{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:20:28Z","timestamp":1791825628223,"version":"4.3.4"},"reference-count":53,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,5,1]]},"abstract":"<jats:p>BVR-B (biliverdin-IX\u03b2 reductase) also known as FR (flavin reductase) is a promiscuous enzyme catalysing the pyridine-nucleotide-dependent reduction of a variety of flavins, biliverdins, PQQ (pyrroloquinoline quinone) and ferric ion. Mechanistically it is a good model for BVR-A (biliverdin-IX\u03b1 reductase), a potential pharmacological target for neonatal jaundice and also a potential target for adjunct therapy to maintain protective levels of biliverdin-IX\u03b1 during organ transplantation. In a commentary on the structure of BVR-B it was noted that one outstanding issue remained: whether the mechanism was a concerted hydride transfer followed by protonation of a pyrrolic anion or protonation of the pyrrole followed by hydride transfer. In the present study we have attempted to address this question using QM\/MM (quantum mechanics\/molecular mechanics) calculations. QM\/MM potential energy surfaces show that the lowest energy pathway proceeds with a positively charged pyrrole intermediate via two transition states. These initial calculations were performed with His153 as the source of the proton. However site-directed mutagenesis studies with both the H153A and the H153N mutant reveal that His153 is not required for catalytic activity. We have repeated the calculation with a solvent hydroxonium donor and obtain a similar energy landscape indicating that protonation of the pyrrole is the most likely first step followed by hydride transfer and that the required proton may come from bulk solvent. The implications of the present study for the design of inhibitors of BVR-A are discussed.<\/jats:p>","DOI":"10.1042\/bj20071495","type":"journal-article","created":{"date-parts":[[2008,4,14]],"date-time":"2008-04-14T16:06:13Z","timestamp":1208189173000},"page":"475-484","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Computational and experimental studies on the catalytic mechanism of biliverdin-IX\u03b2 reductase"],"prefix":"10.1042","volume":"411","author":[{"given":"Liam\u00a0J.","family":"Smith","sequence":"first","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seamus","family":"Browne","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian\u00a0J.","family":"Mulholland","sequence":"additional","affiliation":[{"name":"Computational Chemistry Centre, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy\u00a0J.","family":"Mantle","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2008,4,14]]},"reference":[{"key":"2021112214142811000_B1","doi-asserted-by":"crossref","first-page":"4517","DOI":"10.1111\/j.1432-1033.2004.04411.x","article-title":"Crystal structure of heme oxygenase-1 from cyanobacterium Synechocystis sp. 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