{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ENPP5 is a member of the ecto‐nucleotide pyrophosphatase/phosphodiesterase (ENPP) family whose biological function has begun to emerge through recent structural, biochemical, and neural characterization studies. Structural analyses of human and murine ENPP5 have revealed that a unique amino acid substitution—replacement of a key phenylalanine with a tyrosine—restricts its ability to efficiently degrade nucleotide di‐ and triphosphates. However, reversion of this substitution confers the ability to hydrolyze these molecules, and notably, ENPP5 can cleave nicotinamide adenine dinucleotide (NAD). This activity suggests that ENPP5 may participate in NAD‐based neurotransmission, thereby linking its enzymatic function with neuromodulatory signaling in the brain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to these insights from structural and substrate specificity studies, immunological analyses have further supported a neural role for ENPP5. Antibody generation strategies directed against native ectonucleotidases have included ENPP5 and demonstrated its expression as a neural oligomannosidic glycoprotein. In rat brain membranes, ENPP5 has been identified as a 50‐kDa protein that, although not displaying classical nucleotide phosphodiesterase or lysophospholipase D activities in immunoprecipitates, is suggested to mediate aspects of neural cell communication."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Complementary studies have reported alterations in the N-glycosylation of brain ENPP5 in models of neurological dysfunction, implying that post-translational modification of ENPP5 might modulate its neural function and potentially contribute to disease processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n More broadly, review analyses of the ENPP family have grouped ENPP5 with other nucleotide-hydrolyzing members (such as ENPP1, ENPP3, and ENPP4), emphasizing that while many family members share common catalytic domains, subtle structural differences determine substrate preference and biological specificity. In this context, ENPP5 appears to be uniquely adapted for roles in neuronal signaling rather than the metabolism of classical nucleotides."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alexei Gorelik, Antsa Randriamihaja, Katalin Illes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A key tyrosine substitution restricts nucleotide hydrolysis by the ectoenzyme NPP5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/febs.14266"}], "href": "https://doi.org/10.1111/febs.14266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28898552"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28898552"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yoshihide Ohe, Hiroshi Ohnishi, Hideki Okazawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of nucleotide pyrophosphatase-5 as an oligomannosidic glycoprotein in rat brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(03)01454-2"}], "href": "https://doi.org/10.1016/s0006-291x(03"}, {"type": "t", "text": "01454-2) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12927778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12927778"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alessio Cortelazzo, Claudio De Felice, Roberto Guerranti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Abnormal N-glycosylation pattern for brain nucleotide pyrophosphatase-5 (NPP-5) in Mecp2-mutant murine models of Rett syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neures.2015.10.002"}], "href": "https://doi.org/10.1016/j.neures.2015.10.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26476268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26476268"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Razvan Borza, Fernando Salgado-Polo, Wouter H Moolenaar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2021.101526"}], "href": "https://doi.org/10.1016/j.jbc.2021.101526"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34958798"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34958798"}]}]}]}