TY - JOUR
T1 - Transcriptional regulation of NAD metabolism in bacteria
T2 - NrtR family of Nudix-related regulators
AU - Rodionov, Dmitry A.
AU - De Ingeniis, Jessica
AU - Mancini, Chiara
AU - Cimadamore, Flavio
AU - Zhang, Hong
AU - Osterman, Andrei L.
AU - Raffaelli, Nadia
N1 - Funding Information:
We want to thank Dr Giulio Magni and Dr Silverio Ruggieri (Università Politecnica delle Marche, Ancona, Italy) for discussions and advice in the field of NAD metabolic biochemistry, Dr Mikhail Gelfand (IITP, Moscow, Russia) for useful discussions and comments during the preparation of this article and Dr Andrei Mironov (Moscow State University, Russia) for software for the analysis of regulons. We are grateful to the Midwest Center for Structural Genomics team for sharing the results of structural analysis that were instrumental for our functional prediction of the novel family of transcriptional regulators. We thank Ross Overbeek, Veronika Vonstein, Gordon Push and other members of The SEED development team at Fellowship for Interpretation of Genomes (FIG) for their help with the use of The SEED genomic resource. This work was partially supported by grants from Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) ‘Characterization of key enzymes of NAD(P) biosynthesis in bacteria and their regulation:essential steps to find targets of new drugs’ (PRIN 2005 to N.R.); National Institute of Health (NIH) ‘Genomics of Coenzyme Metabolism in Bacterial Pathogens’ (1-R01-AI066244-01A2 to A.O.) and Department of Energy (DOE) ‘Integrated Genome-Based Studies of Shewanella Ecophysiology’ (DE-FG02-07ER64384 to A.O.). Funding to pay the Open Access publication charges for this article was provided by National Institute of Health research grant 1-R01-AI066244-01A2.
PY - 2008/4
Y1 - 2008/4
N2 - 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.
AB - 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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U2 - 10.1093/nar/gkn047
DO - 10.1093/nar/gkn047
M3 - Article
C2 - 18276643
AN - SCOPUS:41849121949
SN - 0305-1048
VL - 36
SP - 2047
EP - 2059
JO - Nucleic acids research
JF - Nucleic acids research
IS - 6
ER -