Functional characterization of the acyl carrier protein (PfACP) and beta-ketoacyl ACP synthase III (PfKASIII) from Plasmodium falciparum

Waters, Norman C.; Kopydlowski, Karen M.; Guszczynski, Tadeusz; Wei, Liao; Sellers, Patrice; Ferlan, Jill T; Lee, Patricia; Li, Zhiyu; Woodard, Cassandra L.; Shallom, Shamira; Gardner, Malcolm J.; Prigge, Sean T.

doi:10.1016/s0166-6851(02)00140-8

Cited by 57 publications

(49 citation statements)

References 37 publications

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“…8A and B for the mass spectrometry profiles). The discrepancy between theoretical and determined masses (65 Da) here indicates that a fatty acyl group is probably added to the holo-CpACP1, a phenomenon that has also been described for the bacterially expressed P. falciparum type II ACP (41).…”

Section: Methodsmentioning

confidence: 54%

“…Apicomplexan parasites differ from their human and animal hosts in fatty acid synthesis by possessing either a type II pathway for de novo synthesis of long-chain fatty acids (e.g., P. falciparum) (32,40,41) or uniquely organized type I FAS for making very long chain fatty acids from long-chain fatty acids (e.g., C. parvum) (42,44) or both (e.g., T. gondii and E. tenella) (8). The ACP proteins can be either discrete monofunctional enzymes in a type II pathway or functional domains fused within multifunctional FASs or PKSs.…”

Section: Discussionmentioning

confidence: 99%

“…Bacterial expression systems are commonly used in producing recombinant apicomplexan proteins for functional analysis. Previous studies have shown that recombinant P. falciparum ACP enzymes are mostly in holo form when expressed in E. coli, suggesting bacterial ACPS is capable of activating apicomplexan type II ACP (41). In our previous studies, the 900-kDa CpFAS1 protein has been successfully expressed in bacteria as five individual modules (44).…”

Section: Discussionmentioning

confidence: 99%

“…As a reflection of their divergent parasitic life styles, the fatty acid metabolism is also diverse among apicomplexans. For example, Plasmodium falciparum possesses only type II enzymes that are targeted to the apicoplast for de novo fatty acid synthesis (32,41). However, Cryptosporidium parvum employs only a giant, 900-kDa type I FAS (CpFAS1) that is capable of elongating medium-or long-chain fatty acids (42).…”

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confidence: 99%

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Functional Characterization of an Evolutionarily Distinct Phosphopantetheinyl Transferase in the Apicomplexan Cryptosporidium parvum

Cai¹,

Herschap²,

Zhu

2005

Eukaryot Cell

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Recently, two types of fatty acid synthases (FASs) have been discovered from apicomplexan parasites. Although significant progress has been made in characterizing these apicomplexan FASs, virtually nothing was previously known about the activation and regulation of these enzymes. In this study, we report the discovery and characterization of two distinct types of phosphopantetheinyl transferase (PPTase) that are responsible for synthesizing holo-acyl carrier protein (ACP) from three apicomplexan parasites: surfactin production element (SFP) type in Cryptosporidium parvum (CpSFP-PPT), holo-ACP synthase (ACPS)-type in Plasmodium falciparum (PfACPS-PPT), and both SFP and ACPS types in Toxoplasma gondii (TgSFP-PPT and TgACPS-PPT). CpSFP-PPT and TgSFP-PPT are monofunctional, cytosolic, and phylogenetically related to animal PPTases. However, PfACPS-PPT and TgACPS-PPT are bifunctional (fused with a metal-dependent hydrolase), likely targeted to the apicoplast, and more closely related to proteobacterial PPTases. The function of apicomplexan PPTases has been confirmed by detailed functional analysis using recombinant CpSFP-PPT expressed from an artificially synthesized gene with codon usage optimized for Escherichia coli. The recombinant CpSFP-PPT was able to activate the ACP domains from the C. parvum type I FAS in vitro using either CoA or acetyl-CoA as a substrate, or in vivo when coexpressed in bacteria, with kinetic characteristics typical of PPTases. These observations suggest that the two types of fatty acid synthases in the Apicomplexa are activated and regulated by two evolutionarily distinct PPTases.

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Section: Methodsmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional Characterization of an Evolutionarily Distinct Phosphopantetheinyl Transferase in the Apicomplexan Cryptosporidium parvum

Cai¹,

Herschap²,

Zhu

2005

Eukaryot Cell

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“…Additionally, acetylCoA carboxylase (ACC), which generates the carbon donor malonyl-CoA for FAS, is also represented in P. falciparum genome data (Zuther et al, 1999) and shown to be apicoplast-targeted in T. gondii . Biochemical support for fatty acid synthesis in P. falciparum has followed with functional characterization of several enzymes of FAS (Surolia and Surolia, 2001;Waters et al, 2002;Prigge et al, 2003). Moreover, 14 C-labeled precursors (acetate and malonyl-CoA) are shown in P. falciparum to incorporate into fatty acids (predominantly C10 to C14) in both in vivo and in vitro systems (Surolia and Surolia, 2001).…”

Section: Fatty Acid Biosynthesismentioning

confidence: 99%

The Apicoplast: A Review of the Derived Plastid of Apicomplexan Parasites

Waller

McFadden²

2005

Current Issues in Molecular Biology

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The apicoplast is a plastid organelle, homologous to chloroplasts of plants, that is found in apicomplexan parasites such as the causative agents of Malaria Plasmodium spp. It occurs throughout the Apicomplexa and is an ancient feature of this group acquired by the process of endosymbiosis. Like plant chloroplasts, apicoplasts are semi-autonomous with their own genome and expression machinery. In addition, apicoplasts import numerous proteins encoded by nuclear genes. These nuclear genes largely derive from the endosymbiont through a process of intracellular gene relocation. The exact role of a plastid in parasites is uncertain but early clues indicate synthesis of lipids, heme and isoprenoids as possibilities. The various metabolic processes of the apicoplast are potentially excellent targets for drug therapy.

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Antimalarials

Smithson¹,

Guiguemde²,

Guy³

2010

Burger's Medicinal Chemistry and Drug Discovery

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While the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.

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Functional characterization of the acyl carrier protein (PfACP) and beta-ketoacyl ACP synthase III (PfKASIII) from Plasmodium falciparum

Cited by 57 publications

References 37 publications

Functional Characterization of an Evolutionarily Distinct Phosphopantetheinyl Transferase in the Apicomplexan Cryptosporidium parvum

Functional Characterization of an Evolutionarily Distinct Phosphopantetheinyl Transferase in the Apicomplexan Cryptosporidium parvum

The Apicoplast: A Review of the Derived Plastid of Apicomplexan Parasites

Antimalarials

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