Antioxidant defense in Plasmodium falciparum – data mining of the transcriptome
© Bozdech and Ginsburg; licensee BioMed Central Ltd. 2004
Received: 30 March 2004
Accepted: 09 July 2004
Published: 09 July 2004
The intraerythrocytic malaria parasite is under constant oxidative stress originating both from endogenous and exogenous processes. The parasite is endowed with a complete network of enzymes and proteins that protect it from those threats, but also uses redox activities to regulate enzyme activities. In the present analysis, the transcription of the genes coding for the antioxidant defense elements are viewed in the time-frame of the intraerythrocytic cycle. Time-dependent transcription data were taken from the transcriptome of the human malaria parasite Plasmodium falciparum. Whereas for several processes the transcription of the many participating genes is coordinated, in the present case there are some outstanding deviations where gene products that utilize glutathione or thioredoxin are transcribed before the genes coding for elements that control the levels of those substrates are transcribed. Such insights may hint to novel, non-classical pathways that necessitate further investigations.
Materials and Methods
Enzymes and proteins involved in redox metabolism and their gene/locus in the P. falciparum genome.
Fe-superoxide dismutase (possibly an Mn enzyme)
Glutathione biosynthesis and reccycling
Lactoylglutathione lyase (glyoxalase I)
Hydoxyacylglutathione hydrolase (glyoxalase II)
Thioredoxin synthesis and recycling
Trx peroxidase (TPxP) is a
Ribonucleotide reductase, small chain
Oxidative protein folding
Results and Discussion
This analysis relates exclusively to the intraerythrocytic phase of the parasite's life cycle. It should be underscored that some of the functions assigned to the respective gene products are putative and have not been verified by biochemical analyses. Such are the cases of thioredoxin-like proteins (MAL13P1.225, PFI0790w, PFI1250w), glutaredoxin-like proteins (MAL6P1.72, PFC0205c), peroxiredoxin (MAL7P1.159), protein disulfide isomerases. The data that was analysed here are expression levels of mRNA. This is a long way from what one ideally would like: expression levels of the functional proteins. The functional meaning of transcription analysis is useful but it does not tell the complete story of gene expression. Functions are performed by proteins and as long as their stability and life span are not known, it may be possible to imply the onset of expression but not its termination. Hence, a short-lived transcription may be less informative than a longer-lived one because the latter indicates that the protein is expressed at least for this duration of time. Nevertheless, when transcription is evaluated by considering a set of biochemically inter-related enzymes and proteins, some information about their coordinated expression may be gained. In what follows, the different elements of the redox metabolism of the parasite will be discussed in functional "clusters", in order to obtain a methodological overview.
We start our analysis with superoxide dismutase, a major producer of H2O2 in cells. Then the enzymes involved in the biosynthesis and recycling of glutathione will be discussed, followed by those that utilize glutathione. The thioredoxin system is also discussed in a similar order.
In addition to dismutated O2-, H2O2 can also be generated directly by some metabolic processes, such as the production of pyridoxal phosphate (peaking at 18 HPI) or the action of dihydroorotate oxidase (peaking at 20 HPI). The parasite deals with this initial threat by means of the glutathione and the thioredoxin (Trx) systems that compose the cellular antioxidant defenses of both the parasite (see below) and the host cell compartment if and when the peroxide reaches it.
The glutathione system – biosynthesis and recycling
The glutathione system – utilization
It might be expected that genes coding enzymes that utilize GSH will be transcribed after those that synthesize and recycle it. This is indeed the case for most components, but there are exceptions that require alternative interpretations. In most eukaryote cells the reduction of H2O2 and lipid peroxides at the expense of reduced glutathione (GSH) is mediated by glutathione peroxidase (EC: 184.108.40.206; GPx). However, biochemical characterization of the parasite's recombinant protein indicates that this enzyme has an overwhelming preference for Trx over GSH . Hence, the purported GPx gene is actually coding for a Trx peroxidase and the reduction of H2O2 and lipid peroxides is done by other means. GPx must therefore be classified within the Trx system as is discussed below.
A recombinant parasite glutathione-S-transferase (EC: 220.127.116.11; GST) has been produced and shown to reduce cumene-hydroperoxide but not lipid-hydroperoxide. GST, thus, compensates partially for the absence of a genuine GPx. Significantly, the GST-coding gene is transcribed during most of the parasite's intra-eryhtrocytic life cycle. Although the major role of this enzyme is to conjugate GSH to various toxic substances, preparing them for export, a small percentage of its activity entails peroxidative action. One wonders about the source of GSH needed for these activities during the early stages, before the peaking of GSH synthesis and recycling.
Other GSH-utilizing mechanisms operate in the parasite. Most notably are functions catalyzed by glutaredoxins. Glutaredoxin has vicinal thiols in the active site enabling it to catalyse glutathione-disulfide oxidoreductions such as the reduction of ribonucleotide reductase as well as the direct reduction of H2O2. Glutaredoxins are generally reduced by glutathione, but Trx can serve as an alternative substrate. One gene coding for glutaredoxin (PFC0271c) and two genes coding for glutaredoxin-like proteins (the exact function is unknown) have been found in the genome of P. falciparum. As shown in Fig. 4 the glutaredoxin-coding gene is transcribed maximally between 19 and 28 HPI, thus coinciding with the transcription of its putative substrate ribonucleotide reductase (maximal transcription 31–33 HPI) suggesting that glutaredoxin is the major reducer of this enzyme. On the other hand, glutaredoxin-like proteins do not possess the classical conserved active site motif of glutaredoxins, they have only 1-Cys residue, and are not active in the general glutaredoxin assay .
More than 200 mammalian proteins with reactive sulfhydryl sites have been identified in recent years as candidates for coordinate redox control of diverse cell functions . The state of sulfhydryl oxidation is maintained by thioredoxins, glutaredoxins, and glutathione . Outstanding among these proteins are proteases that are activated by reduction and inhibited by oxidation. The possible comparable regulation of the activity of falcipains has not been investigated heretofore. Such regulation is underscored by the recent demonstration that falcipains are not restricted to haemoglobin digestion , but are also involved in invasion  and rupture of the mature schizont , The present analysis establishes the time-scale of such possible regulation.
The glyoxalase pathway
Genes coding for two other enzymes that involve the utilization or the generation of GSH have been identified in the genome of P. falciparum: lactoylglutathione lyase (EC: 18.104.22.168; glyoxalase I) and hydoxyacylglutathione hydrolase (EC: 22.214.171.124; glyoxalase II) and their biochemical functions have been revealed . These enzymes participate in a metabolic pathway that catalyses the detoxification of α-oxoaldehydes to the corresponding aldonic acids, using catalytic amount of GSH as cofactor. α-Oxoaldehydes react with guanyl residues in DNA and RNA, and with cysteine, lysine and arginine residues in proteins. The modification of DNA induces mutagenesis and apoptosis. The modification of proteins leads to protein degradation and activation of a cytokine-mediated immune response . A possible substrate of the glyoxalase system in the parasite is the glycolytic intermediate dihydroxyacetone phosphate that forms spontaneously the toxic electrophile methylglyoxal, an α-oxoaldehyde. Although this detoxification system seems essential to the parasite (about 10 % of the lactate produced in P. falciparum is D-lactate, the final product of the glyoxalase pathway) it needs only catalytic amounts of GSH that is essentially recycled by the system itself. Glyoxalase I has been recently cloned, expressed and its biochemical properties have been characterized . The transcripts of glyoxalase I gene peaks at 28 HPI, while those of the two genes coding for glyoxalase II peak at 12 and 25 HPI, suggesting the expression of glyoxalase I determines the onset of the detoxification pathway. The importance of this pathway to the parasite can be inferred from the inhibitory effect of glyoxalase inhibitors on parasite growth , but the pathway probably draws little on the stores of GSH.
Oxidative protein folding – a source of GSSG and ROS
Post-translational modification and maturation of proteins in the endoplasmic reticulum involves disulfide formation . This activity is mediated by protein-disulfide isomerases (PDI) and oxidoreductin, both having Trx-like activity. In the oxidizing environment of the endoplasmic reticulum, PDI catalyzes both the oxidation and isomerization of disulfides on nascent polypeptides and simultaneously becomes itself reduced . Four genes coding for PDI are transcribed during the erythrocytic cycle. Their gene ID's and times of maximal transcript level are (data not shown): MAL8P1.17 (31 HPI), PFI0950w (33 HPI), PF11_0352 (32 HPI), PF13_0272 (34 HPI; this gene has not been annotated as PDI, but close inspection of its homology to other genes clearly indicates that it is a PDI) and PF14_0694 (39 HPI). As indicated by one of the reviewers of this report, although these genes were annotated as PDI in PlasmoDB, no evidence indicates they are "true" PDI. Only the translated MAL8P1.17 gene shows the classical organization of PDI. The others contain either one active site (instead of two) and in that case, they could act as weak oxido-reducatses activity but not as isomerases. Alternatively, they have mutated amino acids (Cys->Ser; data not shown) in the active site and in that case, they may act as isomerase but certainly not as oxido-isomerase. The late transcription of the PDI gene may be involved in the maturation of merozoite proteins, such as the EBA-175, that accumulate in the micronemes and characteristically contain conserved cysteine domains  and the rhoptry protein apical membrane antigen 1 (AMA-1)  known for its numerous disulfide bonds. Some of these genes seem to have a transit signal sequence that may suggest their localization to the endoplasmic reticulum. Recently, oxidoreductin (Ero1p) has been identified as a candidate enzyme for the maintenance of redox status in the ER. Oxidoreductin of P. falciparum (PF11_0251) peaks twice, at 6HPI and at 33 HPI). Oxidoreductin, is oxidized by molecular oxygen in an FAD-dependent manner, thereby producing O2-, is an FAD-dependent enzyme. Oxidoreductin subsequently acts as a specific oxidant of reduced PDI, which can then directly oxidize again disulfide bonds in folding proteins. Thus, this activity results in ROS production. GSH can also participate in the reduction of -S-S- bonds in oxidized proteins and thereby be oxidized to GSSG. It is not clear how glutathione is transported across the ER membrane, but cells involved in intensive secretion are also known to secrete GSSG. In the plasmodium-infected RBC, the destination of such GSSG is presumably the host cell compartment. The quantitative contribution of these processes to the overall oxidative stress and glutathione metabolism is impossible to evaluate at the present time.
The thioredoxin system
Thioredoxins (Trx) are small disulphide-containing redox proteins that have been found in all the kingdoms of living organisms . Trx serves as a general protein disulphide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of two vicinal cysteine thiol groups to a disulphide, accompanied by the transfer of 2 electrons and 2 protons. The net result is the covalent interconversion of a disulphide and a dithiol. Oxidized Trx is recycled by Trx reductase (TrxR) along the following path:
TrxR-S2 + NADPH + H+ _ TrxR-(SH)2 + NADP+ (1)
Trx-S2 + TrxR-(SH)2 _ Trx-(SH)2 + TrxR-S2 (2)
Protein-S2 + Trx-(SH)2 _ Protein-(SH)2 + Trx-S2 (3)
TrxR catalyses the reduction of oxidised thioredoxin (Trx-S2) by NADPH using FAD and its redox-active disulphide (steps 1 and 2). Reduced thioredoxin (TrxR-(SH)2) then directly reduces the disulphide in the substrate protein (step 3).
Implications for transcription control
In previous functional analyses of the transcriptome of P. falciparum it was contended (and shown) that the parasite has evolved a functionally concerted mode of transcriptional regulation. Thus, functional clusters of genes related to a particular function are transcribed in rational sequence that corresponds to the timing of the physiology and the biochemistry of the intraerythrocytic phase of the parasite life cycle. In-phase co-expression was observed for genes of many general processes such as RNA and DNA synthesis and for parasite-specific processes such as erythrocyte invasion. From the present study, it is clear that both in the glutathione and the thioredoxin systems not all transcriptions are in phase. A detailed analysis of this complex expression pattern reveals rational connections between gene expression and metabolic function of the protein products. For most factors of both studied systems, the expression of users (GSH and Trx users) lags behind that of the producers (de novo synthesis and recycling). However, there are exceptions to this rule, which represent unexpected chains of events in classical biological systems (predators never precede their prey). Such discrepancies point out to possible missing links in the metabolic pathways based on the current status of the gene sequencing and annotations. Alternatively, these could indicate a nonlinear relationship between transcription and translation. Only detailed analysis of the time-dependent levels of protein and of the pertinent low molecular weight substrates/products can solve this apparent paradox and hints to the unresolved meaning of the variable duration of the transcripts: is it related to transcript or to protein stability.
We thank Professor W.D. Stein for critical reading of the manuscript and his helpful suggestions.
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