id: P35914
gene_symbol: HMGCL
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HMGCL encodes mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase (HL;
  EC 4.1.3.4), the enzyme that catalyzes the shared terminal step of ketogenesis
  and leucine catabolism: the cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA
  into acetoacetate and acetyl-CoA. The enzyme adopts a (beta/alpha)8 TIM-barrel
  fold and functions as a disulfide-linked homodimer (also observed as homotetramer),
  requiring a divalent metal cation (Mg2+ or Mn2+) coordinated by active-site
  residues including His233, His235, Asp42 and Asn275. The mature protein resides in
  the mitochondrial matrix; an unprocessed precursor form retaining the N-terminal
  mitochondrial leader together with a C-terminal Cys-Lys-Leu peroxisomal targeting
  motif is also imported into peroxisomes, giving the protein a dual mitochondrial/peroxisomal
  localization. HMGCL is most highly expressed in liver, the principal ketogenic
  tissue, where ketone bodies serve as an alternative energy source for extrahepatic
  tissues. Loss-of-function variants cause the autosomal-recessive disease HMG-CoA
  lyase deficiency (3-hydroxy-3-methylglutaric aciduria, MIM 246450), which blocks
  both ketone-body synthesis and leucine degradation and presents with hypoketotic
  hypoglycemia and metabolic acidosis, often precipitated by fasting or catabolic stress.
alternative_products:
- name: '1'
  id: P35914-1
- name: 2 (HMGCS2delta5,6)
  id: P35914-2
  sequence_note: VSP_047444
- name: 3 (HMGCS2delta5,6,7)
  id: P35914-3
  sequence_note: VSP_047444, VSP_043788
existing_annotations:
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically-inferred core molecular function. HMGCL is the HMG-CoA lyase
      catalyzing cleavage of (S)-HMG-CoA to acetoacetate + acetyl-CoA, the defining
      activity of the enzyme family and well supported by direct assays.
    action: ACCEPT
    reason: >-
      This is the correct, specific core molecular function of HMGCL and is
      corroborated by multiple experimental IDA annotations and by biochemical
      characterization of the recombinant human enzyme.
    supported_by:
    - reference_id: PMID:8102917
      supporting_text: "matrix enzyme that catalyzes the last step of ketogenesis"
    - reference_id: PMID:22847177
      supporting_text: "catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to acetoacetate and acetyl-CoA"
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically-inferred involvement in leucine catabolism. HMG-CoA is the
      penultimate intermediate of leucine degradation, and HMGCL performs its terminal
      cleavage; this is a shared core biological process.
    action: ACCEPT
    reason: >-
      Correct core BP. The HMG-CoA cleavage step is the common final step of both
      ketogenesis and leucine catabolism.
    supported_by:
    - reference_id: PMID:22847177
      supporting_text: "This reaction is the common final step in ketogenesis and leucine catabolism"
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically-inferred involvement in ketogenesis. HMGCL catalyzes the last
      committed step producing acetoacetate, a ketone body; a core biological process.
    action: ACCEPT
    reason: >-
      Correct core BP, supported by direct enzymatic characterization and by the
      liver-enriched expression pattern consistent with a ketogenic role.
    supported_by:
    - reference_id: PMID:8102917
      supporting_text: "matrix enzyme that catalyzes the last step of ketogenesis"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically-inferred mitochondrial site of action, consistent with the
      mature matrix enzyme and its N-terminal mitochondrial targeting sequence.
    action: ACCEPT
    reason: >-
      HMGCL acts in the mitochondrion; the mitochondrial matrix term is the more
      specific localization retained as core.
    supported_by:
    - reference_id: PMID:8670134
      supporting_text: "27-residue N-terminal mitochondrial targeting sequence"
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO mapping to the root catalytic-activity term. Correct but far too
      general given the well-defined HMG-CoA lyase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong, but uninformative; the specific term GO:0004419 (hydroxymethylglutaryl-CoA
      lyase activity) fully captures the molecular function.
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated multi-method annotation (ARBA/InterPro/RHEA/EC) to the specific HMG-CoA
      lyase activity, mapped from EC 4.1.3.4 / RHEA:24404.
    action: ACCEPT
    reason: >-
      Correct specific molecular function, consistent with the UniProt catalytic
      activity and experimental evidence.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location keyword mapping to mitochondrial matrix, matching
      the documented location of the mature enzyme.
    action: ACCEPT
    reason: >-
      Correct core localization of the mature processed enzyme; consistent with
      experimental and structural work.
    supported_by:
    - reference_id: PMID:8102917
      supporting_text: "matrix enzyme that catalyzes the last step of ketogenesis"
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location keyword mapping to peroxisome, reflecting the
      unprocessed precursor form imported into peroxisomes.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peroxisomal localization is genuine (dual targeting of the unprocessed precursor)
      but is a secondary compartment whose function is unresolved; the mitochondrial
      matrix is the core catalytic location.
    supported_by:
    - reference_id: PMID:9869651
      supporting_text: "localization in both mitochondria and peroxisomes"
- term:
    id: GO:0016833
    label: oxo-acid-lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO mapping to the parent oxo-acid-lyase class. Correct but less specific
      than hydroxymethylglutaryl-CoA lyase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Accurate parent term but superseded by the specific GO:0004419; retained as
      over-annotation rather than core.
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA machine-learning annotation to ketone body biosynthesis, matching the
      established ketogenic role of HMGCL.
    action: ACCEPT
    reason: >-
      Correct core BP, redundant with experimental and IBA annotations to the same term.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl-Compara transfer of mitochondrial localization from the mouse ortholog
      (P38060), consistent with the mitochondrial matrix enzyme.
    action: ACCEPT
    reason: >-
      Correct compartment; the more specific mitochondrial matrix term is retained as core.
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara transfer of leucine catabolism involvement from the mouse
      ortholog, matching the shared terminal step performed by HMGCL.
    action: ACCEPT
    reason: >-
      Correct core BP, redundant with IBA/NAS/TAS annotations to the same term.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Curator sequence-similarity transfer of mitochondrial matrix localization from
      the mouse ortholog (P38060).
    action: ACCEPT
    reason: >-
      Correct core localization of the mature enzyme.
    supported_by:
    - reference_id: PMID:8102917
      supporting_text: "matrix enzyme that catalyzes the last step of ketogenesis"
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Curator sequence-similarity transfer of peroxisomal localization from the mouse
      ortholog, matching the dual-targeting biology.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peroxisomal localization is real but a secondary, non-core compartment.
    supported_by:
    - reference_id: PMID:9869651
      supporting_text: "localization in both mitochondria and peroxisomes"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput identification of HMGCL as a member of the high-confidence human
      mitochondrial proteome (MitoCoP), consistent with its mitochondrial localization.
    action: ACCEPT
    reason: >-
      Supports the mitochondrial compartment; core localization is captured more
      specifically as mitochondrial matrix.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: "MitoCoP) of 1,134 protein-coding genes"
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IDA
  original_reference_id: PMID:8027038
  qualifier: enables
  review:
    summary: >-
      Direct assay of purified recombinant human HMG-CoA lyase expressed in E. coli,
      establishing the enzyme's catalytic activity.
    action: ACCEPT
    reason: >-
      Experimental evidence for the core molecular function of HMGCL.
    supported_by:
    - reference_id: PMID:8027038
      supporting_text: "a mitochondrial matrix protein"
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IDA
  original_reference_id: PMID:12464283
  qualifier: enables
  review:
    summary: >-
      Direct characterization of purified human HMG-CoA lyase (peroxisomal/unprocessed
      isoform) demonstrating DTT-stimulated lyase activity.
    action: ACCEPT
    reason: >-
      Experimental support for the core molecular function.
    supported_by:
    - reference_id: PMID:12464283
      supporting_text: "substantial (eightfold) dithiothreitol (DTT) stimulation of activity"
- term:
    id: GO:0005198
    label: structural molecule activity
  evidence_type: IDA
  original_reference_id: PMID:12464283
  qualifier: enables
  review:
    summary: >-
      This IDA appears to derive from the paper's analysis of HMGCL oligomeric status
      (dimer vs monomer, Cys323-mediated crosslinking). Self-assembly of a catalytic
      homodimer is not a "structural molecule activity" in the GO sense (a structural
      constituent such as a cytoskeletal or matrix building block).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      HMGCL is a catalytic enzyme, not a structural molecule; the term is a mischosen
      molecular function. It is retained (not removed) as an experimental annotation but
      flagged as over-annotated and non-core.
    supported_by:
    - reference_id: PMID:12464283
      supporting_text: "the results suggest that these proteins are predominantly dimers"
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:12464283
  qualifier: located_in
  review:
    summary: >-
      Direct study of the peroxisomal (unprocessed precursor) isoform of human HMGCL.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peroxisomal localization is genuine but a secondary compartment; mitochondrial
      matrix is the core catalytic location.
    supported_by:
    - reference_id: PMID:12464283
      supporting_text: "peroxisomal isoform of human"
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:12464283
  qualifier: part_of
  review:
    summary: >-
      Reflects the observation that HMGCL is predominantly a homodimer (and can form
      higher-order/tetrameric species). The generic protein-containing complex term is
      uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      HMGCL is a disulfide-linked homodimer, so the annotation is technically true, but
      the term is too generic to convey function; the homodimeric quaternary structure
      is better captured in core_functions/notes.
    supported_by:
    - reference_id: PMID:12464283
      supporting_text: "the results suggest that these proteins are predominantly dimers"
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  qualifier: located_in
  review:
    summary: >-
      Reactome peroxisomal-import event placing HMGCL cargo in the peroxisomal matrix
      after PEX5-mediated translocation. Consistent with the dual-targeting biology.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peroxisomal matrix localization is real but secondary/non-core relative to the
      mitochondrial matrix catalytic site.
    supported_by:
    - reference_id: PMID:9869651
      supporting_text: "localization in both mitochondria and peroxisomes"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  qualifier: located_in
  review:
    summary: >-
      This Reactome annotation places HMGCL in the cytosol as a transient step of the
      generic PEX5-dependent peroxisomal protein-import pathway (cargo in the cytosol
      before translocation), not as evidence of a functional cytosolic catalytic pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transient import-intermediate localization only; HMGCL is not a bona fide cytosolic
      enzyme (the ER/cytosolic HMG-CoA lyase activity in brain/lung is HMGCLL1, a distinct
      gene product). Retained as non-core rather than removed.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033236
  qualifier: located_in
  review:
    summary: >-
      Duplicate cytosolic annotation from the PEX5 docking/translocation-module Reactome
      event; represents the same import-intermediate cytosolic step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same rationale as the other cytosol annotation: transient step of peroxisomal
      import, not a core cytosolic function.
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:8027038
  qualifier: involved_in
  review:
    summary: >-
      Broad lipid-metabolism annotation. HMGCL produces ketone bodies, which are lipid
      precursors, but the specific ketone-body biosynthesis and leucine-catabolism terms
      are the informative descriptors.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-general; superseded by GO:0046951 (ketone body biosynthetic process) and
      GO:0006552 (L-leucine catabolic process).
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: TAS
  original_reference_id: PMID:8027038
  qualifier: involved_in
  review:
    summary: >-
      Author-stated involvement of HMGCL in leucine catabolism (terminal HMG-CoA cleavage
      step shared with ketogenesis).
    action: ACCEPT
    reason: >-
      Correct core BP, redundant with IBA/IEA/NAS annotations to the same term.
    supported_by:
    - reference_id: PMID:22847177
      supporting_text: "This reaction is the common final step in ketogenesis and leucine catabolism"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74180
  qualifier: located_in
  review:
    summary: >-
      Reactome reaction "HMG CoA => acetoacetic acid + acetyl CoA" places the HMGCL dimer
      in the mitochondrial matrix as the catalytic site.
    action: ACCEPT
    reason: >-
      Correct core localization of the catalytically active enzyme.
    supported_by:
    - reference_id: PMID:8102917
      supporting_text: "matrix enzyme that catalyzes the last step of ketogenesis"
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IDA
  original_reference_id: PMID:22847177
  qualifier: enables
  review:
    summary: >-
      HMG-CoA lyase activity IDA. NOTE: the primary subject of this paper is HMGCLL1
      (er-cHL), a distinct ER/cytosolic homolog; mitochondrial HMGCL (mHL) is used as
      the reference/comparison enzyme and its lyase activity is described.
    action: ACCEPT
    reason: >-
      The molecular function asserted (HMG-CoA lyase activity) is unambiguously correct
      for HMGCL and is independently supported by multiple other IDA/IBA/structural
      references, so it is retained as core. Flagged only because the paper's novel focus
      is the HMGCLL1 gene product, not P35914 itself.
    supported_by:
    - reference_id: PMID:22847177
      supporting_text: "catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to acetoacetate and acetyl-CoA"
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IDA
  original_reference_id: PMID:22865860
  qualifier: enables
  review:
    summary: >-
      HMG-CoA lyase activity IDA. NOTE: this paper characterizes HMGCLL1, an
      extramitochondrial HMG-CoA lyase encoded by a different gene, and compares it to
      mitochondrial HMGCL as the reference enzyme.
    action: ACCEPT
    reason: >-
      The asserted molecular function is correct for HMGCL and independently well
      supported; retained as core. Flagged because the paper's primary subject is HMGCLL1.
      Per curation policy this experimental annotation is not removed.
    supported_by:
    - reference_id: PMID:22865860
      supporting_text: "cleave HMG-CoA to"
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:22847177
  qualifier: involved_in
  review:
    summary: >-
      Ketone-body biosynthesis IDA. As above, the paper's novel subject is HMGCLL1, with
      mitochondrial HMGCL described as the ketone-body-producing reference enzyme.
    action: ACCEPT
    reason: >-
      Ketone-body biosynthesis is a correct core BP for HMGCL, redundant with the IBA/IEA
      and PMID:9200711 annotations; retained. Flagged because of the paper's HMGCLL1 focus.
    supported_by:
    - reference_id: PMID:22847177
      supporting_text: "The mitochondrial isoform contributes to ketone body production"
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:22865860
  qualifier: involved_in
  review:
    summary: >-
      Ketone-body biosynthesis IDA associated with the HMGCLL1 characterization paper,
      which compares against mitochondrial HMGCL.
    action: ACCEPT
    reason: >-
      Correct core BP for HMGCL, independently supported; retained. Flagged for the same
      HMGCLL1-focus reason.
    supported_by:
    - reference_id: PMID:22865860
      supporting_text: "HMGCLL1 is an extramitochondrial"
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IDA
  original_reference_id: PMID:8670134
  qualifier: enables
  review:
    summary: >-
      Direct assay of purified precursor (pHL) and mature (mHL) human HMG-CoA lyase,
      showing similar catalytic properties (Km for HMG-CoA ~44.8 uM, kcat).
    action: ACCEPT
    reason: >-
      Experimental support for the core molecular function of HMGCL.
    supported_by:
    - reference_id: PMID:8670134
      supporting_text: "is found in both mitochondria and peroxisomes"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:9869651
  qualifier: located_in
  review:
    summary: >-
      Direct demonstration of mitochondrial HMGCL by density-gradient fractionation and
      pulse-chase processing studies in human cells.
    action: ACCEPT
    reason: >-
      Correct compartment; mitochondrial matrix retained as the more specific core term.
    supported_by:
    - reference_id: PMID:9869651
      supporting_text: "localization in both mitochondria and peroxisomes"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: NAS
  original_reference_id: PMID:8102917
  qualifier: located_in
  review:
    summary: >-
      Author statement that HMGCL is a homodimeric mitochondrial matrix enzyme catalyzing
      the last step of ketogenesis.
    action: ACCEPT
    reason: >-
      Correct core localization; consistent with all other localization evidence.
    supported_by:
    - reference_id: PMID:8102917
      supporting_text: "matrix enzyme that catalyzes the last step of ketogenesis"
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: NAS
  original_reference_id: PMID:9200711
  qualifier: involved_in
  review:
    summary: >-
      Author-stated involvement of HMGCL in leucine catabolism, in a paper focused on
      cation binding (His235) of the human enzyme.
    action: ACCEPT
    reason: >-
      Correct core BP, redundant with IBA/IEA/TAS annotations to the same term.
    supported_by:
    - reference_id: PMID:22847177
      supporting_text: "This reaction is the common final step in ketogenesis and leucine catabolism"
- term:
    id: GO:0000287
    label: magnesium ion binding
  evidence_type: IDA
  original_reference_id: PMID:9200711
  qualifier: enables
  review:
    summary: >-
      Direct evidence that HMGCL binds a dissociable divalent cation (Mg2+ or Mn2+)
      required for activity, with His235 contributing to cation binding.
    action: ACCEPT
    reason: >-
      Well-supported specific molecular function; the enzyme requires a divalent metal
      cofactor for catalysis (Mg2+ documented biochemically and structurally).
    supported_by:
    - reference_id: PMID:9200711
      supporting_text: "divalent cation (e.g. Mg2+ or Mn2+) that is required for activity"
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IDA
  original_reference_id: PMID:9200711
  qualifier: enables
  review:
    summary: >-
      Direct characterization of wild-type and H235 mutant human HMG-CoA lyase,
      measuring catalytic activity and Km for HMG-CoA.
    action: ACCEPT
    reason: >-
      Experimental support for the core molecular function.
    supported_by:
    - reference_id: PMID:9200711
      supporting_text: "human 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase"
- term:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  evidence_type: IDA
  original_reference_id: PMID:9869651
  qualifier: enables
  review:
    summary: >-
      Direct study of HMGCL (HL, EC 4.1.3.4) demonstrating that mitochondrial HL
      catalyzes the last step of ketogenesis.
    action: ACCEPT
    reason: >-
      Experimental support for the core molecular function.
    supported_by:
    - reference_id: PMID:9869651
      supporting_text: "approximately 31.0 kDa) catalyzes the last step of ketogenesis"
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9869651
  qualifier: located_in
  review:
    summary: >-
      Direct demonstration of peroxisomal HMGCL by density-gradient fractionation;
      peroxisomal HL is absent in Zellweger (peroxisome-deficient) cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peroxisomal localization is genuine but secondary; peroxisomal HL function is
      unresolved, so the mitochondrial matrix remains the core catalytic location.
    supported_by:
    - reference_id: PMID:9869651
      supporting_text: "localization in both mitochondria and peroxisomes"
- term:
    id: GO:0030145
    label: manganese ion binding
  evidence_type: IDA
  original_reference_id: PMID:9200711
  qualifier: enables
  review:
    summary: >-
      Direct evidence that HMGCL uses a divalent cation activator that can be Mn2+ as
      well as Mg2+; Mn2+ interactions were probed by ESR.
    action: ACCEPT
    reason: >-
      Documented divalent-cation cofactor requirement satisfied by Mn2+ (used
      experimentally to probe the metal site); a legitimate specific MF.
    supported_by:
    - reference_id: PMID:9200711
      supporting_text: "divalent cation (e.g. Mg2+ or Mn2+) that is required for activity"
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:9200711
  qualifier: involved_in
  review:
    summary: >-
      Involvement in ketone-body biosynthesis via the HMG-CoA cleavage step, in the
      context of the human enzyme's cation-dependent catalysis.
    action: ACCEPT
    reason: >-
      Correct core BP, redundant with IBA/IEA/IDA annotations to the same term.
    supported_by:
    - reference_id: PMID:22847177
      supporting_text: "The mitochondrial isoform contributes to ketone body production"
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IDA
  original_reference_id: PMID:16330550
  qualifier: enables
  review:
    summary: >-
      Crystal structure with a bound activator cation identifies Asn275, Asp42, His233
      and His235 as cation ligands. Metal ion binding is the generic parent of the
      specific magnesium/manganese binding terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct but generic; the specific divalent-cation binding is better captured by
      GO:0000287 (magnesium) and GO:0030145 (manganese). Retained as over-annotation.
    supported_by:
    - reference_id: PMID:16330550
      supporting_text: "activator cation ligands included Asn(275), "
core_functions:
- description: >-
    Catalyzes the shared terminal step of ketogenesis and leucine catabolism: the
    cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetoacetate
    and acetyl-CoA (EC 4.1.3.4, RHEA:24404), acting as a divalent-cation-dependent
    homodimeric enzyme in the mitochondrial matrix.
  molecular_function:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  directly_involved_in:
  - id: GO:0046951
    label: ketone body biosynthetic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:8102917
    supporting_text: "matrix enzyme that catalyzes the last step of ketogenesis"
  - reference_id: PMID:22847177
    supporting_text: "catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to acetoacetate and acetyl-CoA"
- description: >-
    Performs the terminal HMG-CoA cleavage step of L-leucine degradation, the same
    reaction shared with ketogenesis, in the mitochondrial matrix.
  molecular_function:
    id: GO:0004419
    label: hydroxymethylglutaryl-CoA lyase activity
  directly_involved_in:
  - id: GO:0006552
    label: L-leucine catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:22847177
    supporting_text: "This reaction is the common final step in ketogenesis and leucine catabolism"
- description: >-
    Binds a required divalent metal cation (Mg2+ or Mn2+) at the active site,
    coordinated by residues including His233, His235, Asp42 and Asn275; the cation is
    essential for lyase catalysis.
  molecular_function:
    id: GO:0000287
    label: magnesium ion binding
  supported_by:
  - reference_id: PMID:9200711
    supporting_text: "divalent cation (e.g. Mg2+ or Mn2+) that is required for activity"
  - reference_id: PMID:16330550
    supporting_text: "activator cation ligands included Asn(275), "
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: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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12464283
  title: Investigation of the oligomeric status of the peroxisomal isoform of human
    3-hydroxy-3-methylglutaryl-CoA lyase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Characterizes purified peroxisomal (unprocessed) HMGCL
      isoform; DTT-stimulated lyase activity and Cys323-dependent homodimerization.
      Supports the lyase-activity, peroxisome and homodimer annotations; does NOT
      support a "structural molecule activity" MF.
- id: PMID:16330550
  title: 'Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights
    into catalysis and the molecular basis for hydroxymethylglutaric aciduria.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. 2.1 A crystal structure of human mitochondrial HMGCL with
      bound activator cation; identifies Asn275/Asp42/His233/His235 cation ligands and
      the (beta/alpha)8 barrel fold. Directly supports metal-ion binding and catalysis.
- id: PMID:22847177
  title: Characterization of a novel HMG-CoA lyase enzyme with a dual location in
    endoplasmic reticulum and cytosol.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text available. Primary subject is HMGCLL1 (er-cHL), a distinct ER/cytosolic
      HMG-CoA lyase homolog encoded by a different gene; mitochondrial HMGCL (mHL) is the
      reference/comparison enzyme. Its introduction cleanly states HMGCL function
      (HMG-CoA cleavage; common final step of ketogenesis + leucine catabolism), which is
      what is quoted here. The GOA IDA annotations of P35914 to this paper are therefore
      biologically correct for HMGCL but the paper's novel focus is HMGCLL1.
- id: PMID:22865860
  title: Identification and characterization of an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA
    lyase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Characterizes HMGCLL1 as an extramitochondrial (ER/cytosol)
      HMG-CoA lyase distinct from mitochondrial HMGCL, using mitochondrial HMGCL as the
      reference enzyme. GOA IDA annotations of P35914 to this paper describe the correct
      HMGCL function but the paper itself is about the HMGCLL1 gene product.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text available. Defines the high-confidence human mitochondrial proteome
      (MitoCoP, 1,134 protein-coding genes); provides high-throughput support for
      HMGCL's mitochondrial localization.
- id: PMID:8027038
  title: '3-Hydroxy-3-methylglutaryl-CoA lyase: expression and isolation of the recombinant
    human enzyme and investigation of a mechanism for regulation of enzyme activity.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Expresses and isolates recombinant human HMGCL (mitochondrial
      matrix protein) and studies Cys323 thiol/disulfide regulation. Supports the
      lyase-activity IDA; the co-cited "lipid metabolic process" is over-general.
- id: PMID:8102917
  title: '3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning and characterization
    of a mouse liver HL cDNA and subchromosomal mapping of the human and mouse HL
    genes.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. States HMGCL is "a homodimeric mitochondrial matrix enzyme
      that catalyzes the last step of ketogenesis" - directly supports matrix
      localization, homodimer and ketogenesis annotations.
- id: PMID:8670134
  title: Characterization of the hydroxymethylglutaryl-CoA lyase precursor, a protein
    targeted to peroxisomes and mitochondria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Shows HMGCL precursor (retaining the mitochondrial leader and
      a C-terminal Cys-Lys-Leu PTS) is dual-targeted to peroxisomes and mitochondria;
      precursor and mature enzyme have similar catalytic properties. Supports dual
      localization and lyase activity.
- id: PMID:9200711
  title: Evidence supporting a role for histidine-235 in cation binding to human 3-hydroxy-3-methyglutaryl-CoA
    lyase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Site-directed mutagenesis and ESR show HMGCL requires a
      dissociable divalent cation (Mg2+ or Mn2+) and that His235 contributes to cation
      binding. Directly supports magnesium/manganese ion binding.
- id: PMID:9869651
  title: '3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and processing in
    peroxisomes and mitochondria.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Demonstrates HMGCL dual mitochondrial/peroxisomal
      localization (peroxisomal HL absent in Zellweger cells) and that mitochondrial HL
      catalyzes the last step of ketogenesis; peroxisomal HL function is unresolved.
- id: Reactome:R-HSA-74180
  title: HMG CoA => acetoacetic acid + acetyl CoA
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction placing the HMGCL homodimer in the mitochondrial matrix
      catalyzing HMG-CoA to acetyl-CoA + acetoacetate. Supports matrix localization and
      the core reaction.
- id: Reactome:R-HSA-9033235
  title: Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Generic PEX5-dependent peroxisomal import event. The cytosol and peroxisomal-matrix
      localizations derived from it are import-pathway intermediates for HMGCL cargo, not
      evidence of a functional cytosolic HMGCL pool.
- id: Reactome:R-HSA-9033236
  title: PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation
    Module)
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Generic peroxisomal docking/translocation-module event; source of a duplicate
      cytosol (import-intermediate) annotation, not a core cytosolic function.