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dc.contributor.authorFleming, John V.
dc.contributor.authorFajardo, Ignacio
dc.contributor.authorLanglois, Michael R.
dc.contributor.authorSanchez-Jimenez, Francisca
dc.contributor.authorWang, Timothy C.
dc.date2022-08-11T08:09:43.000
dc.date.accessioned2022-08-23T16:41:03Z
dc.date.available2022-08-23T16:41:03Z
dc.date.issued2004-04-20
dc.date.submitted2008-03-26
dc.identifier.citationBiochem J. 2004 Aug 1;381(Pt 3):769-78. <a href="http://dx.doi.org/10.1042/BJ20031553">Link to article on publisher's site</a>
dc.identifier.issn1470-8728 (Electronic)
dc.identifier.doi10.1042/BJ20031553
dc.identifier.pmid15089748
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39804
dc.description.abstractFull-length rat HDC (L-histidine decarboxylase) translated in reticulocyte cell lysate reactions is inactive, whereas C-terminally truncated isoforms are capable of histamine biosynthesis. C-terminal processing of the approximately 74 kDa full-length protein occurs naturally in vivo, with the production of multiple truncated isoforms. The minimal C-terminal truncation required for the acquisition of catalytic competence has yet to be defined, however, and it remains unclear as to why truncation is needed. Here we show that approximately 74 kDa HDC monomers can form dimers, which is the conformation in which the enzyme is thought to be catalytically active. Nevertheless, the resulting dimer is unable to establish pyridoxal phosphate-dependent interactions with an L-histidine substrate analogue. Protein sequences localized to between amino acids 617 and 633 specifically mediate this inhibition. Removing this region or replacing the entire C-terminus with non-HDC protein sequences permitted interactions with the substrate analogue to be re-established. This corresponded exactly with the acquisition of catalytic competence, and the ability to decarboxylate natural L-histidine substrate. These studies suggested that the approximately 74 kDa full-length isoform is deficient in substrate binding, and demonstrated that C-terminally truncated isoforms with molecular masses between approximately 70 kDa and approximately 58 kDa have gradually increasing specific activities. The physiological relevance of our results is discussed in the context of differential expression of HDC isoforms in vivo.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15089748&dopt=Abstract ">Link to article in PubMed</a>
dc.subjectAlternative Splicing
dc.subjectAnimals
dc.subjectCOS Cells
dc.subjectCatalysis
dc.subjectCell Line
dc.subjectCercopithecus aethiops
dc.subjectDimerization
dc.subjectElectrophoretic Mobility Shift Assay
dc.subjectEnzyme Activation
dc.subjectHistidine
dc.subjectHistidine Decarboxylase
dc.subjectinhibitors
dc.subjectIsoenzymes
dc.subjectMethylhistidines
dc.subjectOligonucleotides
dc.subjectPeptides
dc.subjectProtein Structure, Tertiary
dc.subjectPyridoxal Phosphate
dc.subjectRats
dc.subjectRecombinant Proteins
dc.subjectSubstrate Specificity
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectMolecular, Genetic, and Biochemical Nutrition
dc.titleThe C-terminus of rat L-histidine decarboxylase specifically inhibits enzymic activity and disrupts pyridoxal phosphate-dependent interactions with L-histidine substrate analogues
dc.typeJournal Article
dc.source.journaltitleThe Biochemical journal
dc.source.volume381
dc.source.issuePt 3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1259&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/260
dc.identifier.contextkey472834
refterms.dateFOA2022-08-23T16:41:03Z
html.description.abstract<p>Full-length rat HDC (L-histidine decarboxylase) translated in reticulocyte cell lysate reactions is inactive, whereas C-terminally truncated isoforms are capable of histamine biosynthesis. C-terminal processing of the approximately 74 kDa full-length protein occurs naturally in vivo, with the production of multiple truncated isoforms. The minimal C-terminal truncation required for the acquisition of catalytic competence has yet to be defined, however, and it remains unclear as to why truncation is needed. Here we show that approximately 74 kDa HDC monomers can form dimers, which is the conformation in which the enzyme is thought to be catalytically active. Nevertheless, the resulting dimer is unable to establish pyridoxal phosphate-dependent interactions with an L-histidine substrate analogue. Protein sequences localized to between amino acids 617 and 633 specifically mediate this inhibition. Removing this region or replacing the entire C-terminus with non-HDC protein sequences permitted interactions with the substrate analogue to be re-established. This corresponded exactly with the acquisition of catalytic competence, and the ability to decarboxylate natural L-histidine substrate. These studies suggested that the approximately 74 kDa full-length isoform is deficient in substrate binding, and demonstrated that C-terminally truncated isoforms with molecular masses between approximately 70 kDa and approximately 58 kDa have gradually increasing specific activities. The physiological relevance of our results is discussed in the context of differential expression of HDC isoforms in vivo.</p>
dc.identifier.submissionpathoapubs/260
dc.contributor.departmentDivision of Digestive Diseases and Nutrition
dc.source.pages769-78


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