GLDC is the P protein (glycine decarboxylase) of the mitochondrial glycine cleavage system (GCS), a pyridoxal-5'-phosphate (PLP)-dependent homodimeric enzyme (EC 1.4.4.2) encoded on human chromosome 9. It catalyses the first, committed step of glycine catabolism: it binds the alpha-amino group of glycine through its PLP cofactor (covalently attached as a Schiff base to Lys754), decarboxylates the glycine to release CO2, and transfers the residual aminomethyl moiety to the lipoic-acid (lipoamide) arm of the H protein (GCSH) rather than releasing free methylamine. Together with the T protein (AMT), the L protein (DLD) and the H protein (GCSH), GLDC forms the glycine cleavage system, the major route of glycine degradation, which links glycine to one-carbon/folate metabolism and serine biosynthesis. The mature protein localises to the mitochondrial matrix after cleavage of an N-terminal transit peptide. Loss-of-function variants in GLDC are the most common cause (~80% of cases) of nonketotic hyperglycinemia (glycine encephalopathy), an autosomal recessive disorder characterised by accumulation of glycine in body fluids, neonatal seizures and severe encephalopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004375 glycine dehydrogenase (decarboxylating) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. The phylogenetic (IBA) annotation to glycine dehydrogenase (decarboxylating) activity is the correct, informative MF for the GCS P protein and is corroborated by experimental and TAS evidence in this same gene. Reason: GLDC is the P protein of the glycine cleavage system and catalyses the PLP-dependent decarboxylation of glycine (EC 1.4.4.2). This IBA is concordant with the EXP, IDA and TAS annotations to the same term. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt The P protein (GLDC) binds the alpha-amino group of glycine |
| GO:0019464 glycine decarboxylation via glycine cleavage system | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. This is the most specific process term for GLDC: glycine decarboxylation carried out as the P-protein step of the glycine cleavage system. Reason: Matches the experimentally established role of GLDC as the P protein of the GCS and is the preferred, most-informative process term for this gene. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt remaining methylamine moiety is then transferred to the lipoamide |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Correct subcellular localisation. GLDC acts in the mitochondrion (matrix). This IBA is consistent with IDA, HTP and TAS localisation evidence. Reason: GLDC carries an N-terminal mitochondrial transit peptide and the GCS operates in the mitochondrial matrix; mitochondrion is the correct compartment, though the matrix (GO:0005759) is more precise. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0004375 glycine dehydrogenase (decarboxylating) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the core catalytic MF via EC 1.4.4.2 / RHEA:24304 and InterPro. Correct and concordant with experimental evidence. Reason: The EC/RHEA and InterPro mappings correctly capture the glycine dehydrogenase (decarboxylating) activity of the P protein. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt EC=1.4.4.2 |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic localisation from the UniProt Subcellular Location vocabulary (SL-0173, Mitochondrion). Correct. Reason: Consistent with the curated UniProt subcellular location and with IDA/HTP/TAS evidence. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0006520 amino acid metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Very general parent process. GLDC does participate in amino acid metabolism, but this is far broader than its actual role in glycine cleavage. Reason: Correct as a broad InterPro-based grouping term; the informative process is the more specific GO:0019464 (glycine decarboxylation via glycine cleavage system). Broad IEA parents may be retained. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt The glycine cleavage system catalyzes the degradation of |
| GO:0006544 glycine metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Broad but correct grouping term. GLDC is central to glycine metabolism; GO:0019464 is the more specific catabolic term. Reason: Accurate InterPro-based parent term consistent with the enzyme acting on glycine. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt The glycine cleavage system catalyzes the degradation of |
| GO:0006546 glycine catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Correct process: GLDC catalyses the first step of glycine degradation. This is the direct parent of the more specific GO:0019464. Reason: Glycine catabolic process accurately describes the pathway GLDC initiates; concordant with IDA and TAS annotations to the same term. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt The glycine cleavage system catalyzes the degradation of |
| GO:0016829 lyase activity | IEA GO_REF:0000002 | REMOVE | Summary: Wrong-branch electronic mapping. GLDC is classified EC 1.4.4.2, an oxidoreductase acting on the CH-NH2 group of donors (glycine dehydrogenase (decarboxylating)); it is not a lyase. The lyase term derives from the broad PLP-fold InterPro signature IPR001597 (aromatic-amino-acid beta-eliminating lyase / threonine aldolase), which over-generalises to a lyase MF that does not apply to this enzyme. Reason: This is a demonstrably incorrect electronic (IEA/InterPro) MF inference: the enzyme's molecular function is glycine dehydrogenase (decarboxylating) activity (GO:0004375, an oxidoreductase, EC 1.4.4.2), captured accurately by other annotations. Lyase activity is the wrong ontology branch for this protein and is safe to remove per the IEA-mis-mapping criterion. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt EC=1.4.4.2 |
| GO:0005960 glycine cleavage complex | NAS PMID:28244183 Nonketotic hyperglycinemia: Functional assessment of missens... | ACCEPT | Summary: Correct complex membership. GLDC is the P protein subunit of the four-protein glycine cleavage system (P/GLDC, T/AMT, L/DLD, H/GCSH). Reason: Well-established: GLDC is a bona fide subunit of the glycine cleavage complex. Curated by ComplexPortal. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt P (GLDC), T (GCST), L (DLD) and H (GCSH) |
| GO:0019464 glycine decarboxylation via glycine cleavage system | NAS PMID:24467211 Glycine decarboxylase is an unusual amino acid decarboxylase... | ACCEPT | Summary: Core process, independently supported by the mechanistic study of Go et al. (2014), which shows GLDC decarboxylates glycine and hands the aminomethyl group to the H protein within the GCS. Reason: The cited mechanistic paper directly characterises GLDC-catalysed glycine decarboxylation as the P-protein step of the glycine cleavage system. Supporting Evidence: PMID:24467211 aminomethyl moiety is instead transferred to an accessory H-protein |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) localisation to mitochondrion. Consistent with all other localisation evidence. Reason: Direct immunofluorescence evidence supports mitochondrial localisation, concordant with the transit peptide and matrix localisation. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0004375 glycine dehydrogenase (decarboxylating) activity | EXP PMID:1993704 The glycine cleavage system. Molecular cloning of the chicke... | ACCEPT | Summary: Experimental support for the core catalytic function. Kume et al. cloned the human glycine decarboxylase cDNA and characterised the PLP-binding active-site region essential for enzyme activity. Reason: Direct experimental characterisation of human glycine decarboxylase, including the PLP-binding lysine and glycine-rich phosphate-binding region that organise the active site. Supporting Evidence: PMID:1993704 The pyridoxal phosphate binding site lysine and a glycine-rich region |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteomics localises GLDC to mitochondria, concordant with all other localisation evidence. Reason: GLDC was identified in a high-confidence quantitative human mitochondrial proteome; this HTP evidence agrees with the transit peptide, IDA immunofluorescence and matrix TAS annotations. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693967 | ACCEPT | Summary: Most precise localisation: the glycine decarboxylation reaction occurs in the mitochondrial matrix. Retained as the informative compartment. Reason: The GCS operates in the mitochondrial matrix; Reactome places the GLDC-catalysed decarboxylation there. This is the preferred, more specific cellular-component term. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0036255 response to methylamine | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Peripheral regulatory response inferred by similarity from rat (P15505). Reflects that GCS P-protein activity is inhibited in the presence of methylamine, not a distinct biological role of GLDC. Reason: Derived from an activity-regulation observation (methylamine inhibits the enzyme). It is a plausible ISS-transferred response but does not represent a core function of GLDC; retained as non-core. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt Inhibited in presence |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported: the functional P protein is a homodimer. Retained as a supporting (non-core) molecular function underpinning the catalytic unit. Reason: UniProt records GLDC as a homodimer (by similarity to rat P15505), and the PLP-dependent active site is formed in the dimer. Real but ancillary to the catalytic MF. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt Homodimer (By similarity) |
| GO:0070280 pyridoxal binding | ISS GO_REF:0000024 | MODIFY | Summary: The cofactor is pyridoxal 5'-phosphate (PLP), covalently bound as a Schiff base at Lys754, not free pyridoxal. The more accurate MF is pyridoxal phosphate binding (GO:0030170), which UniProt itself also carries. Reason: GLDC binds pyridoxal 5'-phosphate (the phosphorylated, active cofactor), attached as N6-(pyridoxal phosphate)lysine at Lys754; the specific, accurate term is GO:0030170 pyridoxal phosphate binding rather than the more general pyridoxal binding. Proposed replacements: pyridoxal phosphate binding Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt Name=pyridoxal 5'-phosphate file:human/GLDC/GLDC-uniprot.txt N6-(pyridoxal phosphate)lysine |
| GO:1903442 response to lipoic acid | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Peripheral regulatory response inferred by similarity from rat (P15505), reflecting that P-protein activity is stimulated by lipoic acid (the lipoamide arm of the H protein is the physiological acceptor). Reason: Derived from an activity-regulation observation (lipoic acid stimulates the enzyme). Consistent with the mechanism but not a core function; retained as non-core. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt Stimulated by lipoic acid |
| GO:0004375 glycine dehydrogenase (decarboxylating) activity | IDA PMID:28244183 Nonketotic hyperglycinemia: Functional assessment of missens... | ACCEPT | Summary: Direct experimental support for the core catalytic MF: enzymatic assays of GCS P-protein activity for wild-type and NKH missense variants expressed in COS7 cells. Reason: Bravo-Alonso et al. measured residual GCS P-protein (glycine decarboxylase) activity for GLDC constructs, directly assaying this molecular function. Supporting Evidence: PMID:28244183 assess the residual activity and mutant protein stability |
| GO:0005739 mitochondrion | IDA PMID:28244183 Nonketotic hyperglycinemia: Functional assessment of missens... | ACCEPT | Summary: Direct evidence of mitochondrial localisation; the same study also reported NKH variants with altered (partially cytosolic) localisation, confirming the wild-type mitochondrial targeting. Reason: Localisation of GLDC to mitochondria was directly assessed; consistent with the transit peptide and all other localisation evidence. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0006546 glycine catabolic process | IDA PMID:28244183 Nonketotic hyperglycinemia: Functional assessment of missens... | ACCEPT | Summary: Direct evidence linking GLDC to glycine catabolism: NKH variants cause loss or reduction of glycine catabolic process, as characterised functionally in this study. Reason: The functional assessment demonstrates that pathogenic GLDC variants impair the glycine catabolic process, confirming GLDC's role in it. The more specific term is GO:0019464. Supporting Evidence: PMID:28244183 assess the residual activity and mutant protein stability |
| GO:0009055 electron transfer activity | TAS PMID:2268343 One of the two genomic copies of the glycine decarboxylase c... | MARK AS OVER ANNOTATED | Summary: Likely over-annotation / mis-assignment. GLDC is a PLP-dependent glycine decarboxylase (EC 1.4.4.2); it does not act as an electron carrier. Within the glycine cleavage system, the redox/electron-transfer role belongs to the L protein (DLD, dihydrolipoamide dehydrogenase, FAD-dependent), not to the P protein. The cited reference (Sakakibara et al. 1990) is about a genomic deletion of the glycine decarboxylase gene in an NKH patient and provides no support for an electron transfer activity. Reason: The molecular function of GLDC is glycine dehydrogenase (decarboxylating) activity, captured by multiple experimental and electronic annotations; electron transfer activity is not a function of the P protein and is not supported by the cited paper. Flagged as over-annotated rather than removed because it is an author-statement (TAS) annotation whose full text was not reviewed. Supporting Evidence: file:human/GLDC/GLDC-uniprot.txt The P protein (GLDC) binds the alpha-amino group of glycine |
| GO:0004375 glycine dehydrogenase (decarboxylating) activity | TAS PMID:1996985 Structural and expression analyses of normal and mutant mRNA... | ACCEPT | Summary: Author-stated support for the core catalytic function: expression of normal human P-protein cDNA in COS7 cells reconstituted glycine decarboxylase activity comparable to human liver, whereas the NKH mutant (Phe756del) had none. Reason: Kure et al. demonstrated glycine decarboxylase activity for the wild-type human enzyme and its abolition by an NKH-causing deletion, supporting the catalytic MF. Supporting Evidence: PMID:1996985 showed no activity, indicating that the three-base deletion could cause NKH |
| GO:0006546 glycine catabolic process | TAS PMID:1996985 Structural and expression analyses of normal and mutant mRNA... | ACCEPT | Summary: Author-stated support that GLDC drives glycine catabolism: loss of P-protein activity from an NKH deletion causes the glycine-accumulation phenotype, linking the enzyme to the glycine catabolic process. Reason: Consistent with GLDC's role in glycine degradation; the loss-of-activity mutant establishes the connection to glycine catabolism. GO:0019464 is the more specific term. Supporting Evidence: PMID:1996985 showed no activity, indicating that the three-base deletion could cause NKH |
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