The biosynthesis of nicotinamide adenine dinucleotides in bacteria

doi:10.1016/S0083-6729(01)61003-3

Vitamins & Hormones

Volume 61, 2001, Pages 103-119

https://doi.org/10.1016/S0083-6729(01)61003-3 Get rights and content

Abstract

The nicotinamide adenine dinucleotides (NAD, NADH, NADP, and NADPH) are essential cofactors in all living systems and function as hydride acceptors (NAD, NADP) and hydride donors (NADH, NADPH) in biochemical redox reactions. The six-step bacterial biosynthetic pathway begins with the oxidation of aspartate to iminosuccinic acid, which is then condensed with dihydroxyacetone phosphate to give quinolinic acid. Phosphoribosylation and decarboxylation of quinolinic acid gives nicotinic acid mononucleotide. Adenylation of this mononucleotide followed by amide formation completes the biosynthesis of NAD. An additional phosphorylation gives NADP. This review focuses on the mechanistic enzymology of this Dathwav in bacteria.

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A quest for novel antibiotics and revitalizing older ones (such as nitrofurantoin) for treatment of difficult-to-treat Gram-negative bacterial infections has become increasingly popular. The precise antibacterial activity of nitrofurantoin is still not fully understood. Furthermore, although the prevalence of nitrofurantoin resistance remains low currently, the drug’s fast-growing consumption worldwide highlights the need to comprehend the emerging resistance mechanisms. Here, we used multidisciplinary techniques to discern the exact mechanism of nitrofurantoin action and high-level resistance in Klebsiella pneumoniae, a common cause of urinary tract infections for which nitrofurantoin is the recommended treatment. We found that the expression of multiple genes related to membrane transport (including active efflux and passive diffusion of drug molecules) and nitroreductase activity was modified in nitrofurantoin-resistant strains, including oqxR, the transcriptional regulator of the oqxAB efflux pump. Furthermore, complex interconnected metabolic pathways that potentially govern the nitrofurantoin-killing mechanisms (e.g., aminoacyl-tRNA biosynthesis) and nitrofurantoin resistance (riboflavin metabolism) were significantly inhibited following nitrofurantoin treatment. Our study could help inform the improvement of nitrofuran derivatives, the development of new pharmacophores, or drug combinations to support the resurgence of nitrofurantoin in the management of multidrug resistant K. pneumouniae infection.
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Citation Excerpt :
Quinolinate synthase (NadA), which appears mainly as a dimeric protein of 80 kDa (Ollagnier-de Choudens et al., 2005), contains an oxygen-sensitive [4Fe–4S] cluster required to catalyze the condensation of 2-iminosuccinate with dihydroxyacetone phosphate (DHAP) to produce quinolinate (Ceciliani et al., 2000; Cicchillo et al., 2005; Ollagnier-de Choudens et al., 2005). We know that the concentration of NAD(H) and NADP(H) in vivo remains relatively stable, and the pool is maintained by a combination of gene expression regulation, feedback inhibition, and cofactor degradation [The NAD(P) recycling and salvage pathways] (Begley et al., 2001). The expression of NadB and NadA was reported to be repressed by a DNA binding transcriptional repressor NadR (Begley et al., 2001; Tritz and Chandler, 1973).
Quinolinic acid (QA) is a key intermediate of nicotinic acid (Niacin) which is an essential human nutrient and widely used in food and pharmaceutical industries. In this study, a quinolinic acid producer was constructed by employing comprehensive engineering strategies. Firstly, the quinolinic acid production was improved by deactivation of NadC (to block the consumption pathway), NadR (to eliminate the repression of L-aspartate oxidase and quinolinate synthase), and PtsG (to slow the glucose utilization rate and achieve a more balanced metabolism, and also to increase the availability of the precursor phosphoenolpyruvate). Further modifications to enhance quinolinic acid production were investigated by increasing the oxaloacetate pool through overproduction of phosphoenolpyruvate carboxylase and deactivation of acetate-producing pathway enzymes. Moreover, quinolinic acid production was accelerated by assembling NadB and NadA as an enzyme complex with the help of peptide-peptide interaction peptides RIAD and RIDD, which resulted in up to 3.7 g/L quinolinic acid being produced from 40 g/L glucose in shake-flask cultures. A quinolinic acid producer was constructed in this study, and these results lay a foundation for further engineering of microbial cell factories to efficiently produce quinolinic acid and subsequently convert this product to nicotinic acid for industrial applications.
Structural basis for the catalytic activities of the multifunctional enzyme quinolinate synthase
2020, Coordination Chemistry Reviews
Citation Excerpt :
The de novo pathway II of QA synthesis, which is likely the oldest one, initially involves the condensation of the glycolysis product dihydroxyacetone phosphate (DHAP) and iminoaspartate (IA) [2]. The latter substrate is generated from the oxidation of l-Asp by either the flavin-containing enzyme l-Asp oxidase NadB, present, for instance, in Escherichia coli and Pyrococcus horikoshi (Ph), or by the l-Asp dehydrogenase NadX, found, for example, in Thermotoga maritima (Tm) and Methanococcus maripaludis [2–4]. IA can also be obtained by combining oxaloacetate with ammonium ions, an approach that is often used in in vitro experiments [5].
The [4Fe-4S]-containing enzyme quinolinate synthase, also called NadA, catalyzes the synthesis of quinolinic acid (QA) using what is probably the oldest pathway to generate this universal precursor of the biological cofactor nicotinamide dinucleotide (NAD). QA synthesis involves the condensation of dihydroxyacetone phosphate (DHAP) and iminoaspartate (IA), dephosphorylation, isomerization, cyclization and two dehydration steps. This remarkable series of reactions take place in a narrow active site defined by the convergence of the three homologous domains of NadA. The catalytically essential [4Fe-4S] cluster is found at one end of this site and is connected to the protein surface through a tunnel that can be open or closed depending on the nature (or absence) of the bound ligand. Crystal structures and X-ray diffraction data are available from the Protein Data Bank for complexes of NadA with inhibitors, substrate analogs, at least one substrate (DHAP), product and potential intermediates of QA synthesis. In this review, we have used this information to propose a coherent and comprehensive view of NadA catalysis from a structural viewpoint.

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The biosynthesis of nicotinamide adenine dinucleotides in bacteria

Abstract

Arch. Biochem. Biophys.

Protein Expression Purif.

Gene

Structure

FEBS Lett.

Arch. Biochem. Biophys.

Structure

J. Biol. Chem.

J. Struct. Biol.

FEBS Lett.

Structure

J. Mol. Biol.

Structure

Structure

J. Biol. Chem.

Biochim. Biophys. Acta

J. Mol. Biol.

The crystal structure and mechanism of orotidine 5′-monophosphate decarboxylase

Purification, gene cloning, targeted knockout, overexpression, and biochemical characterization of the major pyrazinamidase from Mycobacterium smegmatis

J. Bacterial.

Nutritional Biochemistry

Evidence for two NAD kinases in Salmonella typhimurium

J. Bacteriol.

Glu-tRNAGln amidotransferase: A novel heterotrimeric enzyme required for correct decoding of glutamine codons during translation

Protein A of quinolinate synthetase is the site of oxygen poisoning of pyridine nucleotide coenzyme synthesis in Escherichia coli

Free Radical Biol. Med.

Kinetics and mechanism of decarboxylation of some pyridinecarboxylic acids in aqueous solution. II

Can. J. Chem.

Molecular biology of pyridine nucleotide biosynthesis in Escherichia coli. Cloning and characterization of quinolinate synthesis genes nadA and nadB

Eur. J. Biochem.

Nicotinamide adenine dinucleotide biosynthesis and pyridine nucleotide cycle metabolism in microbial systems

Microbiol. Reu.

Identification, cloning, and expression of the Escherichia coli pyrazinamidase and nicotinamidase gene, pncA

Antimicrob. Agents Chemother

Kinetic mechanism of nicotinic acid phosphoribosyltransferase: Implications for energy coupling

Biochemistry

Glu-tRNA^Gln amidotransferase: A novel heterotrimeric enzyme required for correct decoding of glutamine codons during translation