Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
A key tyrosine substitution restricts nucleotide hydrolysis by the ectoenzyme NPP5.
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Wild-type ENPP5 is inactive on canonical NPP substrates such as p-nitrophenyl-TMP and lacks activity on common nucleotides (ATP, ADP, UTP). A Phe-to-Tyr substitution (Tyr73) in the nucleotide-binding slot restricts hydrolysis; reversal (Y73F) restores activity on NDPs/NTPs.
"Structural comparison with close homologs revealed a key phenylalanine to tyrosine substitution that prevents efficient hydrolysis of nucleotide diphosphates and triphosphates; reversal of this mutation enabled degradation of these molecules."
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NPP5 cleaves NAD, hinting at a role in NAD-based neurotransmission. ENPP5 also contains an enzyme-specific metal binding motif adjacent to the active site (third Zn site).
"Interestingly, NPP5 is able to cleave nicotinamide adenine dinucleotide (NAD), suggesting a potential role of this enzyme in NAD-based neurotransmission."
Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity.
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ENPP5 is a single-pass type I transmembrane ectoenzyme (N-terminal signal peptide, C-terminal TM helix); contrast with type II ENPP1/ENPP3.
"ENPP4, ENPP5, and ENPP7 are single-pass type I membrane proteins, while ENPP6 is GPI-anchored to the plasma membrane (11)."
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Hypothesized role in NAD-based neurotransmission awaits in vivo genetic validation.
"This suggests a role for ENPP5 in NAD-based neurotransmission, but this hypothesis awaits validation using Enpp5 KO mice."
Deep research on ENPP5 function
Deep research on ENPP5 function (falcon / Edison Scientific Literature)
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ENPP5 is best annotated as a cell-surface Zn-dependent ecto-phosphodiesterase/pyrophosphatase with narrow substrate specificity; wild-type activity favors NAD+, ADP-ribose, UDP-glucose; minimal activity on ATP/ADP/UTP. Tyr73 serves as a gatekeeper residue.
"ENPP5 is best annotated as a cell-surface, Zn-dependent ecto-phosphodiesterase/pyrophosphatase with narrow substrate selectivity, showing strongest activity toward NAD (and detectable activity toward ADPR and UDPG) under in vitro conditions."
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Catalytic efficiency for NAD+ is very low (KM > 1 mM), so any physiological role likely operates in microenvironments with locally elevated NAD (e.g., synaptic clefts).
"ENPP5's highest catalytic rate was observed on NAD+/NADH, but the catalytic efficiency for NAD+ is very low (0.00067 s-1 uM-1)."