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Journal of Bacteriology, December 2002, p. 6906-6917, Vol. 184, No. 24
0021-9193/02/$04.00+0     DOI: 10.1128/JB.184.24.6906-6917.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Ribosylnicotinamide Kinase Domain of NadR Protein: Identification and Implications in NAD Biosynthesis

Oleg V. Kurnasov,1 Boris M. Polanuyer,1,{dagger} Shubha Ananta,1 Roman Sloutsky,1,{ddagger} Annie Tam,2 Svetlana Y. Gerdes,1 and Andrei L. Osterman1*

Integrated Genomics, Inc., Chicago, Illinois 60612,1 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 148532

Received 16 May 2002/ Accepted 21 August 2002

NAD is an indispensable redox cofactor in all organisms. Most of the genes required for NAD biosynthesis in various species are known. Ribosylnicotinamide kinase (RNK) was among the few unknown (missing) genes involved with NAD salvage and recycling pathways. Using a comparative genome analysis involving reconstruction of NAD metabolism from genomic data, we predicted and experimentally verified that bacterial RNK is encoded within the 3' region of the nadR gene. Based on these results and previous data, the full-size multifunctional NadR protein (as in Escherichia coli) is composed of (i) an N-terminal DNA-binding domain involved in the transcriptional regulation of NAD biosynthesis, (ii) a central nicotinamide mononucleotide adenylyltransferase (NMNAT) domain, and (iii) a C-terminal RNK domain. The RNK and NMNAT enzymatic activities of recombinant NadR proteins from Salmonella enterica serovar Typhimurium and Haemophilus influenzae were quantitatively characterized. We propose a model for the complete salvage pathway from exogenous N-ribosylnicotinamide to NAD which involves the concerted action of the PnuC transporter and NRK, followed by the NMNAT activity of the NadR protein. Both the pnuC and nadR genes were proven to be essential for the growth and survival of H. influenzae, thus implicating them as potential narrow-spectrum drug targets.

* Corresponding author. Mailing address: Integrated Genomics, Inc., 2201 W. Campbell Park Dr., Chicago, IL 60612. Phone: (312) 491-0846, ext. 213. Fax: (312) 491-0856. E-mail: andrei{at}integratedgenomics.com.

{dagger} Present address: Pharmacia Corp., Skokie, Ill.

{ddagger} Present address: Department of Human Genetics, Biological Sciences Division, University of Chicago, Chicago, Ill.

Journal of Bacteriology, December 2002, p. 6906-6917, Vol. 184, No. 24
0021-9193/02/$04.00+0     DOI: 10.1128/JB.184.24.6906-6917.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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