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CBS activity, contributing to cellular redox homeostasis, is positively regulated by<jats:sc> S<\/jats:sc>\u2010adenosyl\u2010<jats:sc>L<\/jats:sc>\u2010methionine (AdoMet) but fully inhibited upon CO or NO\u2022 binding to a noncatalytic heme moiety. Despite extensive studies, the molecular basis of several pathogenic <jats:italic>CBS<\/jats:italic> mutations is not yet fully understood. Here we found that the ferrous heme of the reportedly mild p.P49L CBS variant has altered spectral properties and markedly increased affinity for CO, making the protein much more prone than wild type (WT) CBS to inactivation at physiological CO levels. The higher CO affinity could result from the slightly higher flexibility in the heme surroundings revealed by solving at 2.80\u2010\u00c5 resolution the crystallographic structure of a truncated p.P49L. Additionally, we report that p.P49L displays impaired H<jats:sub>2<\/jats:sub>S\u2010generating activity, fully rescued by PLP supplementation along the purification, despite a minor responsiveness to AdoMet. Altogether, the results highlight how increased propensity to CO inactivation of an otherwise WT\u2010like variant may represent a novel pathogenic mechanism in classical homocystinuria.<\/jats:p>","DOI":"10.1155\/2017\/8940321","type":"journal-article","created":{"date-parts":[[2017,3,22]],"date-time":"2017-03-22T22:44:27Z","timestamp":1490222667000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A Clinically Relevant Variant of the Human Hydrogen Sulfide\u2010Synthesizing Enzyme Cystathionine <i>\u03b2<\/i>\u2010Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?"],"prefix":"10.1155","volume":"2017","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3919-8280","authenticated-orcid":false,"given":"Jo\u00e3o B.","family":"Vicente","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2026-0163","authenticated-orcid":false,"given":"Henrique G.","family":"Cola\u00e7o","sequence":"additional","affiliation":[]},{"given":"Francesca","family":"Malagrin\u00f2","sequence":"additional","affiliation":[]},{"given":"Paulo E.","family":"Santo","sequence":"additional","affiliation":[]},{"given":"Andr\u00e9","family":"Gutierres","sequence":"additional","affiliation":[]},{"given":"Tiago M.","family":"Bandeiras","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Leandro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8307-2282","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"Brito","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5301-0681","authenticated-orcid":false,"given":"Alessandro","family":"Giuffr\u00e8","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2017,3,22]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5339"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2014.5869"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.08.007"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00024.2015"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m808026200"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m109.010868"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4433"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2014.5933"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-18144-8_12"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24372"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313683110"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1414545111"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m114.610782"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi701159y"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2009.01.009"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9826052"},{"key":"e_1_2_9_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0162-0134(01)00335-x"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085544"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.507533"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.681221"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00040.2008"},{"key":"e_1_2_9_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22604"},{"key":"e_1_2_9_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119658109"},{"key":"e_1_2_9_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4480"},{"key":"e_1_2_9_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.c116.742213"},{"key":"e_1_2_9_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.08.025"},{"key":"e_1_2_9_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/micc.12253"},{"key":"e_1_2_9_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m112.414706"},{"key":"e_1_2_9_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi300421z"},{"key":"e_1_2_9_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2016.03.030"},{"key":"e_1_2_9_31_2","first-page":"1","article-title":"The natural history of homocystinuria due to cystathionine beta-synthase deficiency","volume":"37","author":"Mudd S. 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