Knockout studies reveal an important role of plasmodium lipoic acid protein ligase a1 for asexual blood stage parasite survival

Günther, S., Matsuscheski, K. and Muller, S. (2009) Knockout studies reveal an important role of plasmodium lipoic acid protein ligase a1 for asexual blood stage parasite survival. PLoS ONE, 4(5), e5510. (doi: 10.1371/journal.pone.0005510) (PMID:19434237) (PMCID:PMC2677453)

Abstract

Lipoic acid (LA) is a dithiol-containing cofactor that is essential for the function of a-keto acid dehydrogenase complexes. LA acts as a reversible acyl group acceptor and 'swinging arm' during acyl-coenzyme A formation. The cofactor is post-translationally attached to the acyl-transferase subunits of the multienzyme complexes through the action of octanoyl (lipoyl): <i>N</i>-octanoyl (lipoyl) transferase (LipB) or lipoic acid protein ligases (LplA). Remarkably, apicomplexan parasites possess LA biosynthesis as well as scavenging pathways and the two pathways are distributed between mitochondrion and a vestigial organelle, the apicoplast. The apicoplast-specific LipB is dispensable for parasite growth due to functional redundancy of the parasite's lipoic acid/octanoic acid ligases/transferases. In this study, we show that <i>LplA1</i> plays a pivotal role during the development of the erythrocytic stages of the malaria parasite. Gene disruptions in the human malaria parasite <i>P.falciparum</i> consistently were unsuccessful while in the rodent malaria model parasite <i>P. berghei</i> the <i>LplA1</i> gene locus was targeted by knock-in and knockout constructs. However, the <i>LplA1</i> ^(-) mutant could not be cloned suggesting a critical role of LplA1 for asexual parasite growth <i>in vitro</i> and <i>in vivo</i>. These experimental genetics data suggest that lipoylation during expansion in red blood cells largely occurs through salvage from the host erythrocytes and subsequent ligation of LA to the target proteins of the malaria parasite.

• Item Type: Articles
• Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Muller, Professor Sylke
• Authors: Günther, S., Matsuscheski, K., and Muller, S.
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Published Online: 01 January 2009
• Copyright Holders: © 2009 Gunther et al.
• First Published: First published in PLoS ONE 2009 4(5): e5510
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher