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Chapter 9 : Regulation of NAD(P) Metabolism in Salmonella
Category: History of Science; Microbial Genetics and Molecular Biology
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John Roth commonly refers to the biosynthesis and recycling of nicotinamide adenine dinucleotide (NAD) (and the related cofactor NADP) as the navel of the universe since they are required for hundreds of the fundamental, and thus highly conserved, biochemical reactions of life. In this chapter, the author reviews what is known about NAD biosynthesis in Salmonella enterica (including work done while he was a graduate student in the Roth lab). There are two enzymes known to directly control the NAD to NADP ratio; one is NAD kinase (which produces NADP from NAD), and the other is NADP phosphatase (which runs the opposing reaction forming NAD from NADP). As new NAD(P)-related genes are identified through genomic, genetic, and biochemical approaches, we can increase our understanding of the interplay between cellular regulation of NAD(P) levels and NAD(P)- dependent processes. The chapter ends with the current thoughts on approaches for identifying novel NAD(P)-associated pathways or genes.
Key Concept Ranking
- Circular Double-Stranded DNA
NAD(P) biosynthetic pathway of S. enterica serovar Typhimurium. The gene encoding each enzyme activity is indicated by solid lines if known or by dashed lines if unknown. Unknown activities include NMN deamidase, NADP phosphatase, NAD(P) pyrophosphatase, NAD glycohydrolase, NMN glycohydrolase, and pyridine transport proteins.
The NAD(P) biosynthetic pathway is feedback regulated by NAD+ and NADPH. The NAD(P) biosynthetic enzymes affected by feedback inhibition (A). The activities regulated by NadR are indicated in bold. The nadB, pncB, nadA, and pnuC genes are transcriptionally repressed by NadR when NAD+ levels are low, while the NmR kinase activity of NadR is enzymatically inhibited by NAD+. In addition, NAD kinase is potently inhibited by in vivo levels of NADPH. A schematic diagram of the regulation of NadR by NAD+ (B). NadR acts as a transcriptional repressor when NAD+ levels are high but acts as a NmR kinase when NAD+ levels are low.
NadK is essential as shown by segregation of a duplication containing both wild-type (nadK+) and nadK:Cm (swap) alleles (A). Colonies of a strain with a duplication spanning the nadK region growing on rich medium with X-gal, in the presence and absence of chloramphenicol (B). When chloramphenicol is present, duplication segregation is lethal due to the requirement for nadK+ .
Conserved genomic clusters harboring NAD(P) biosynthetic genes. The genomic clustering of NAD(P) biosynthetic genes with other NAD(P) biosynthetic genes (A), with recN (B), and with ybeB and yhbZ (C) in phylogenetically diverse bacterial genomes.