Transcriptional regulation of NAD metabolism in bacteria: NrtR family of Nudix-related regulators

Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Nucleic Acids Research (Impact Factor: 9.11). 05/2008; 36(6):2047-59. DOI: 10.1093/nar/gkn047
Source: PubMed


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.

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Available from: Flavio Cimadamore
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    • "Most of the predicted regulators belonged to the protein families whose members were known to regulate pathways for carbohydrate metabolism, such as the AraC, GntR, LacI, and ROK families [46-49]. Two novel regulators for the arabinose and xylose utilization pathways, AraR (BT0354) and XylR (BT0791), belonged to the NrtR family of regulators that were demonstrated to control NAD biosynthesis in other bacterial phyla [50,51]. The experimental characterization of the NrtR-like sugar-responsive regulators in B. thetaiotaomicron is currently underway and will be published elsewhere (D.A. Rodionov, unpublished). "
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