Nicotinate and nicotinamide metabolism

Nicotinic acid (anionic form: nicotinate) is also known as niacin or vitamin B3. Nicotinamide is the amide derivative of nicotinic acid. Nicotinate and nicotinamide are essential for organisms as the precursors for generation of coenzymes, NAD+ and NADP+, which are essential for redox reactions and carry electrons from one reaction to another. They therefore exist in oxidised (NAD(P)+) and reduced (NAD(P)H) forms. These coenzymes are crucial for many metabolic pathways including glycolysis, TCA cycle, pentose phosphate cycle, fatty acid biosynthesis and metabolism pathways and many others. The apicomplexans such as Plasmodium falciparum and Toxoplasma gondii cannot synthesise nicotinate and nicotinamide de novo, but, they can salvage it from host or extracellular medium. These organisms can incorporate salvaged vitamin B3 derivatives to synthesise NAD+ and NADP+. Both P. falciparum and T. gondii possesses the genes for the enzymes which catalyse generation of NAD+ and NADP+ from nicotinate salvaged from host. In addition, both of them possess the enzyme nicotinamidase suggesting that nicotinamide can also be salvaged for NAD(P)+ generation. Time-dependent transcription of P. falciparum genes coding these enzymes are available (http://malaria.ucsf.edu/comparison/index.php) and was analysed [1]. The study conducted by Zerez and Ginsburg demonstrated 10-fold increase in NAD+ content and more than 3-fold difference in nicotinate phosphoribosyltransferase activity in P. falciparum-infected erythrocytes compared to uninfected erythrocytes. The nicotinamidase activity was undetectable in uninfected samples and very high levels of activity were observed in infected erythrocytes demonstrating Plasmodium’s ability to utilise nicotinamide from host/medium and synthesise nicotinate. The genes encoding enzymes nicotinamide phosphoribosyltransferase and NAD pyrophosphorylase was not identified in either P. falciparum or T. gondii genomes. The 3.5-fold increase in nicotinamide phosphoribosyltransferase activity was seen in infected erythrocytes, although the activity is about 1/65th of that of nicotinate phosphoribosyltransferase activity [2]. The difference in the activity of NAD pyrophosphorylase is not significant between uninfected and infected samples. It is not known whether P. falciparum possess these enzymes or whether P. falciparum nicotinate phosphoribosyltransferase enzyme can also accept nicotinamide as substrate in higher nicotinamide concentrations. These enzymes were not included in MPMP pathway of nicotinate and nicotinamide metabolism. As these two enzymes are not present in T. gondii genome and no biochemical evidence is yet available for T. gondii, they are not incorporated into the pathway below.

 

Enzyme EC Number Gene id Protein localisation Localisation data source
Pyridine nucleotide transhydrogenase 1.6.1.2 TGME49_301210 Apicoplast Previous publication
Pyridine nucleotide transhydrogenase 1.6.1.2 TGME49_318650    
Nicotinate phosphoribosyltransferase 2.4.2.11 TGME49_208530 Cytosol Previous publication
NAD+ kinase 2.7.1.23 TGME49_244700    
Nicotinate-nucleotide adenylyltransferase 2.7.7.18 TGME49_305840    
Nicotinamidase 3.5.1.19 TGME49_281990    
NAD+ synthase 6.3.5.1 TGME49_269800    

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Nicotinate Host    
Nicotinamide Host    
PRPP Pentose phosphate cycle    
Glutamine Glutamate metabolism Glutamate Glutamate metabolism