ALG5

UniProt ID: Q9Y673
Organism: Homo sapiens
Review Status: IN PROGRESS
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Gene Description

ALG5 is an endoplasmic reticulum membrane glycosyltransferase that transfers glucose from UDP-glucose to dolichyl phosphate, producing dolichyl-phosphate glucose. This lipid-linked donor supplies the glucose residues added by ALG6, ALG8 and ALG10 during assembly of the N-linked glycan precursor. Human ALG5 complements yeast alg5 deficiency. Monoallelic pathogenic variants cause atypical polycystic kidney disease and interstitial fibrosis, associated with impaired N-glycosylation and maturation of polycystin-1.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004581 dolichyl-phosphate beta-glucosyltransferase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (PAN-GO) inference of the core catalytic molecular function. ALG5 is the dolichyl-phosphate beta-glucosyltransferase (Dol-P-Glc synthase, EC 2.4.1.117), the defining activity of this conserved GT2-family enzyme.
Reason: This is the well-established core molecular function of ALG5, supported by direct enzymatic/complementation characterization of the human protein and conserved across orthologs used in the IBA inference. It represents the core function of the gene.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
EC=2.4.1.117
GO:0005789 endoplasmic reticulum membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference that ALG5 acts in the ER membrane, consistent with its role in dolichol-linked oligosaccharide assembly on the ER membrane.
Reason: ALG5 is a single-pass ER membrane protein and its catalysis occurs at the ER membrane; this is the correct core cellular location.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0006488 dolichol-linked oligosaccharide biosynthetic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference that ALG5 participates in dolichol-linked oligosaccharide (LLO) biosynthesis. ALG5 supplies Dol-P-Glc, the glucose donor used by ALG6/ALG8/ALG10 for the terminal glucosylation steps of the LLO.
Reason: This is the core biological process in which ALG5 acts and is well supported by the pathway context; represents a core function of the gene.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
donor substrate used sequentially by ALG6, ALG8 and ALG10 to add
GO:0004581 dolichyl-phosphate beta-glucosyltransferase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated (RHEA/EC-based) assignment of the dolichyl-phosphate beta-glucosyltransferase activity from EC 2.4.1.117 / RHEA:15401. This matches the experimentally characterized catalytic activity of human ALG5.
Reason: The EC/RHEA-to-GO mapping is correct and specific; it captures the core catalytic activity. Duplicates the IBA/TAS MF annotations, which is acceptable.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
EC=2.4.1.117
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Automated assignment of ER membrane localization from the UniProt subcellular-location keyword mapping (SL-0097).
Reason: Consistent with the experimentally supported ER membrane localization of ALG5; correct and appropriately specific.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding
IPI
PMID:32353859
A SARS-CoV-2 protein interaction map reveals targets for dru... 		KEEP AS NON CORE
Summary: IntAct IPI recording a physical interaction between ALG5 and the SARS-CoV-2 accessory protein ORF3a (P0DTC3), detected in a proteome-wide virus-host interactome screen. This is a non-informative protein binding term that does not describe ALG5's endogenous molecular function.
Reason: The curated physical interaction is retained as a context-dependent association. Bare protein binding does not describe the endogenous dolichyl-phosphate glucosyltransferase function or establish that the partner is a catalytic substrate.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
Q9Y673; P0DTC3: 3a; Xeno; NbExp=4
GO:0005515 protein binding
IPI
PMID:32838362
Virus-Host Interactome and Proteomic Survey Reveal Potential... 		KEEP AS NON CORE
Summary: IntAct IPI recording the ALG5-SARS-CoV-2 ORF3a (P0DTC3) interaction from a virus-host interactome/proteomic survey. Non-informative protein binding.
Reason: The curated physical interaction is retained as a context-dependent association. Bare protein binding does not describe the endogenous dolichyl-phosphate glucosyltransferase function or establish that the partner is a catalytic substrate.
Supporting Evidence:
PMID:32838362
ORF3a
GO:0005515 protein binding
IPI
PMID:33060197
Comparative host-coronavirus protein interaction networks re... 		KEEP AS NON CORE
Summary: IntAct IPI recording the ALG5-SARS-CoV-2 ORF3a (P0DTC3) interaction from a comparative host-coronavirus interactome study. Non-informative protein binding.
Reason: The curated physical interaction is retained as a context-dependent association. Bare protein binding does not describe the endogenous dolichyl-phosphate glucosyltransferase function or establish that the partner is a catalytic substrate.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
Q9Y673; P0DTC3: 3a; Xeno; NbExp=4
GO:0005515 protein binding
IPI
PMID:36217030
A comprehensive SARS-CoV-2-human protein-protein interactome... 		KEEP AS NON CORE
Summary: IntAct IPI recording the ALG5-SARS-CoV-2 ORF3a (P0DTC3) interaction from a comprehensive SARS-CoV-2-human interactome. Non-informative protein binding.
Reason: The curated physical interaction is retained as a context-dependent association. Bare protein binding does not describe the endogenous dolichyl-phosphate glucosyltransferase function or establish that the partner is a catalytic substrate.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
Q9Y673; P0DTC3: 3a; Xeno; NbExp=4
GO:0006487 protein N-linked glycosylation
TAS
Reactome:R-HSA-480985 		ACCEPT
Summary: Reactome-asserted involvement in protein N-linked glycosylation. ALG5 makes Dol-P-Glc, the glucose donor for the terminal LLO glucosylation steps that produce the fully assembled glycan precursor transferred to nascent proteins.
Reason: Correct and central to ALG5 biology; the LLO it helps complete is the donor substrate for N-glycosylation. Core biological process.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
glycan precursors employed in protein asparagine (N)-glycosylation.
GO:0004581 dolichyl-phosphate beta-glucosyltransferase activity
TAS
Reactome:R-HSA-446214 		ACCEPT
Summary: Reactome-asserted dolichyl-phosphate beta-glucosyltransferase activity. Reactome describes ALG5 catalyzing UDP-glucose + dolichyl phosphate to form Dol-P-Glc on the cytosolic face of the ER membrane.
Reason: Correctly captures the core catalytic function with an authoritative pathway-database traceable assertion.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
EC=2.4.1.117
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:10359825
A mutation in the human ortholog of the Saccharomyces cerevi... 		ACCEPT
Summary: Experimental localization of human ALG5 to the ER membrane (Imbach et al. 1999), the study that cloned and functionally characterized the human ALG5 ortholog.
Reason: Experimental support for the correct core localization; consistent with the protein's single-pass ER membrane topology.
Supporting Evidence:
PMID:10359825
have cloned and analyzed the human orthologs to the ALG5 dolichyl phosphate
GO:0098554 cytoplasmic side of endoplasmic reticulum membrane
IGI
PMID:10359825
A mutation in the human ortholog of the Saccharomyces cerevi... 		ACCEPT
Summary: ALG5 is active on the cytoplasmic (cytosolic) face of the ER membrane, where it synthesizes Dol-P-Glc from cytosolic UDP-glucose; supported by yeast genetic interaction / complementation data and the protein's topology (large cytoplasmic catalytic domain).
Reason: Correctly specifies the membrane face on which the catalytic domain acts, consistent with UniProt topology and Reactome. More informative than bare ER membrane.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
most probably active on the cytoplasmic side of the endoplasmic
GO:0006487 protein N-linked glycosylation
IMP
PMID:10359825
A mutation in the human ortholog of the Saccharomyces cerevi... 		ACCEPT
Summary: ALG5's role in N-linked glycosylation demonstrated via functional characterization/complementation of the human ortholog (Imbach et al. 1999).
Reason: Experimental (mutant-phenotype/complementation) support for a core biological process of ALG5. Full text not in cache; deferring to curator per policy.
Supporting Evidence:
PMID:10359825
Expression of the human ALG5 and ALG6 cDNA could partially
GO:0004581 dolichyl-phosphate beta-glucosyltransferase activity
IGI
PMID:10359825
A mutation in the human ortholog of the Saccharomyces cerevi... 		ACCEPT
Summary: Dolichyl-phosphate beta-glucosyltransferase activity of human ALG5 inferred from genetic interaction / complementation of the S. cerevisiae alg5 deficiency by the human ALG5 cDNA (Imbach et al. 1999).
Reason: Experimental support (functional complementation) for the core catalytic function. Core molecular function of the gene.
Supporting Evidence:
PMID:10359825
Expression of the human ALG5 and ALG6 cDNA could partially
GO:0006488 dolichol-linked oligosaccharide biosynthetic process
IMP
PMID:10359825
A mutation in the human ortholog of the Saccharomyces cerevi... 		ACCEPT
Summary: ALG5's role in dolichol-linked oligosaccharide (LLO) biosynthesis supported by functional characterization of the human ortholog; ALG5 provides the Dol-P-Glc glucose donor for the terminal LLO glucosylation steps.
Reason: Experimental support for the core biological process of ALG5. Core function of the gene.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
donor substrate used sequentially by ALG6, ALG8 and ALG10 to add
GO:0098556 cytoplasmic side of rough endoplasmic reticulum membrane
IGI
PMID:10359825
A mutation in the human ortholog of the Saccharomyces cerevi... 		ACCEPT
Summary: A more granular restatement of the cytoplasmic-face ER-membrane location of active ALG5 (rough ER membrane, cytoplasmic side).
Reason: Consistent with the protein's topology and site of catalysis; slightly more specific granularity of GO:0098554. Retained.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
most probably active on the cytoplasmic side of the endoplasmic
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: High-throughput MS detection of ALG5 in a membrane-proteome preparation (NK-like cell line). Localizes the protein to bulk membrane without specifying the ER.
Reason: The generic membrane term is far less informative than the well-supported endoplasmic reticulum membrane term; this HDA localization is redundant with, and subsumed by, the specific ER membrane annotations. Flagged as over-annotation rather than removed (it is not incorrect, merely uninformative).
Supporting Evidence:
PMID:19946888
identified 1843 proteins with high confidence scores
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-446214 		ACCEPT
Summary: Reactome-asserted ER membrane localization of ALG5, consistent with the experimental and phylogenetic ER-membrane annotations.
Reason: Correct core localization from an authoritative pathway database; duplicates other ER membrane annotations, which is acceptable.
Supporting Evidence:
file:human/ALG5/ALG5-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane

Core Functions

Dolichyl-phosphate beta-glucosyltransferase (Dol-P-Glc synthase) that transfers glucose from UDP-alpha-D-glucose onto dolichyl phosphate to form dolichyl beta-D-glucosyl phosphate (Dol-P-Glc) on the cytosolic face of the ER membrane.

Molecular Function:
dolichyl-phosphate beta-glucosyltransferase activity
Directly Involved In:
dolichol-linked oligosaccharide biosynthetic process
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • file:human/ALG5/ALG5-uniprot.txt
    donor substrate used sequentially by ALG6, ALG8 and ALG10 to add

Supplies Dol-P-Glc, the lipid-linked glucose donor used by ALG6, ALG8 and ALG10 for the three terminal glucosylation steps of the dolichol-linked oligosaccharide, thereby contributing to protein N-linked glycosylation.

Molecular Function:
dolichyl-phosphate beta-glucosyltransferase activity
Directly Involved In:
protein N-linked glycosylation
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • file:human/ALG5/ALG5-uniprot.txt
    glycan precursors employed in protein asparagine (N)-glycosylation.

References

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Suggested Questions for Experts

Q: Is the reduced N-glycosylation phenotype in ALG5-CDG and PKD7 driven predominantly by loss of the terminal glucosylation steps (ALG6/ALG8/ALG10) that depend on Dol-P-Glc, or does Dol-P-Glc have additional roles?

Suggested Experiments

Experiment: Reconstitute purified recombinant human ALG5 with dolichyl phosphate and UDP-glucose to measure Dol-P-Glc synthase kinetics, and test the PKD7 missense variants (R208H, R212H) for loss of catalytic activity.

Hypothesis: PKD7-associated ALG5 missense variants reduce or abolish Dol-P-Glc synthase activity, explaining the downstream N-glycosylation defect.

Deep Research

Falcon

(ALG5-deep-research-falcon.md)

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📚 Additional Documentation

Notes

(ALG5-notes.md)

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