ALG12

Summary: The inherited alpha-1,6-mannosyltransferase activity can be resolved to the specific human ALG12 reaction.

Reason: PAINT places the linkage-specific activity at PTN000509189, and human ALG12 supports this ancestral assertion. Human patient-cell biochemistry and cDNA rescue additionally resolve the Dol-P-Man donor and Man7GlcNAc2-PP-Dol acceptor, supporting refinement to GO:0052917 for this target. This is a target-level specificity refinement, not a failure of the ancestral-node placement or a claim that every descendant has the exact same substrate.

Proposed replacements: dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity

Summary: ALG12 acts as an integral endoplasmic reticulum membrane enzyme.

Reason: The PTN000509188 ER-membrane ancestral assertion agrees with the human ALG12 location and lipid-linked substrate chemistry. Retain the membrane resolution asserted by PAINT; the separate lumenal-side annotation describes the active face.

Summary: ALG12 catalyzes a precursor-assembly step of protein N-linked glycosylation.

Reason: The PTN000509189 assertion is supported by the human ALG12 reaction and rescue of defective precursor assembly. ALG12 performs the mannose-transfer step rather than merely being a substrate of glycosylation. Target experimental evidence among the PAINT descendants is legitimate grounding of the ancestral inference.

Summary: The UniProt location mapping identifies the ER membrane.

Reason: UniProtKB-SubCell:SL-0097 maps the curated ER-membrane location. This is the membrane in which ALG12 processes its lipid-linked donor and acceptor; no mapping failure is apparent.

Summary: The true family-level glycosyltransferase assertion can be refined to the experimentally resolved ALG12 reaction.

Reason: InterPro:IPR005599 supports glycosyltransferase activity, while human ALG12 patient-cell biochemistry and rescue resolve transfer from Dol-P-Man to Man7GlcNAc2-PP-Dol. Refine the general molecular function to GO:0052917 for this target. The broad family mapping is biologically sound; the more specific replacement depends on target evidence and is not proposed as a universal mapping for the entire InterPro family.

Proposed replacements: dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity

Summary: The Rhea/EC mapping specifies the ALG12 mannose-transfer reaction.

Reason: RHEA:29535 and EC:2.4.1.260 identify transfer from dolichyl-phosphate-mannose to the Man7 lipid-linked precursor. Human mutant-cell biochemistry and wild-type rescue support this exact activity.

Summary: ALG12 catalyzes eighth-mannose addition in dolichol-linked oligosaccharide biosynthesis.

Reason: The Reactome parent pathway includes this precursor-assembly reaction. ALG12 directly makes the Man8 intermediate, and patient fibroblasts accumulate the preceding intermediate when its function is impaired.

Summary: Human ALG12 function is supported by patient-cell glycan profiling and yeast complementation.

Reason: PMID:12217961 reports Man7 intermediates in patient fibroblasts and rescue of the yeast alg12 defect by normal human ALG12 cDNA, whereas the tested human mutant alleles fail to rescue. These assays support the assigned specific catalytic identity; they are not a purified-human-enzyme kinetic measurement.

Summary: ALG12 performs its mannose-transfer reaction on the lumenal face of the ER membrane.

Reason: The original ER mannosyltransferase context and the lumenal Dol-P-Man-dependent precursor reaction support the curator inference. The GO-CAM activity in model 65c57c3400000687 independently records this same source-specific inference; it is additional curation of the same evidence, not an independent experiment.

Summary: ALG12-dependent precursor assembly supports protein N-linked glycosylation in human fibroblasts.

Reason: PMID:11983712 links the F142V defect to impaired eighth-mannose addition and shows normalization of the patient-cell precursor pattern after wild-type ALG12 transduction. The study also follows transfer of truncated glycans onto protein, connecting the enzyme step to N-glycosylation.

Summary: A second human patient study links ALG12 activity to N-glycan precursor quality.

Reason: PMID:12093361 reports partial loss of serum transferrin N-glycans and transfer of the accumulated Man7 precursor onto newly synthesized glycoproteins. Wild-type cDNA normalizes mannosyltransferase activity in patient fibroblasts; the rescue is cellular enzyme activity, not a demonstrated correction of circulating transferrin in the patient.

Summary: Human ALG12 deficiency disrupts lipid-linked oligosaccharide assembly.

Reason: The eighth-mannose defect and restoration of the precursor pattern after human wild-type ALG12 transduction directly place the enzyme in this biosynthetic process. The cached abstract reports the precursor defect and normalization by wild-type transduction; the externally read Figure 5 control comparison and its access route are documented in the source notes.

Summary: ALG12 activity is required for conversion of the Man7 lipid-linked intermediate.

Reason: PMID:12093361 reports severely reduced enzyme activity, accumulation of Man7GlcNAc2-PP-Dol and normalization of the enzyme activity by wild-type cDNA. This supports the biosynthetic reaction performed by ALG12, with patient fibroblasts as the assay system.

Summary: The human F142V patient-cell defect identifies the ALG12 mannosyltransferase reaction.

Reason: The specific eighth-mannose block, human ALG12 sequence identification and restoration of precursor biosynthesis by the wild-type gene support the Dol-P-Man-dependent alpha-1,6 reaction. Retain the mutant-phenotype evidence code and the exact reaction term.

Summary: Human mutant-cell enzyme assays support the specific ALG12 reaction.

Reason: The patient fibroblasts described in PMID:12093361 have severely reduced Dol-P-Man:Man7GlcNAc2-PP-Dol mannosyltransferase activity. Normalization after wild-type cDNA expression supports the direct catalytic assignment.

Summary: The Reactome reaction resolves the donor and acceptor more precisely than generic mannosyltransferase activity.

Reason: R-HSA-446198 explicitly describes eighth-mannose transfer using Dol-P-Man in the ER lumen. Refine this reaction-specific assertion to GO:0052917, which captures the resolved donor, acceptor and alpha-1,6 linkage, rather than changing the activity category.

Proposed replacements: dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity

Summary: The disease event identifies the normal ALG12 reaction whose activity is impaired.

Reason: R-HSA-4720497 describes defective ALG12 alleles in the context of the normal eighth-mannose transfer. Refine the generic catalytic term to the established wild-type reaction GO:0052917. This gene-level judgment does not assert that the listed disease variants retain normal activity, and the original disease-event reference is preserved.

Proposed replacements: dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity

Summary: The disease reaction places ALG12 in the ER membrane.

Reason: The reaction compartment agrees with the curated human ALG12 membrane location. The disease-event provenance describes impaired catalytic variants; it does not by itself demonstrate a separate location for every mutant.

Summary: The membrane-proteome annotation is compatible with the integral membrane enzyme.

Reason: ALG12 is a multipass ER membrane enzyme that transfers mannose between dolichol-linked substrates, so membrane residence is part of its core catalytic role. GO:0016020 includes proteins embedded in or attached to the lipid bilayer. The YTS proteomic source supports a broad membrane assignment; it does not independently resolve the ER or lumenal face. Retain the curator's target identification with explicit deference because independent human ALG12 chemistry and the curated ER-membrane location support the asserted compartment.

Summary: Biochemical profiling places ALG12 in lipid-linked oligosaccharide biosynthesis.

Reason: The primary study profiles lipid-linked glycans and shows the failure of eighth-mannose addition in human patient cells, with recovery of mature precursors after wild-type gene transduction. These data support the biosynthetic step executed by ALG12.

Summary: The normal ALG12 reaction is located in the ER membrane.

Reason: R-HSA-446198 places the donor-dependent reaction at the ER lumenal membrane face, consistent with the human UniProt ER-membrane entry. Retain the source compartment without changing it to a finer location.

Summary: The original study identifies ALG12 as an ER mannosyltransferase.

Reason: PMID:12217961 explicitly places the enzyme in the ER, and the lipid-linked reaction and curated membrane location support this core reaction compartment. The organelle and its lumenal membrane face are compatible resolutions of the same core location; this source need not resolve the finer membrane face to support the ER assertion.

Summary: The original source does not yet resolve ALG12 participation in protein folding.

Reason: The accessible original-paper preview establishes precursor glycosylation defects and complementation, but the complete Results and Discussion needed to adjudicate the NAS folding statement were not recovered. GO:0006457 concerns assistance in polypeptide assembly and is not restricted to classical chaperones; being a glycosyltransferase does not alone disprove participation. Retain uncertainty about the specific folding role while the precursor-assembly function remains established. The cached structural study places glycan processing by glucosidases and UGGT in the calnexin/calreticulin folding cycle, downstream of lipid-linked precursor synthesis. Its requirement for complete branches concerns efficient processing; human ALG12-deficient fibroblasts can still glucosylate truncated Man7 glycans (PMID:11983712). This distinguishes the established precursor reaction from an independently demonstrated ALG12 folding step without resolving the unread original NAS claim.