{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hexosaminidase D (HexD), encoded by the "}, {"type": "i", "children": [{"type": "t", "text": "HEXDC"}]}, {"type": "t", "text": " gene, is a recently characterized member of the mammalian β‐hexosaminidase family that is distinct from the classical lysosomal hexosaminidases. Studies have shown that HexD is a nucleocytoplasmic enzyme whose catalytic function involves the cleavage of terminal N‐acetylhexosamine residues from diverse substrates. Detailed kinetic and mechanistic investigations reveal that HexD operates as a retaining glycosidase through a substrate-assisted mechanism, with a marked preference for β-N-acetylgalactosaminide substrates over β-N-acetylglucosaminide, exhibiting an optimal pH near neutrality (approximately 6.5–7.0). Key catalytic residues, such as Asp148 and Glu149, have been identified as critical for its activity, and the enzyme is potently inhibited by specific inhibitors like Gal-NAG-thiazoline. Moreover, HexD is thermostable and, in human tissues, accounts for a substantial portion of total β-N-acetylgalactosaminidase activity—for instance, contributing to about 50% of the activity measured in synovial membranes and fibroblasts, where its expression is modulated by factors such as transforming growth factor β. Its localization within both the nucleus and cytoplasm, along with its presence in extracellular vesicles, suggests roles not only in routine glycan catabolism but also in regulatory cellular processes. In addition, altered methylation patterns in "}, {"type": "i", "children": [{"type": "t", "text": "HEXDC"}]}, {"type": "t", "text": " have been linked to disease states, implying a connection of HexD with immune system regulation and even neuropsychiatric conditions. Collectively, these findings establish HexD as the third major class 20 glycosidase in mammals, with unique substrate specificity and catalytic properties that point to considerable physiological and potentially pathophysiological significance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mária Pásztói, Barbara Sódar, Petra Misják, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The recently identified hexosaminidase D enzyme substantially contributes to the elevated hexosaminidase activity in rheumatoid arthritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunol Lett (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.imlet.2012.10.012"}], "href": "https://doi.org/10.1016/j.imlet.2012.10.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23099419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23099419"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Matthew G Alteen, Verena Oehler, Ivana Nemčovičová, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of Human Nucleocytoplasmic Hexosaminidase D."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.biochem.5b01285"}], "href": "https://doi.org/10.1021/acs.biochem.5b01285"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27149221"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27149221"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Martin Gutternigg, Dubravko Rendić, Regina Voglauer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mammalian cells contain a second nucleocytoplasmic hexosaminidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20081630"}], "href": "https://doi.org/10.1042/BJ20081630"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19040401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19040401"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jonathan Knights, Yasunori Sato, Nahoko Kaniwa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic factors associated with gemcitabine pharmacokinetics, disposition, and toxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenet Genomics (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/FPC.0000000000000016"}], "href": "https://doi.org/10.1097/FPC.0000000000000016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24225399"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24225399"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Clara Snijders, Adam X Maihofer, Andrew Ratanatharathorn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Epigenetics (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13148-019-0798-7"}], "href": "https://doi.org/10.1186/s13148-019-0798-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31931860"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31931860"}]}]}]}