title: Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein.
abstract: Mycobacterium tuberculosis (Mtb) mounts a stubborn defense against oxidative and nitrosative components of the immune response. Dihydrolipoamide dehydrogenase (Lpd) and dihydrolipoamide succinyltransferase (SucB) are components of alpha-ketoacid dehydrogenase complexes that are central to intermediary metabolism. We find that Lpd and SucB support Mtb's antioxidant defense. The peroxiredoxin alkyl hydroperoxide reductase (AhpC) is linked to Lpd and SucB by an adaptor protein, AhpD. The 2.0 angstrom AhpD crystal structure reveals a thioredoxin-like active site that is responsive to lipoamide. We propose that Lpd, SucB (the only lipoyl protein detected in Mtb), AhpD, and AhpC together constitute a nicotinamide adenine dinucleotide (reduced)-dependent peroxidase and peroxynitrite reductase. AhpD thus represents a class of thioredoxin-like molecules that enables an antioxidant defense.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bryk
authors.forename: C D
authors.initials: CD
authors.lastname: Lima
authors.forename: H
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: P
authors.initials: P
authors.lastname: Tempst
authors.forename: C
authors.initials: C
authors.lastname: Nathan
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000975:Antioxidants; D001665:Binding Sites; D002384:Catalysis; D003001:Cloning, Molecular; D003460:Crystallization; D018360:Crystallography, X-Ray; D008058:Dihydrolipoamide Dehydrogenase / Q000378:metabolism*; D006860:Hydrogen Bonding; D006861:Hydrogen Peroxide / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D010544:Peroxidases / Q000737:chemistry* / Q000378:metabolism*; D054464:Peroxiredoxins; D030421:Peroxynitrous Acid / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009243:NAD; D030421:Peroxynitrous Acid; D013879:Thioredoxins; D008063:Thioctic Acid; C013091:lipoamide; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D010544:Peroxidases; D054464:Peroxiredoxins; C109110:peroxynitrite reductase; D008058:Dihydrolipoamide Dehydrogenase; D000217:Acyltransferases; C021515:dihydrolipoamide succinyltransferase