Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Combined Automated Annotation using Multiple IEA Methods
The metabolic serine hydrolases and their functions in mammalian physiology and disease.
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AADACL4 is grouped with AADAC and AADACL2 among the metabolic serine hydrolases that are too poorly characterised to predict a substrate, and is described as completely unannotated.
"AADAC is highly homologous to several related lipases, AADACL1, 2, and 4, the latter two of which remain completely unannotated."
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No candidate substrate, selective inhibitor or knockout mouse had been described for AADACL4 or its closest relatives.
"Candidate endogenous substrates, selective inhibitors, or knockout mice have not, to our knowledge, been described for AADAC or the related enzymes AADACL2 and AADACL4."
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The founding family member AADAC is a membrane-associated hydrolase acting on arylacetamide xenobiotics, which frames the substrate classes worth testing for AADACL4.
"AADAC is a 45 kDa membrane-associated hydrolase highly expressed in the human liver that has been implicated in the hydrolysis of arylacetamide xenobiotics including flutamide and phenacetin."
Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening.
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An active-site-directed fluorophosphonate probe labels the large majority of mammalian metabolic serine hydrolases, which makes activity-based profiling a realistic first assay for a dark family member with an intact triad.
"We show here that the vast majority (> 80%) of mammalian metabolic SHs can be labeled in proteomes by a single, active site-directed fluorophosphonate probe."
Single-cell transcriptomics defines keratinocyte differentiation in avian scutate scales.
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A chicken gene named AADACL4B is upregulated during keratinocyte differentiation and enriched in interscale rather than scale epidermis, a lead for an epidermal role in the subfamily that is not transferable to human AADACL4 on this evidence.
"Many of the genes upregulated during differentiation of back skin keratinocytes28, such as KRT9L4, LOR1, KRT9L3, BDH1L, EDQM2, SPTSSB, EDQM1, AADACL4B, LIPML2, and ELOVL4 (Table 2) were enriched in interscale versus scale epidermis."
The DNA sequence and biological annotation of human chromosome 1.
UniProtKB entry Q5VUY2 (ADCL4_HUMAN), Arylacetamide deacetylase-like 4
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UniProt assigns AADACL4 to the GDXG lipolytic enzyme family by curator inference.
"Belongs to the 'GDXG' lipolytic enzyme family."
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The membrane localisation is a curator inference over a predicted N-terminal signal anchor, with no experimental support.
"SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type II"
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The single transmembrane segment is annotated as a signal anchor for a type II membrane protein, placing the catalytic domain on the lumenal or extracellular face.
"Helical; Signal-anchor for type II membrane protein"
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UniProt records no protein-level detection for AADACL4; the entry is inferred from homology.
"PE 3: Inferred from homology;"
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AADACL4 is classified as a dark target with no chemical or functional probes.
"Pharos; Q5VUY2; Tdark."
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Transcript expression is described as choroid-enhanced, with broad low-level expression across many tissues.
"HPA; ENSG00000204518; Tissue enhanced (choroid)."
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The PAN-GO human reference-genome effort contributes no evolutionary-model annotations to this entry, in contrast to the two GO_Central IBA rows in GOA.
"PAN-GO; Q5VUY2; 0 GO annotations based on evolutionary models."
Is human AADACL4 a catalytically competent GDXG hydrolase?
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The three UniProt-annotated active-site positions of AADACL4 are genuinely serine, aspartate and histidine, so the catalytic triad is present rather than merely inherited as an annotation.
"Triad residues in sequence order: **SDH**"
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The nucleophilic serine lies in a canonical G-x-S-x-G elbow, as required for an active alpha/beta-hydrolase.
"Nucleophile elbow pentapeptide around Ser193: `GESVG`"
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The GDXG oxyanion-hole motif is present upstream of the nucleophile.
"Residues 119-121: `HGG` (the GDXG oxyanion-hole motif)"
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The donors of the membrane IBA row do not agree on a specific compartment, which is why the general membrane term is the correct level for AADACL4.
"Distinct specific locations across the donors: **4**"
PANTHER node PTN009058710: which GO term is true of every donor? (shared node-level audit for AADACL2, AADACL3 and AADACL4)
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No candidate term below GO:0016787 survives every donor of PTN009058710, so the generic term PAINT chose is the exact least common ancestor of the donor set rather than an under-specific approximation to it.
"No donor refutes `GO:0016787`, and every more specific candidate is refuted by at least one donor."
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The two more specific candidates fail on different axes: the two kynurenine formamidases put GO:0052689 out of reach, and soybean HIDH's threonine nucleophile puts GO:0017171 out of reach.
"GO:0052689 carboxylic ester hydrolase activity: TRUE 14, FALSE 2, UNDETERMINED 0"
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Soybean HIDH is bifunctional rather than a pure lyase, holding an IDA carboxylesterase annotation as well as its dehydratase activity, so it does not threaten the hydrolase parent at all.
"So HIDH is a genuine, if physiologically minor, carboxylic-ester hydrolase; it refutes the *serine* term only."
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The mechanism term is true of every donor PAINT cites at the family node PTN009058713 and held by IDA in all three of them, which is where it should be placed instead of at the deep node.
"all three carry `GO:0017171` by IDA"
Affinage mechanistic annotation for AADACL4 (human)
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The affinage record for AADACL4 is empty, reporting no mechanistic discoveries and no citations.
"No mechanistic discoveries found in literature."