Apicoplast and Endoplasmic Reticulum Cooperate in Fatty Acid Biosynthesis in Apicomplexan Parasite Toxoplasma gondii

Ramakrishnan, S.; Docampo, Melissa D.; MacRae, James I.; Pujol, François M.; Brooks, Carrie F.; Dooren, Giel G. van; Hiltunen, J. Kalervo; Kastaniotis, Alexander J.; McConville, Malcolm J.; Striepen, Boris

doi:10.1074/jbc.m111.310144

Cited by 140 publications

(228 citation statements)

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“…1). The absence of the plastidial stearoyl-ACP desaturase in C. velia is consistent with what has been found in the apicoplasts of apicomplexans and red algal plastids (Sato & Moriyama, 2007;Ramakrishnan et al, 2012). These medium-chain fatty acids are then transported to the endoplasmic reticulum (ER), where they are modified by elongases and desaturases, resulting in the 20:5 fatty acid.…”

Section: Annotation Of Genes Involved In Galactolipid Synthesis In Csupporting

confidence: 55%

“…1). Furthermore, as in the apicomplexans T. gondii and P. falciparum, the red alga Cyanidioschyzon merolae, and Chromera velia, no stearoyl-ACP Δ9 desaturase has been identified in the plastid (Sato & Moriyama, 2007;Ramakrishnan et al, 2012). Thus we hypothesize that 16:0 is transported out of the plastid and incorporated into phospholipid(s), such as phosphatidylcholine, and subsequently elongated and desaturated within the ER.…”

Section: Annotation Of Genes Involved In Galactolipid Synthesis In Cmentioning

confidence: 99%

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Mono- and digalactosyldiacylglycerol composition of dinoflagellates. VI. Biochemical and genomic comparison of galactolipid biosynthesis betweenChromera velia(Chromerida), a photosynthetic alveolate with red algal plastid ancestry, and the dinoflagellate,Lingulodinium polyedrum

Dahmen

Khadka

Dodson

et al. 2013

European Journal of Phycology

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Chromera velia is a recently discovered, photosynthetic, free-living alveolate that is the closest free-living relative to nonphotosynthetic apicomplexan parasites. Most plastids, regardless of their origin, have membranes composed chiefly of two galactolipids, mono-and digalactosyldiacylglycerol (MGDG and DGDG, respectively). Because of the hypothesized shared red algal origin between the plastids of C. velia and dinoflagellates, our primary objectives were to examine how growth temperature affects MGDG and DGDG composition via positive-ion electrospray/mass spectrometry (ESI/MS) and positive ion/electrospray/ mass spectrometry/mass spectrometry (ESI/MS/MS), and to examine galactolipid biosynthetic genes to determine if shared ancestry translates into shared MGDG and DGDG composition. When growing at 20°C, C. velia produces eicosapentaenoic acidrich 20:5(n-3)/20:5(n-3) (sn-1/sn-2) MGDG and 20:5(n-3)/20:5(n-3) DGDG as its primary galactolipids, with relative percentage compositions of approximately 35 and 60%, respectively. At 30°C these are lessened by approximately 5 and 8%, respectively, by the corresponding production of 20:5/20:4 forms of these lipids. The presence of 20:5 at the sn-1 position is similar to what has been observed previously in a cluster of peridinin-containing dinoflagellates, but the presence of 20:5(n-3) at the sn-2 position is extremely rare. Thus, the forms of MGDG and DGDG in C. velia displayed similarities and differences to what has been observed in peridinin-containing dinoflagellates, such as Lingulodinium polyedrum, which produces 20:5/18:5 and 20:5/18:4 as the major forms of MGDG and DGDG. We develop conceptual models from the galactolipids observed and galactolipid-relevant gene annotations to explain the presence of polyunsaturated fatty acid-containing MGDG and DGDG in both L. polyedrum and C. velia.

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Section: Annotation Of Genes Involved In Galactolipid Synthesis In Csupporting

confidence: 55%

Section: Annotation Of Genes Involved In Galactolipid Synthesis In Cmentioning

confidence: 99%

Mono- and digalactosyldiacylglycerol composition of dinoflagellates. VI. Biochemical and genomic comparison of galactolipid biosynthesis betweenChromera velia(Chromerida), a photosynthetic alveolate with red algal plastid ancestry, and the dinoflagellate,Lingulodinium polyedrum

Dahmen

Khadka

Dodson

et al. 2013

European Journal of Phycology

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“…Indeed, computational and experimental studies show that T. gondii ACL is essential when accompanied by deletion of the other source of cytosolic acetyl-CoA, acetyl-CoA synthase (ACS) [83]. It follows that reduced levels of mitochondrial [BCKDH E1/ knockout (KO)] or cytoplasmic (ACL-ACS double KO) acetyl-CoA may have implications for the activities and balance of fatty acid biosynthesis and/or acetylation [84][85][86][87][88].…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

“…These cells alternate between rapid replication in the host to a transient extracellular phase in search of new host cells. During this switch in states, changes in metabolic needs are reflected by massive reduction in fatty acid synthesis for membrane lipids [84], and a simultaneous rise in GABA synthesis which may act as an energy reserve, fuelling the TCA cycle via the GABA shunt ( Figure 3) [54]. In this shunt, glutamate is first decarboxylated to GABA by glutamate decarboxylase (GAD).…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

“…After FASII, fatty acids can be further elongated at the endoplasmic reticulum (ER) membrane [84,85], while FASI (a large cytosolic enzyme that, in many eukaryotes, is responsible for all fatty acid biosynthesis) may also contribute to fatty acid production in T. gondii. Both elongation and FASI require acetyl-CoA as a carbon donor, and this can theoretically be made in the cytosol via acylcitrate lyase (ACL, Figure 3) using citrate exported from the mitochondrion.…”

Section: Outstanding Questionsmentioning

confidence: 99%

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Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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Pages 15apicomplexan mitochondrion in energy generation has remained unclear, given the glucosereplete intracellular nature of the environmental niches of these parasites and the apparent reduction of mitochondrial metabolic pathways [4][5][6][7]. For example, apicomplexan mitochondria lack 'type I' NADH dehydrogenase (NDH, complex I of the ETC) and many apparently lack the enzymes and transporters required for fatty acid b-oxidation [8,9]. Furthermore, the pyruvate dehydrogenase complex (PDH) responsible for conversion of pyruvate into acetyl-CoA -an obligate fuel for the TCA cycle -is only present in the apicoplast [10]. Consequently, there was no obvious entry point to allow catalysis of glycolytic pyruvate by the TCA cycle [10][11][12][13][14]. Despite this, there is overwhelming evidence that apicomplexans rely on a functional and canonical TCA cycle (as reviewed [4,5,15]), and apicomplexan genome annotations indicate the presence of all enzymes of the TCA cycle. Only one clade of apicomplexans, Cryptosporidium spp., show evidence of outright loss of the TCA cycle, but these taxa retain only a highly reduced mitochondrion, the mitosome, and have also lost their apicoplast [5,8,16].This review highlights how metabolomics technologies coupled to genetic manipulation have helped in unraveling apicomplexan parasite plasticity in carbon source utilization through different life stages, revealing a complex and sometimes counter-intuitive pattern of metabolic gains, losses, and reassignments. These changes have presumably been tailored to allow these parasites to thrive within their various host niches, but may constitute some much-needed Achilles' heels in the fight against these devastating diseases. Plasmodium falciparum and the Glycolytic DeceitGlycolysis has long appeared to be the main source of ATP and NAD(P)H in the erythrocytic stages of the malaria parasites, [5,[17][18][19][20][21]. Indeed, glucose uptake in P. falciparum-infected red blood cells (RBCs) has been observed to increase 75-100-fold compared to uninfected RBC [22][23][24][25]. Up to 93% of glucose is converted directly to lactate in asexual stages [26][ 4 _ T D $ D I F F ] and is ultimately excreted into the surrounding host cell. Perturbation of glucose uptake is detrimental to parasite growth [27,28], suggesting that glycolysis is an important part of the parasite's strategy for rapid proliferation. In a manner analogous to the Warburg effect observed in highly-proliferative cancer lines and other rapidly-growing cells (e.g., yeast and bloodstream Trypanosoma spp.), Plasmodium (in erythrocytic stages) has opted for fast generation of ATP through substrate-level phosphorylation and secretion of lactate as an end-product (aerobic fermentative glycolysis), as opposed to the 'slow but efficient' mitochondrial oxidative phosphorylation and complete oxidation [29]. Reasons for this dependence on glycolytic fermentation remain unclear -after all, blood stages of Plasmodium certainly have access to oxygen -but it may be a way of avoiding excessiv...

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Examination of Secondary Metabolite Biosynthesis in Apicomplexa

2023

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Natural product discovery has traditionally relied on the isolation of small molecules from producing species, but genome-sequencing technology and advances in molecular biology techniques have expanded efforts to a wider array of organisms. Protists represent an underexplored kingdom for specialized metabolite searches despite bioinformatic analysis that suggests they harbor distinct biologically active small molecules. Specifically, pathogenic apicomplexan parasites, responsible for billions of global infections, have been found to possess multiple biosynthetic gene clusters, which hints at their capacity to produce polyketide metabolites. Biochemical studies have revealed unique features of apicomplexan polyketide synthases, but to date, the identity and function of the polyketides synthesized by these megaenzymes remains unknown. Herein, we discuss the potential for specialized metabolite production in protists and the possible evolution of polyketide biosynthetic gene clusters in apicomplexan parasites. We then focus on a polyketide synthase from the apicomplexan Toxoplasma gondii to discuss the unique domain architecture and properties of these proteins when compared to previously characterized systems, and further speculate on the possible functions for polyketides in these pathogenic parasites.

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Apicoplast and Endoplasmic Reticulum Cooperate in Fatty Acid Biosynthesis in Apicomplexan Parasite Toxoplasma gondii

Cited by 140 publications

References 51 publications

Mono- and digalactosyldiacylglycerol composition of dinoflagellates. VI. Biochemical and genomic comparison of galactolipid biosynthesis betweenChromera velia(Chromerida), a photosynthetic alveolate with red algal plastid ancestry, and the dinoflagellate,Lingulodinium polyedrum

Mono- and digalactosyldiacylglycerol composition of dinoflagellates. VI. Biochemical and genomic comparison of galactolipid biosynthesis betweenChromera velia(Chromerida), a photosynthetic alveolate with red algal plastid ancestry, and the dinoflagellate,Lingulodinium polyedrum

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Examination of Secondary Metabolite Biosynthesis in Apicomplexa

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