Targeting [NAD.sup.+] metabolism in the human malaria parasite Plasmodium falciparum

Nicotinamide adenine dinucleotide ([NAD.sup.+]) is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated [NAD.sup.+] levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2014-04, Vol.9 (4)
Main Authors: O'Hara, Jessica K, Kerwin, Lewis J, Cobbold, Simon A, Tai, Jonathan, Bedell, Thomas A, Reider, Paul J, Llinas, Manuel
Format: Article
Language:English
Subjects:
Distribution
Genetic aspects
Health aspects
Malaria
Niacinamide
Physiological aspects
Plasmodium falciparum
Purines
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nicotinamide adenine dinucleotide ([NAD.sup.+]) is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated [NAD.sup.+] 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.sup.+]. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize [NAD.sup.+] de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the [NAD.sup.+] 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.sup.+] 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.sup.+] metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0094061