title: The structure of Lactococcus lactis thioredoxin reductase reveals molecular features of photo-oxidative damage.
abstract: The NADPH-dependent homodimeric flavoenzyme thioredoxin reductase (TrxR) provides reducing equivalents to thioredoxin, a key regulator of various cellular redox processes. Crystal structures of photo-inactivated thioredoxin reductase (TrxR) from the Gram-positive bacterium Lactococcus lactis have been determined. These structures reveal novel molecular features that provide further insight into the mechanisms behind the sensitivity of this enzyme toward visible light. We propose that a pocket on the si-face of the isoalloxazine ring accommodates oxygen that reacts with photo-excited FAD generating superoxide and a flavin radical that oxidize the isoalloxazine ring C7α methyl group and a nearby tyrosine residue. This tyrosine and key residues surrounding the oxygen pocket are conserved in enzymes from related bacteria, including pathogens such as Staphylococcus aureus. Photo-sensitivity may thus be a widespread feature among bacterial TrxR with the described characteristics, which affords applications in clinical photo-therapy of drug-resistant bacteria.
authors.affiliation: Department of Biotechnology and Biomedicine, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Nicklas
authors.initials: N
authors.lastname: Skjoldager
authors.affiliation: Department of Chemistry, Technical University of Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Blanner Bang
authors.affiliation: Department of Biotechnology and Biomedicine, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Rykær
authors.affiliation: Department of Biotechnology and Biomedicine, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Olof
authors.initials: O
authors.lastname: Björnberg
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
authors.affiliation: Department of Biotechnology and Biomedicine, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Birte
authors.initials: B
authors.lastname: Svensson
authors.affiliation: Department of Chemistry, Technical University of Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Harris
authors.affiliation: Department of Biotechnology and Biomedicine, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Hägglund
mesh_terms: D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005415:Flavins / Q000737:chemistry / Q000378:metabolism; D013294:Lactococcus lactis / Q000201:enzymology* / Q000528:radiation effects*; D008027:Light; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D055668:Photochemical Processes; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005415:Flavins; D005182:Flavin-Adenine Dinucleotide; C008173:isoalloxazine; D013880:Thioredoxin-Disulfide Reductase