title: Transcriptional regulation of NAD metabolism in bacteria: NrtR family of Nudix-related regulators.
abstract: A novel family of transcription factors responsible for regulation of various aspects of NAD synthesis in a broad range of bacteria was identified by comparative genomics approach. Regulators of this family (here termed NrtR for Nudix-related transcriptional regulators), currently annotated as ADP-ribose pyrophosphatases from the Nudix family, are composed of an N-terminal Nudix-like effector domain and a C-terminal DNA-binding HTH-like domain. NrtR regulons were reconstructed in diverse bacterial genomes by identification and comparative analysis of NrtR-binding sites upstream of genes involved in NAD biosynthetic pathways. The candidate NrtR-binding DNA motifs showed significant variability between microbial lineages, although the common consensus sequence could be traced for most of them. Bioinformatics predictions were experimentally validated by gel mobility shift assays for two NrtR family representatives. ADP-ribose, the product of glycohydrolytic cleavage of NAD, was found to suppress the in vitro binding of NrtR proteins to their DNA target sites. In addition to a major role in the direct regulation of NAD homeostasis, some members of NrtR family appear to have been recruited for the regulation of other metabolic pathways, including sugar pentoses utilization and biogenesis of phosphoribosyl pyrophosphate. This work and the accompanying study of NiaR regulon demonstrate significant variability of regulatory strategies for control of NAD metabolic pathway in bacteria.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Rodionov
authors.forename: Jessica
authors.initials: J
authors.lastname: De Ingeniis
authors.forename: Chiara
authors.initials: C
authors.lastname: Mancini
authors.forename: Flavio
authors.initials: F
authors.lastname: Cimadamore
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Osterman
authors.forename: Nadia
authors.initials: N
authors.lastname: Raffaelli
mesh_terms: D001419:Bacteria / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D001665:Binding Sites; D002874:Chromosome Mapping; D002876:Chromosomes, Bacterial; D015964:Gene Expression Regulation, Bacterial; D016680:Genome, Bacterial; D023281:Genomics; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism*; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D011755:Pyrophosphatases / Q000737:chemistry; D018085:Regulon; D014157:Transcription Factors / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; D009243:NAD; D011755:Pyrophosphatases; C019620:ADPribose pyrophosphatase