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Journal of Bacteriology, July 2001, p. 3974-3981, Vol. 183, No. 13
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.13.3974-3981.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

NadN and e (P4) Are Essential for Utilization of NAD and Nicotinamide Mononucleotide but Not Nicotinamide Riboside in Haemophilus influenzae

Gabriele Kemmer,1 Thomas J. Reilly,2 Joachim Schmidt-Brauns,1 Gary W. Zlotnik,3 Bruce A. Green,3 Michael J. Fiske,3 Mark Herbert,4 Anita Kraiß,1 Stefan Schlör,1 Arnold Smith,2 and Joachim Reidl1,*

Zentrum für Infektionsforschung, Universität Würzburg, 97070 Würzburg, Germany1; University of Missouri, Columbia, Missouri2; Wyeth-Lederle Vaccines, West Henrietta, New York 14586-97283; and Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom4

Received 22 January 2001/Accepted 12 April 2001

Haemophilus influenzae has an absolute requirement for NAD (factor V) because it lacks almost all the biosynthetic enzymes necessary for the de novo synthesis of that cofactor. Factor V can be provided as either nicotinamide adenosine dinucleotide (NAD), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) in vitro, but little is known about the source or the mechanism of uptake of these substrates in vivo. As shown by us earlier, at least two gene products are involved in the uptake of NAD, the outer membrane lipoprotein e (P4), which has phosphatase activity and is encoded by hel, and a periplasmic NAD nucleotidase, encoded by nadN. It has also been observed that the latter gene product is essential for H. influenzae growth on media supplemented with NAD. In this report, we describe the functions and substrates of these two proteins as they act together in an NAD utilization pathway. Data are provided which indicate that NadN harbors not only NAD pyrophosphatase but also NMN 5'-nucleotidase activity. The e (P4) protein is also shown to have NMN 5'-nucleotidase activity, recognizing NMN as a substrate and releasing NR as its product. Insertion mutants of nadN or deletion and site-directed mutants of hel had attenuated growth and a reduced uptake phenotype when NMN served as substrate. A hel and nadN double mutant was only able to grow in the presence of NR, whereas no uptake of NMN was observed.

* Corresponding author. Mailing address: Zentrum für Infektionsforschung, Universität Würzburg, Röntgenring 11, 97070 Würzburg, Germany. Phone: (49) 931 312153. Fax: (49) 931 312578. E-mail: joachim.reidl{at}mail.uni-wuerzburg.de.

Journal of Bacteriology, July 2001, p. 3974-3981, Vol. 183, No. 13
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.13.3974-3981.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.