HMGCL

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:8102917 matrix enzyme that catalyzes the last step of ketogenesis PMID:22847177 catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to acetoacetate and acetyl-CoA
GO:0006552 L-leucine catabolic process	IBA GO_REF:0000033	ACCEPT	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. Reason: Correct core BP. The HMG-CoA cleavage step is the common final step of both ketogenesis and leucine catabolism. Supporting Evidence: PMID:22847177 This reaction is the common final step in ketogenesis and leucine catabolism
GO:0046951 ketone body biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred involvement in ketogenesis. HMGCL catalyzes the last committed step producing acetoacetate, a ketone body; a core biological process. Reason: Correct core BP, supported by direct enzymatic characterization and by the liver-enriched expression pattern consistent with a ketogenic role. Supporting Evidence: PMID:8102917 matrix enzyme that catalyzes the last step of ketogenesis
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred mitochondrial site of action, consistent with the mature matrix enzyme and its N-terminal mitochondrial targeting sequence. Reason: HMGCL acts in the mitochondrion; the mitochondrial matrix term is the more specific localization retained as core. Supporting Evidence: PMID:8670134 27-residue N-terminal mitochondrial targeting sequence
GO:0003824 catalytic activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO mapping to the root catalytic-activity term. Correct but far too general given the well-defined HMG-CoA lyase activity. Reason: Not wrong, but uninformative; the specific term GO:0004419 (hydroxymethylglutaryl-CoA lyase activity) fully captures the molecular function.
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IEA GO_REF:0000120	ACCEPT	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. Reason: Correct specific molecular function, consistent with the UniProt catalytic activity and experimental evidence.
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location keyword mapping to mitochondrial matrix, matching the documented location of the mature enzyme. Reason: Correct core localization of the mature processed enzyme; consistent with experimental and structural work. Supporting Evidence: PMID:8102917 matrix enzyme that catalyzes the last step of ketogenesis
GO:0005777 peroxisome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular-location keyword mapping to peroxisome, reflecting the unprocessed precursor form imported into peroxisomes. 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. Supporting Evidence: PMID:9869651 localization in both mitochondria and peroxisomes
GO:0016833 oxo-acid-lyase activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO mapping to the parent oxo-acid-lyase class. Correct but less specific than hydroxymethylglutaryl-CoA lyase activity. Reason: Accurate parent term but superseded by the specific GO:0004419; retained as over-annotation rather than core.
GO:0046951 ketone body biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine-learning annotation to ketone body biosynthesis, matching the established ketogenic role of HMGCL. Reason: Correct core BP, redundant with experimental and IBA annotations to the same term.
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-Compara transfer of mitochondrial localization from the mouse ortholog (P38060), consistent with the mitochondrial matrix enzyme. Reason: Correct compartment; the more specific mitochondrial matrix term is retained as core.
GO:0006552 L-leucine catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-Compara transfer of leucine catabolism involvement from the mouse ortholog, matching the shared terminal step performed by HMGCL. Reason: Correct core BP, redundant with IBA/NAS/TAS annotations to the same term.
GO:0005759 mitochondrial matrix	ISS GO_REF:0000024	ACCEPT	Summary: Curator sequence-similarity transfer of mitochondrial matrix localization from the mouse ortholog (P38060). Reason: Correct core localization of the mature enzyme. Supporting Evidence: PMID:8102917 matrix enzyme that catalyzes the last step of ketogenesis
GO:0005777 peroxisome	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Curator sequence-similarity transfer of peroxisomal localization from the mouse ortholog, matching the dual-targeting biology. Reason: Peroxisomal localization is real but a secondary, non-core compartment. Supporting Evidence: PMID:9869651 localization in both mitochondria and peroxisomes
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput identification of HMGCL as a member of the high-confidence human mitochondrial proteome (MitoCoP), consistent with its mitochondrial localization. Reason: Supports the mitochondrial compartment; core localization is captured more specifically as mitochondrial matrix. Supporting Evidence: PMID:34800366 MitoCoP) of 1,134 protein-coding genes
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IDA PMID:8027038 3-Hydroxy-3-methylglutaryl-CoA lyase: expression and isolati...	ACCEPT	Summary: Direct assay of purified recombinant human HMG-CoA lyase expressed in E. coli, establishing the enzyme's catalytic activity. Reason: Experimental evidence for the core molecular function of HMGCL. Supporting Evidence: PMID:8027038 a mitochondrial matrix protein
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IDA PMID:12464283 Investigation of the oligomeric status of the peroxisomal is...	ACCEPT	Summary: Direct characterization of purified human HMG-CoA lyase (peroxisomal/unprocessed isoform) demonstrating DTT-stimulated lyase activity. Reason: Experimental support for the core molecular function. Supporting Evidence: PMID:12464283 substantial (eightfold) dithiothreitol (DTT) stimulation of activity
GO:0005198 structural molecule activity	IDA PMID:12464283 Investigation of the oligomeric status of the peroxisomal is...	MARK AS OVER ANNOTATED	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). 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. Supporting Evidence: PMID:12464283 the results suggest that these proteins are predominantly dimers
GO:0005777 peroxisome	IDA PMID:12464283 Investigation of the oligomeric status of the peroxisomal is...	KEEP AS NON CORE	Summary: Direct study of the peroxisomal (unprocessed precursor) isoform of human HMGCL. Reason: Peroxisomal localization is genuine but a secondary compartment; mitochondrial matrix is the core catalytic location. Supporting Evidence: PMID:12464283 peroxisomal isoform of human
GO:0032991 protein-containing complex	IDA PMID:12464283 Investigation of the oligomeric status of the peroxisomal is...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:12464283 the results suggest that these proteins are predominantly dimers
GO:0005782 peroxisomal matrix	TAS Reactome:R-HSA-9033235	KEEP AS NON CORE	Summary: Reactome peroxisomal-import event placing HMGCL cargo in the peroxisomal matrix after PEX5-mediated translocation. Consistent with the dual-targeting biology. Reason: Peroxisomal matrix localization is real but secondary/non-core relative to the mitochondrial matrix catalytic site. Supporting Evidence: PMID:9869651 localization in both mitochondria and peroxisomes
GO:0005829 cytosol	TAS Reactome:R-HSA-9033235	KEEP AS NON CORE	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. 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-9033236	KEEP AS NON CORE	Summary: Duplicate cytosolic annotation from the PEX5 docking/translocation-module Reactome event; represents the same import-intermediate cytosolic step. Reason: Same rationale as the other cytosol annotation: transient step of peroxisomal import, not a core cytosolic function.
GO:0006629 lipid metabolic process	IDA PMID:8027038 3-Hydroxy-3-methylglutaryl-CoA lyase: expression and isolati...	MARK AS OVER ANNOTATED	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. Reason: Over-general; superseded by GO:0046951 (ketone body biosynthetic process) and GO:0006552 (L-leucine catabolic process).
GO:0006552 L-leucine catabolic process	TAS PMID:8027038 3-Hydroxy-3-methylglutaryl-CoA lyase: expression and isolati...	ACCEPT	Summary: Author-stated involvement of HMGCL in leucine catabolism (terminal HMG-CoA cleavage step shared with ketogenesis). Reason: Correct core BP, redundant with IBA/IEA/NAS annotations to the same term. Supporting Evidence: PMID:22847177 This reaction is the common final step in ketogenesis and leucine catabolism
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-74180	ACCEPT	Summary: Reactome reaction "HMG CoA => acetoacetic acid + acetyl CoA" places the HMGCL dimer in the mitochondrial matrix as the catalytic site. Reason: Correct core localization of the catalytically active enzyme. Supporting Evidence: PMID:8102917 matrix enzyme that catalyzes the last step of ketogenesis
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IDA PMID:22847177 Characterization of a novel HMG-CoA lyase enzyme with a dual...	ACCEPT	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. 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. Supporting Evidence: PMID:22847177 catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to acetoacetate and acetyl-CoA
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IDA PMID:22865860 Identification and characterization of an extramitochondrial...	ACCEPT	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. 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. Supporting Evidence: PMID:22865860 cleave HMG-CoA to
GO:0046951 ketone body biosynthetic process	IDA PMID:22847177 Characterization of a novel HMG-CoA lyase enzyme with a dual...	ACCEPT	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. 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. Supporting Evidence: PMID:22847177 The mitochondrial isoform contributes to ketone body production
GO:0046951 ketone body biosynthetic process	IDA PMID:22865860 Identification and characterization of an extramitochondrial...	ACCEPT	Summary: Ketone-body biosynthesis IDA associated with the HMGCLL1 characterization paper, which compares against mitochondrial HMGCL. Reason: Correct core BP for HMGCL, independently supported; retained. Flagged for the same HMGCLL1-focus reason. Supporting Evidence: PMID:22865860 HMGCLL1 is an extramitochondrial
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IDA PMID:8670134 Characterization of the hydroxymethylglutaryl-CoA lyase prec...	ACCEPT	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). Reason: Experimental support for the core molecular function of HMGCL. Supporting Evidence: PMID:8670134 is found in both mitochondria and peroxisomes
GO:0005739 mitochondrion	IDA PMID:9869651 3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and p...	ACCEPT	Summary: Direct demonstration of mitochondrial HMGCL by density-gradient fractionation and pulse-chase processing studies in human cells. Reason: Correct compartment; mitochondrial matrix retained as the more specific core term. Supporting Evidence: PMID:9869651 localization in both mitochondria and peroxisomes
GO:0005759 mitochondrial matrix	NAS PMID:8102917 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning an...	ACCEPT	Summary: Author statement that HMGCL is a homodimeric mitochondrial matrix enzyme catalyzing the last step of ketogenesis. Reason: Correct core localization; consistent with all other localization evidence. Supporting Evidence: PMID:8102917 matrix enzyme that catalyzes the last step of ketogenesis
GO:0006552 L-leucine catabolic process	NAS PMID:9200711 Evidence supporting a role for histidine-235 in cation bindi...	ACCEPT	Summary: Author-stated involvement of HMGCL in leucine catabolism, in a paper focused on cation binding (His235) of the human enzyme. Reason: Correct core BP, redundant with IBA/IEA/TAS annotations to the same term. Supporting Evidence: PMID:22847177 This reaction is the common final step in ketogenesis and leucine catabolism
GO:0000287 magnesium ion binding	IDA PMID:9200711 Evidence supporting a role for histidine-235 in cation bindi...	ACCEPT	Summary: Direct evidence that HMGCL binds a dissociable divalent cation (Mg2+ or Mn2+) required for activity, with His235 contributing to cation binding. Reason: Well-supported specific molecular function; the enzyme requires a divalent metal cofactor for catalysis (Mg2+ documented biochemically and structurally). Supporting Evidence: PMID:9200711 divalent cation (e.g. Mg2+ or Mn2+) that is required for activity
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IDA PMID:9200711 Evidence supporting a role for histidine-235 in cation bindi...	ACCEPT	Summary: Direct characterization of wild-type and H235 mutant human HMG-CoA lyase, measuring catalytic activity and Km for HMG-CoA. Reason: Experimental support for the core molecular function. Supporting Evidence: PMID:9200711 human 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase
GO:0004419 hydroxymethylglutaryl-CoA lyase activity	IDA PMID:9869651 3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and p...	ACCEPT	Summary: Direct study of HMGCL (HL, EC 4.1.3.4) demonstrating that mitochondrial HL catalyzes the last step of ketogenesis. Reason: Experimental support for the core molecular function. Supporting Evidence: PMID:9869651 approximately 31.0 kDa) catalyzes the last step of ketogenesis
GO:0005777 peroxisome	IDA PMID:9869651 3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and p...	KEEP AS NON CORE	Summary: Direct demonstration of peroxisomal HMGCL by density-gradient fractionation; peroxisomal HL is absent in Zellweger (peroxisome-deficient) cells. Reason: Peroxisomal localization is genuine but secondary; peroxisomal HL function is unresolved, so the mitochondrial matrix remains the core catalytic location. Supporting Evidence: PMID:9869651 localization in both mitochondria and peroxisomes
GO:0030145 manganese ion binding	IDA PMID:9200711 Evidence supporting a role for histidine-235 in cation bindi...	ACCEPT	Summary: Direct evidence that HMGCL uses a divalent cation activator that can be Mn2+ as well as Mg2+; Mn2+ interactions were probed by ESR. Reason: Documented divalent-cation cofactor requirement satisfied by Mn2+ (used experimentally to probe the metal site); a legitimate specific MF. Supporting Evidence: PMID:9200711 divalent cation (e.g. Mg2+ or Mn2+) that is required for activity
GO:0046951 ketone body biosynthetic process	IDA PMID:9200711 Evidence supporting a role for histidine-235 in cation bindi...	ACCEPT	Summary: Involvement in ketone-body biosynthesis via the HMG-CoA cleavage step, in the context of the human enzyme's cation-dependent catalysis. Reason: Correct core BP, redundant with IBA/IEA/IDA annotations to the same term. Supporting Evidence: PMID:22847177 The mitochondrial isoform contributes to ketone body production
GO:0046872 metal ion binding	IDA PMID:16330550 Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Ly...	MARK AS OVER ANNOTATED	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. Reason: Correct but generic; the specific divalent-cation binding is better captured by GO:0000287 (magnesium) and GO:0030145 (manganese). Retained as over-annotation. Supporting Evidence: PMID:16330550 activator cation ligands included Asn(275),

Gene Description

Existing Annotations Review

Core Functions

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.

Performs the terminal HMG-CoA cleavage step of L-leucine degradation, the same reaction shared with ketogenesis, in the mitochondrial matrix.

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.

References

📚 Additional Documentation

Notes

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