GLDC

Summary: Retain the experimentally curated catalytic assignment.

Reason: PMID:1993704 identifies human GLDC and its conserved PLP-binding region. Its full experimental text was not obtained; the established catalytic role is independently supported, so there is no basis for reversing the curator.

Summary: Human GLDC inherits the ancestral catalytic function.

Reason: The actual PTHR11773 tree places human AN46 below the activity IBD at AN0/PTN000206531, with no activity-loss annotation on that path. Human experimental evidence and the conserved cofactor-site region support retention. The legitimate human self donor is not circular.

Summary: Retain direct human functional evidence for catalysis.

Reason: The verified abstract of PMID:28244183 describes human variant constructs expressed in COS7 cells with enzymatic assays. Full methods remain unavailable; the known catalytic role and existing IDA are concordant.

Summary: The mapped full catalytic reaction is appropriate.

Reason: EC 1.4.4.2/RHEA:24304 and the two incoming InterPro sources describe the glycine-to-lipoyl-H aminomethyl transfer reaction of GLDC. Preserve these literal sources; the assignment agrees with target biochemistry.

Summary: Human expression experiments establish glycine-cleavage activity.

Reason: PMID:1996985 reports activity after expression of normal human P-protein cDNA in COS7 cells and absent activity for the patient deletion construct. This supports the molecular function, without assigning a new disease-response process.

Summary: The human mitochondrial proteomics study includes GLDC.

Reason: The original Table S1 includes P23378/GLDC in MitoCoP pool 1, with class 1 subtractive, cluster 1 spatial and class 1 importomics classifications. This supports mitochondrial localization, not a particular matrix topology or isoform.

Summary: Retain the phylogenetically supported mitochondrial location.

Reason: The mitochondrial IBD is at eukaryotic AN28/PTN000206533 above human AN46, with the exact human/chicken descendant evidence. The on-path cytosol IRD is not a loss of mitochondrial function. Independent human localization evidence supports the inherited location.

Summary: HPA directly supports human mitochondrial localization.

Reason: The current HPA record classifies mitochondria as supported and shows antibody staining in human CACO-2, Hep-G2 and U2OS cells. Additional uncertain nucleoplasm staining is not promoted to a new annotation.

Summary: Retain the experimentally curated mitochondrial location.

Reason: Full localization methods for PMID:28244183 were not obtained. Its curated IDA agrees with independent human HPA and MitoCoP evidence, so retain the location without inventing assay details from its abstract.

Summary: Retain the supported mitochondrial compartment.

Reason: The UniProt subcellular-location mapping agrees with human localization data. The broader organelle term states the resolution of these observations; the separately supported matrix location need not replace each organelle-level assertion.

Summary: The reaction record explicitly locates its GLDC catalyst in the matrix.

Reason: Current Reactome R-HSA-5693967 identifies the human GLDC catalytic entity in the mitochondrial matrix. Retain this TAS compartment while treating the separate dimer assertion as unresolved; localization need not stand or fall with the assembly model.

Summary: GLDC is the catalytic P component of the glycine cleavage system.

Reason: The established P/H/T/L organization supports the existing complex membership. Membership does not require permanent association of every component or establish the oligomeric state of human P protein.

Summary: True but broad parent of the glycine cleavage process.

Reason: Correct but general: amino acid metabolic process is an ancestor of GO:0019464 glycine decarboxylation via glycine cleavage system, which this gene already carries (IBA, NAS) and whose P-protein step GLDC catalyzes. MODIFY to that descendant; this judges the term, not the evidence, so the IDA and TAS rows are treated the same way, as in every P-, H-, T- and L-protein review of the glycine cleavage system module.

Proposed replacements: glycine decarboxylation via glycine cleavage system

Summary: True but broad parent of the glycine cleavage process.

Reason: Correct but general: glycine metabolic process is an ancestor of GO:0019464 glycine decarboxylation via glycine cleavage system, which this gene already carries (IBA, NAS) and whose P-protein step GLDC catalyzes. MODIFY to that descendant; this judges the term, not the evidence, so the IDA and TAS rows are treated the same way, as in every P-, H-, T- and L-protein review of the glycine cleavage system module.

Proposed replacements: glycine decarboxylation via glycine cleavage system

Summary: True but broad parent of the glycine cleavage process.

Reason: Correct but general: glycine catabolic process is an ancestor of GO:0019464 glycine decarboxylation via glycine cleavage system, which this gene already carries (IBA, NAS) and whose P-protein step GLDC catalyzes. MODIFY to that descendant; this judges the term, not the evidence, so the IDA and TAS rows are treated the same way, as in every P-, H-, T- and L-protein review of the glycine cleavage system module.

Proposed replacements: glycine decarboxylation via glycine cleavage system

Summary: True but broad parent of the glycine cleavage process.

Reason: Correct but general: glycine catabolic process is an ancestor of GO:0019464 glycine decarboxylation via glycine cleavage system, which this gene already carries (IBA, NAS) and whose P-protein step GLDC catalyzes. MODIFY to that descendant; this judges the term, not the evidence, so the IDA and TAS rows are treated the same way, as in every P-, H-, T- and L-protein review of the glycine cleavage system module.

Proposed replacements: glycine decarboxylation via glycine cleavage system

Summary: True but broad parent of the glycine cleavage process.

Reason: Correct but general: glycine catabolic process is an ancestor of GO:0019464 glycine decarboxylation via glycine cleavage system, which this gene already carries (IBA, NAS) and whose P-protein step GLDC catalyzes. MODIFY to that descendant; this judges the term, not the evidence, so the IDA and TAS rows are treated the same way, as in every P-, H-, T- and L-protein review of the glycine cleavage system module.

Proposed replacements: glycine decarboxylation via glycine cleavage system

Summary: Electron transfer restates the redox chemistry of the specific catalytic activity.

Reason: GO:0009055 is defined as 'the directed movement of electrons from one molecular entity to another, typically mediated by electron carriers or acceptors'. GLDC is not an electron carrier: its oxidative decarboxylation of glycine reduces the lipoyl arm of GCSH as part of the single catalytic reaction already captured by GO:0004375 (EC 1.4.4.2). The cited PMID:2268343 abstract reports a genomic deletion in a nonketotic hyperglycinemia patient and makes no electron-transfer claim. The term is not false of the chemistry but is an over-annotation of a separate carrier function.

Summary: The broad domain mapping overstates a physiological lyase function.

Reason: The actual IPR001597 domain maps to GO:0016829, which excludes oxidative cleavage. GLDC performs the established oxidoreductase reaction. In PMID:24467211, H-free turnover consumes excess PLP as a cosubstrate and releases an intermediate; this assay does not establish an additional physiological lyase role.

Summary: Retain the inherited glycine-cleavage process.

Reason: Human AN46 descends from the actual AN0/PTN000206531 process IBD; the rat and yeast source positions and literal donor set were replayed. There is no process-loss annotation on the human path. GLDC catalyzes a step itself and is not merely required as a substrate.

Summary: GLDC directly performs the P-protein step of the glycine cleavage system.

Reason: Human biochemistry resolves decarboxylation and aminomethyl transfer to lipoylated H-protein. GLDC itself performs this step; no additional downstream or ancestor process is proposed.

Summary: In-vitro inhibition of the purified enzyme by methylamine is activity regulation, not a cellular response process.

Reason: GO:0036255 is defined as 'Any process that results in a change in state or activity of a cell or an organism ... as a result of a methylamine stimulus'. The ISS donor (chicken P protein, P15505) supports only inhibition of the purified enzyme by methylamine, a reaction product analog, which UniProt records as activity regulation. No cellular or organismal response mediated by GLDC has been shown, so transferring a response-to-chemical process from an enzyme-kinetic observation over-annotates the gene.

Summary: Homodimer assembly is supported by the chicken ortholog and human structures but is peripheral to catalysis.

Reason: UniProt records the P protein as a homodimer by similarity to the chicken enzyme (P15505), and Reactome models the human catalyst as a GLDC dimer. A recombinant human preparation was reported to be active as a monomer (PMID:24467211, abstract-only in the cache), so the oligomeric state may depend on preparation. Homodimerization is retained as a plausible structural property, not as the core function; the open question is recorded as a knowledge gap.

Summary: Specify binding of the phosphorylated vitamin-B6 cofactor.

Reason: The documented ligand is pyridoxal 5-phosphate (PLP), rather than pyridoxal. Chicken peptide chemistry, the human sequence study and the aligned cofactor-site lysine support GO:0030170. This is a ligand-identity correction, not an ancestry-based refinement or an additional binding core. The retained UniProt record already lists GO:0030170 with GO_Central IBA evidence; this replacement does not propose NEW coverage.

Proposed replacements: pyridoxal phosphate binding

Summary: Stimulation of the purified enzyme by free lipoate is activity regulation, not a cellular response process.

Reason: GO:1903442 is defined as 'Any process that results in a change in state or activity of a cell or an organism ... as a result of a lipoic acid stimulus'. The ISS donor (chicken P15505) shows stimulation of the purified enzyme by free lipoate in the absence of H protein, an in vitro kinetic effect recorded by UniProt as activity regulation. Physiologically the lipoyl group acts covalently bound to GCSH; no cellular response to lipoic acid performed by GLDC has been shown.