Nucleic Acids Research Advance Access originally published online on February 14, 2008
Nucleic Acids Research 2008 36(6):2047-2059; doi:10.1093/nar/gkn047
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Nucleic Acids Research, 2008, Vol. 36, No. 6 2047-2059
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Genomics |
Transcriptional regulation of NAD metabolism in bacteria: NrtR family of Nudix-related regulators
1Burnham Institute for Medical Research, La Jolla, CA 92037, USA, 2Institute for Information Transmission Problems, Russian Academy of Sciences, 127994 Moscow, Russia, 3Istituto di Biotecnologie Biochimiche, Università Politecnica delle Marche, 60131 Ancona, Italy, 4Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 and 5Fellowship for Interpretation of Genomes, Burr Ridge, IL 60527, USA
*To whom correspondence should be addressed. Tel: +39 071 2204 682; Fax: +39 071 2204 677; Email: n.raffaelli{at}univpm.it
Correspondence may also be addressed to Dmitry A. Rodionov. Tel: +1 858 646 31000; Fax: +1 858 795 5249; Email: rodionov{at}burnham.org
Received December 5, 2007. Revised January 8, 2008. Accepted January 24, 2008.
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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