title: Rv2074 is a novel F420 H2 -dependent biliverdin reductase in Mycobacterium tuberculosis.
abstract: Bilirubin is a potent antioxidant that is produced from the reduction of the heme degradation product biliverdin. In mammalian cells and Cyanobacteria, NADH/NADPH-dependent biliverdin reductases (BVRs) of the Rossmann-fold have been shown to catalyze this reaction. Here, we describe the characterization of Rv2074 from Mycobacterium tuberculosis, which belongs to a structurally and mechanistically distinct family of F420 H2 -dependent BVRs (F-BVRs) that are exclusively found in Actinobacteria. We have solved the crystal structure of Rv2074 bound to its cofactor, F420 , and used this alongside molecular dynamics simulations, site-directed mutagenesis and NMR spectroscopy to elucidate its catalytic mechanism. The production of bilirubin by Rv2074 could exploit the anti-oxidative properties of bilirubin and contribute to the range of immuno-evasive mechanisms that have evolved in M. tuberculosis to allow persistent infection.
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: F Hafna
authors.initials: FH
authors.lastname: Ahmed
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: A Elaaf
authors.initials: AE
authors.lastname: Mohamed
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Carr
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: Brendon M
authors.initials: BM
authors.lastname: Lee
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: Karmen
authors.initials: K
authors.lastname: Condic-Jurkic
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: Megan L
authors.initials: ML
authors.lastname: O'Mara
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Jackson
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001664:Biliverdine / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000201:enzymology / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D001664:Biliverdine
keywords: F420; Mycobacterium tuberculosis; bilirubin; biliverdin; biliverdin reductase; enzyme catalysis; flavin/deazaflavin oxidoreductase; mycobacteria