Targeting NAD+ Metabolism in the Human Malaria Parasite Plasmodium falciparum
| Autor: | Lewis J. Kerwin, Manuel Llinás, Jessica K. O'Hara, Thomas A. Bedell, Simon A. Cobbold, Jonathan Tai, Paul J. Reider |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Enzyme Metabolism
lcsh:Medicine Nicotinamide adenine dinucleotide Biochemistry chemistry.chemical_compound 0302 clinical medicine Microbial Physiology Drug Discovery Medicine and Health Sciences Nicotinamide-Nucleotide Adenylyltransferase Enzyme Inhibitors lcsh:Science Enzyme Chemistry chemistry.chemical_classification Protozoans 0303 health sciences Multidisciplinary biology Microbial Growth and Development Malarial Parasites 3. Good health Enzymes Infectious Diseases Metabolic Pathways Nicotinamidase Research Article Drug Research and Development Plasmodium falciparum Microbiology Cofactor 03 medical and health sciences Parasitic Diseases Escherichia coli Humans Metabolomics 030304 developmental biology Microbial Metabolism Enzyme Kinetics Pharmacology Nicotinamide-nucleotide adenylyltransferase lcsh:R Organisms Parasite Physiology Biology and Life Sciences Biological Transport biology.organism_classification NAD Parasitic Protozoans Malaria Metabolic pathway Enzyme Metabolism chemistry biology.protein Enzymology lcsh:Q Parasitology NAD+ kinase Clinical Medicine 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 4, p e94061 (2014) |
| ISSN: | 1932-6203 |
| Popis: | Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+ de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT), is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds. |
| Databáze: | OpenAIRE |
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