts:
  - Langer T
  - Ryan MT
  - Stojanovski D
- question: To what extent does AGK-dependent TIM22 import of sideroflexins (SFXNs) and the resulting one-carbon metabolism defect contribute to Sengers syndrome pathophysiology relative to SLC25/ANT carrier import loss?
  experts:
  - Stojanovski D
  - Stroud DA
suggested_experiments:
- hypothesis: Human AGK does not catalyze physiologically meaningful ceramide phosphorylation in native mitochondrial membranes.
  description: Purify or reconstitute human AGK in mitochondrial membrane-like liposomes and compare phosphorylation of monoacylglycerol, diacylglycerol, ceramide, and sphingosine using matched substrate presentation and kinase-dead AGK controls.
  experiment_type: enzyme reconstitution
- hypothesis: AGK has separable catalytic and TIM22-stabilizing surfaces.
  description: Use endogenous AGK knockout cells rescued with catalytic-site, TIM22-interface, and Sengers syndrome variants, then assay lipid products, TIM22 complex stability, and import/assembly of carrier substrates such as SLC25A4.
  experiment_type: structure-guided rescue and import assay
- hypothesis: AGK loss impairs sideroflexin biogenesis and one-carbon metabolism via the TIM22 import pathway.
  description: In AGK knockout cells, quantify steady-state SFXN protein levels and TIM22-dependent SFXN import, and test whether serine-restricted proliferation defects are rescued by formate supplementation or by re-expression of kinase-dead AGK.
  experiment_type: import assay with metabolic rescue