NADP and NAD utilization in <i>Haemophilus influenzae</i>

Reidl, Joachim; Schlör, Stefan; Kraiss, Anita; Schmidt-Brauns, Joachim; Kemmer, G.; Soleva, E

doi:10.1046/j.1365-2958.2000.01829.x

Cited by 56 publications

(79 citation statements)

References 41 publications

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“…The first report that e (P4) is involved in heme utilization was based on the ability of cloned e (P4) to complement an E. coli hemA mutant for growth on heme, and the apparently reduced ability of a hel insertion mutant to grow on media supplemented with NAD and either heme or hemoglobin [3]. Subsequent studies demonstrated that e (P4) is involved in the utilization of NAD and NADP and led the authors to "argue that the original observed aerobic growth defect of hel mutant strains is based on a deficiency in using factor V and not haemin" [6]. Such a conclusion seems unlikely since 1) it fails to explain the ability of cloned hel to complement a hemA mutant of E. coli for growth on heme and 2) it does not address the fact that there was no reported growth defect for the hel insertion mutants when grown anaerobically.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Reilly et al subsequently identified e (P4) as a phosphomonoesterase [4,5], while Reidl et al reported that e (P4) has NADP phosphatase activity and is required for utilization of NAD and NADP [6]. Reidl et al concluded that the report with respect to heme utilization was erroneous, stating "it seems unlikely that e (P4) is involved in haem uptake" [6]. The fact that growth studies in the original report were performed on media containing NAD [3] supports this view, since e (P4) is necessary for utilization of NAD [3,7]; H. influenzae lacks the enzymes for de novo synthesis of NAD, thus having an absolute requirement for this nutrient [8].…”

Section: Introductionmentioning

confidence: 99%

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Lipoprotein e (P4) of Haemophilus influenzae: role in heme utilization and pathogenesis

Morton

Smith

VanWagoner

et al. 2007

Microbes and Infection

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Lipoprotein e (P4) of Haemophilus influenzae is a phosphomonoesterase, encoded by the hel gene, that has been implicated in the acquisition of heme by this fastidious organism. However, lipoprotein e (P4) is also involved in the utilization of NAD and NMN. Some reports have concluded that the reported heme-related growth defect actually reflects a growth defect for NAD. In the current study hel insertion mutants were constructed and a role for e (P4) in heme acquisition was demonstrated independent of its role in NAD or NMN acquisition. In addition a rat model of infection demonstrated a role for e (P4) in the pathogenesis of invasive disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lipoprotein e (P4) of Haemophilus influenzae: role in heme utilization and pathogenesis

Morton

Smith

VanWagoner

et al. 2007

Microbes and Infection

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“…This model also may hold true for Ftp-containing bacteria that require periplasmic FMN but lack the Shewanella export/nucleotidase pair. There is an analogous mechanism for NAD uptake and processing by an NAD pyrophosphatase in the periplasm of Haemophilus influenza, which has a requirement for the cofactor (79,80). Nonetheless, the possibility of FAD pyrophosphatases in other pathogenic bacteria deserves further investigation.…”

Section: ϩmentioning

confidence: 99%

The TP0796 Lipoprotein of Treponema pallidum Is a Bimetal-dependent FAD Pyrophosphatase with a Potential Role in Flavin Homeostasis

Deka

Brautigam

Liu

et al. 2013

Journal of Biological Chemistry

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Background:The TP0796 lipoprotein of Treponema pallidum belongs to the poorly characterized ApbE superfamily. Results: TP0796 hydrolyzed FAD into FMN and AMP, consistent with the general enzymatic mechanism of an FAD pyrophosphatase. Conclusion: This novel metal-dependent enzyme probably plays an essential role in flavin homeostasis in T. pallidum. Significance: This is the first description of a metal-dependent FAD pyrophosphatase in bacteria.

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“…This implies that NR is the substrate for an as yet unidentified inner membrane transporter. Recently, we presented data showing that two gene products appear to be involved in the NAD utilization pathway of H. influenzae (12)(13)(14). The gene products were identified as the hel-encoded outer membrane lipoprotein e(P4) and a periplasmic protein termed NadN.…”

mentioning

confidence: 99%

Porin OmpP2 of Haemophilus influenzae Shows Specificity for Nicotinamide-derived Nucleotide Substrates

Andersen

Maier

Kemmer

et al. 2003

Journal of Biological Chemistry

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Haemophilus influenzae has an absolute requirement for NAD (factor V) because it lacks all biosynthetic enzymes necessary for de novo synthesis of that cofactor. Therefore, growth in vitro requires the presence of NAD itself, NMN, or nicotinamide riboside (NR). To address uptake abilities of these compounds, we investigated outer membrane proteins. By analyzing ompP2 knockout mutants, we found that NAD and NMN uptake was prevented, whereas NR uptake was not. Through investigation of the properties of purified OmpP2 in artificial lipid membrane systems, the substrate specificity of OmpP2 for NAD and NMN was determined, with K S values of ϳ8 and 4 mM, respectively, in 0.1 M KCl, whereas no interaction was detected for the nucleoside NR and other purine or pyrimidine nucleotide or nucleoside species. Based on our analysis, we assume that an intrinsic binding site within OmpP2 exists that facilitates diffusion of these compounds across the outer membrane, recognizing carbonyl and exposed phosphate groups. Because OmpP2 was formerly described as a general diffusion porin, an additional property of acting as a facilitator for nicotinamide-based nucleotide transport may have evolved to support and optimize utilization of the essential cofactor sources NAD and NMN in H. influenzae.The only known natural habitat of Haemophilus influenzae is the human nasopharynx. H. influenzae is Gram-negative and is able to grow under facultative anaerobic conditions. It is also a human pathogen and is responsible for significant morbidity and mortality in young children (1, 2). To cultivate H. influenzae, a complex medium is required; and if not blood-based, it must contain two growth factors: NAD and hemin (3). In the nasopharynx, H. influenzae finds a relatively constant environment, and the organism has retained a certain degree of flexibility in its ability to utilize nutrients (4) by possessing some limiting metabolic pathway redundancy (5).Early biochemical investigations have established that NMN 1 and nicotinamide riboside (NR) can substitute for NAD, whereas nicotinamide, niacin, or other nicotine-based intermediates of the Preiss-Handler pathway cannot (6 -8). The NAD dependence of H. influenzae was confirmed by the absence of genes encoding the enzymes necessary for the de novo biosynthesis of NAD (9). Accumulation of nicotinamide nucleotides derived from NAD or NR has been demonstrated in H. influenzae and Haemophilus parainfluenzae (10, 11). For H. parainfluenzae, the K m for transport is ϳ0.55 M for NAD and 0.14 M for NR, and the V max for NR is about four times that of NAD (11). This implies that NR is the substrate for an as yet unidentified inner membrane transporter. Recently, we presented data showing that two gene products appear to be involved in the NAD utilization pathway of H. influenzae (12)(13)(14). The gene products were identified as the hel-encoded outer membrane lipoprotein e(P4) and a periplasmic protein termed NadN. Knockout mutations of both genes resulted in growth-deficient phenotypes depending on the...

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NADP and NAD utilization in Haemophilus influenzae

Cited by 56 publications

References 41 publications

Lipoprotein e (P4) of Haemophilus influenzae: role in heme utilization and pathogenesis

Lipoprotein e (P4) of Haemophilus influenzae: role in heme utilization and pathogenesis

The TP0796 Lipoprotein of Treponema pallidum Is a Bimetal-dependent FAD Pyrophosphatase with a Potential Role in Flavin Homeostasis

Porin OmpP2 of Haemophilus influenzae Shows Specificity for Nicotinamide-derived Nucleotide Substrates

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