AU767213B2

AU767213B2 - Genes of the 1-desoxy-D-xylulose biosynthetic pathway

Info

Publication number: AU767213B2
Application number: AU61947/99A
Authority: AU
Inventors: Hassan Jomaa
Original assignee: Jomaa Pharmaka GmbH
Current assignee: Bioagency AG
Priority date: 1998-09-22
Filing date: 1999-09-22
Publication date: 2003-11-06
Anticipated expiration: 2019-09-22
Also published as: TR200100836T2; ID29772A; OA11656A; CA2343919A1; AU6194799A; WO2000017233A2; IL141888A0; CZ2001990A3; NO20011459L; PL348428A1; CN1319134A; SK3922001A3; EE200100174A; EP1115849A2; ATE317007T1; IS5872A; NO20011459D0; DE59913101D1; HUP0203649A2; BG105361A

Description

WO 00/17233 PCT/EP99/07055 -1- Genes of the 1-deoxy-D-xylulose biosynthesis pathway The present invention relates to DNA sequences which, when incorporated into the genome of viruses, eukaryotes and prokaryotes, modify isoprenoid biosynthesis and to a genetic engineering process for the production of these transgenic viruses, eukaryotes and prokaryotes. The invention also relates to a process for the identification of substances having herbicidal, antimicrobial, antiparasitic, antiviral, fungicidal, bactericidal action in plants and antimicrobial, antiparasitic, antimycotic, antibacterial and antiviral action in humans and animals.

The biosynthesis pathway for the formation of isoprenoids via the classical acetate/mevalonate pathway and an alternative mevalonate-independent biosynthesis pathway, the deoxy-D-xylulose phosphate pathway is already known (Rohmer, Knani, Simonin, Sutter, B. and Sahm, H. (1993): Biochem. J. 295: 517-524).

It is, however, not known how and by which pathways it is possible to bring about a change in the isoprenoid concentration in viruses, eukaryotes and prokaryotes by means of the deoxy-D-xylulose phosphate pathway. Figure 1 shows this biosynthesis pathway.

DNA sequences are consequently provided which code for 1-deoxy-D-xylulase 5-phosphate synthase (DOXP synthase), 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DOXP reductoisomerase) or the gcpE protein. All three genes and enzymes are involved in isoprenoid biosynthesis.

Trhe gcpE protein has a iinase function and catalyses the phosphorylation of a sugar or a phosphorus sugar or a precursor of isoprenoid biosynthesis, in particular the phosphorylation of 2-C-methyl-D-erythritol, 2-C-methyl-Derytritol phosphate, in particular 2-C-methyl-Derythritol 4-phosphate, 2-C-methyl-D-erythrose, 2-Cmethyl-D-erythrose] phosphate, in particular 2-C-methyl- D-erythrose.4-phosphate. In the precursor ~of isoprenoid synthesis, the gcpE protein in particular catalyses the phosphorylation of the following substances:

OH

2 (OH) -C (CH 3 =C (OH) -CH 2 -O-PO (OH) 2

CH

2 (OH) -C (CHA)=C (OH) -CH 2

-OH,

OH

2 (OH) -CH (OH 3

-CO-CH

2 PO (OH) 2

CH

2 (OH) -CH (OH 3

-CO-CH

2

OH

CH

2 =C (CH 3 -CO-0H 2 -O-PO (OH) 2

CH

2 =C (OH 3

-CO-CH

2

-OH,

CH

2 =C (OH 3 -CH (OH) -CH 2 -O-PO (OH) 2 0112=C (OH 3 )-CH (OH) -CH 2

-OH,

H

2 (OH) -C (=0112) -C (OH) -CH 2 -O-PO (OH) 2

OH

2 (OH) -C (=CH 2 -C (OH) -CH 2

-OH

CHO-OH (0113 -CH (OH) -CH 2 -O-PO- (OH) 2 ,r CHO-CH (0113 -CH (OH) -CH 2

-OH,

OH

2 (OH) -C (OH) (OH 3 -CH=CH-O-PO (OH) 2

OH

2 (OH) -C (OH) (OH 3

-CH=CH-OH

OH (OH) =C (OH 3 -CH (OH) -CH 2 -O-PO (OH) 2 OH( (OH) =C (013)*-OH (OH) -CH 2

-OH,

30 (CHA 2 HC-CO-CH2-0- PO (OH) 2 (0113 2

(OH

3 2 HC-CH (OH) -CH 2 -O-PO (OH1)2,

(OH

3 2 HC-CH (OH) -CH 2 -3- DOXP synthase catalyses the condensation of pyruvate and glyceraldehyde 3-phosphate to yield l-deoxy-D-xylulose and DOXP reductoisomerase catalyses the conversion of l-deoxy-D-xylulose 5-phosphate into 2-C-methyl-D-erythritol 4-phosphate Fig. ly.

The invention relates to the following DNA sequences: DNA sequences which code for a polypeptide with the amino acid sequence shown in SEQ ID no. 2 or for an analogue or derivative of the polypeptide according to SEQ ID no. 2, in which one or more amino acids have been deleted, added or replaced by other amino acids, wherein the enzymatic action of the polypeptide is retained, and which sequences originate from parasites, wherein sequence variations occurring within the framework of natural strain variability are included, *DNA sequences which code for a polypeptide with the amino 20 acid sequence shown in SEQ ID no. 4 or for an analogue or derivative of the polypeptide according to SEQ ID no. 4, in which one or more amino acids have been deleted, added or replaced by other amino acids, wherein the enzymatic action of the polypeptide is retained, and which sequences originate from parasites, wherein sequence variations occurring within the framework of natural strain variability are included, and DNA sequences which code for a polypeptide with the 30 amino acid sequence shown in SEQ ID no. 6 or for an analogue or derivative of the polypeptide according to SEQ ID no. 6, in which one or more amino acids have been 3adeleted, added or replaced by other amino acids, wherein the catalytic function of the polypeptide is retained.

The genes and the gene products thereof (polypeptides) are shown with their primary structure and are assigned as follows: SEQ ID No. 1: 1-deoxy-D-xylulose 5-phosphate reducto-isomerase gene SEQ ID No. 2: 1-deoxy-D-xylulose 5-phosphate reducto-isomerase SEQ ID No. 3: 1-deoxy-D-xylulose 5-phosphate synthase gene SEQ ID No. 4: 1-deoxy-D-xylulose 5-phosphate synthase [R:\LIBUU]02651 doc:jin WO 00/17233 PCT/EP99/07055 -4- SEQ ID no. 5: gcpE gene SEQ ID no. 6: gcpE proteins.

The DNA sequences all originate from Plasmodium falciparum.

Apart from the DNA sequences stated in the sequence listing, suitable sequences are also those which, as a result of the degeneration of the genetic code, have another DNA sequence, but code for the same peptide or for an analogue or derivative of the polypeptide, in which one or more amino acids have been deleted, added or replaced by other amino acids.

The sequences according to the invention are suitable for the expression of genes in viruses, eukaryotes and prokaryotes which are responsible for isoprenoid biosynthesis in the l-deoxy-D-xylulose pathway.

According to the invention, eukaryotes or eukaryotic cells include animal cells, plant cells, algae, yeasts, fungi, while prokaryotes or prokaryotic cells include bacteria, archaebacteria and eubacteria.

When a DNA sequence is incorporated into a genome on which the above-stated DNA sequence is located, expression of the above-described genes in viruses, eukaryotes and prokaryotes is enabled. The viruses, eukaryotes and prokaryotes transformed'according to the invention are cultivated in a manner known per se and the isoprenoid formed during such cultivation is isolated and optionally purified. Not all isoprenoids need to be WO 00/17233 PCT/EP99/07055 isolated as in some case the isoprenoids are released directly into the ambient air.

The invention furthermore relates to a process for the production of transgenic viruses, eukaryotes and prokaryotes in order to modify the isoprenoid content, which process comprises the following steps.

a) Production of a DNA sequence with the following subsequences i) promoter which is active in viruses, eukaryotes and prokaryotes and ensures the formation of an RNA in the intended target tissue or target cells, ii) DNA sequence which codes for a polypeptide with the amino acid sequence shown in SEQ ID no. 2, 4 or 6 or for an analogue or derivative of the polypeptide according to SEQ ID no. 2, 4 or 6, iii) 5' and 3' untranslated sequence which enables or enhances expression of the stated genes in viruses, eukaryotes and prokaryotes, b) transfer and incorporation of the DNA sequence into the genome of viruses, prokaryotic or eukaryotic cells with or without the use of a vector (for example plasmid, viral DNA).

The intact, whole plants may be regenerated from plant cells transformed in this manner.

The protein-coding sequences with the nucleotide sequences SEQ ID no. 1, SEQ ID no. 3 and SEQ ID no. 5 may be provided with a promoter which ensures transcription in certain organs or cells, which promoter is coupled in WO 00/17233 PCT/EP99/07055 -6sense orientation end of the promoter to the 5' end of the coding sequence) to the sequence which codes the protein to be formed. A termination signal which determines termination of mRNA synthesis is attached to the 3' end of the coding sequence. In order to direct the protein which is to be expressed to certain subcellular compartments, such as chloroplasts, amyloplasts, mitochondria, vacuoles, cytosol or intercellular spaces, a further sequence which codes for a so-called signal sequence or a transit peptide may be inserted between the promoter and the coding sequence. In some cases, it is necessary to insert sequences which code for a signal at the COOH terminus of the protein. The sequence must be in the same reading frame as the coding sequence of the protein. A large number of cloning vectors is available in order to prepare for the introduction of the DNA sequences according to the invention into higher plants, which vectors contain a replication signal for E. coli and a marker which permits selection of the transformed cells. Depending upon the method by which desired genes are introduced into the plant, further DNA sequences may be required. If, for example, the Ti or Ri plasmid is used to transform the plant cells, at least one right border, but frequently the right border and left border of the Ti and Ri plasmid T-DNA must be inserted as a flanking region into the genes to be introduced. The use of T-DNA for transforming plant cells has been intensively investigated and comprehensively described in EP 120516; Hoekama in "The Binary Plant Vector System", Offset-drukkerij Kanters B.V. Alblasserdam (1985), chapter V; Fraley et al., Crit.Rev.Plant Sci. 4, 1-46 and An et al. (1985) EMBO J. 4, 277-287. Once the introduced DNA has been incorporated into the genome, it is WO 00/17233 PCT/EP99/07055 -7generally stable and is also retained in the descendants of the originally transformed cells. It normally contains a selection marker, which imparts to the transformed plant cells resistance to a biocide or an antibiotic, such as kanamycin, G 418, bleomycin, hygromycin or phosphinotricin and others. The particular marker used is thus intended to allow selection of transformed cells from cells lacking the inserted DNA.

Many techniques are available for introducing DNA into a plant. These techniques include transformation with the assistance of agrobacteria, for example Agrobacterium tumefaciens, protoplast fusion, microinjection of DNA, electroporation, as well as ballistic methods and virus infection. Whole plants may then be regenerated from the transformed plant material in a suitable medium which may contain antibiotics or biocides for selection purposes.

No particular requirements are placed upon the plasmids for injection and electroporation. However, if whole plants are to be regenerated from such transformed cells, a selectable marker gene must be present. The transformed cells grow in the plants in the conventional manner (McCormick et al. (1986), Plant Cell Reports 5, 81-84).

The plants may be cultivated normally and be crossed with plants which have the same transformed genome or other genomes. The resultant individuals have the corresponding phenotypic properties.

The present invention also provides expression vectors which contain one or more of the DNA sequences according to the invention. Such expression vectors are obtained by providing the DNA sequences according to the invention with suitable functional regulation signals. Such WO 00/17233 PCT/EP99/07055 -8regulation signals are DNA sequences which are responsible for expression, for example promoters, operators, enhancers, ribosomal binding sites, and are recognised by the host organism.

Further regulation signals, which for example control replication or recombination of the recombinant DNA in the host organism, may optionally also be a constituent part of the expression vector.

The host organisms transformed with the DNA sequences or expression vectors according to the invention are also provided by the present invention.

Suitable host cells and organisms for expressing the enzymes according to the invention are those which comprise no intrinsic enzymes with the function of DOXP synthase, DOXP reductoisomerase or the gcpE protein. This is the case for archaebacteria, animals, fungi, slime moulds and some eubacteria. The absence of such intrinsic enzyme activity substantially facilitates detection and purification of the recombinant enzymes. As a consequence, it is also for the first time possible straightforwardly to measure, in crude extracts from the host cells, the activity and in particular the inhibition of the activity of the recombinant enzymes according to the invention by various chemicals and pharmaceuticals.

The enzymes according to the invention are advantageously then expressed in eukaryotic cells if post-translational modification and native folding of the polypeptide chain is to be achieved. Moreover, depending upon the expression system, it is ensured when expressing genomic WO 00/17233 PCT/EP99/07055 -9- DNA sequences that introns are eliminated by splicing the DNA and the enzymes are produced in the polypeptide sequences characteristic to the parasites. Using recombinant DNA techniques, sequences coding for introns may be eliminated from or inserted for experimental purposes into the DNA sequences to be expressed.

The protein may be isolated from the host cell or the culture supernatant of the host cell using methods known to the person skilled in the art. In vitro reactivation of the enzymes may also be required.

In order to facilitate purification, the enzymes according to the invention or sub-sequences of the enzymes may be expressed as fusion proteins with various peptide chains. Oligo-histidine sequences and sequences derived from glutathione S-transferase, thioredoxin or calmodulin-binding peptides are particularly suitable for this purpose.

The enzymes according to the invention or sub-sequences of the enzymes may furthermore be expressed as fusion proteins with such peptide chains known to the person skilled in the art that the recombinant enzymes are transported into the extracellular medium or into certain compartments of the host cells. Both purification and investigation of the biological activity of the enzymes may consequently be facilitated.

When expressing the enzymes according to the invention, it may prove convenient to modify individual codons.

Purposeful replacement of bases in the coding region may here also be advisable if the codons used in the WO 00/17233 PCT/EP99/07055 parasites differ from the codon use in the heterologous expression system, in order to ensure optimal synthesis of the protein.

The enzymes according to the invention may furthermore be obtained under standardised conditions by in vitro translation by methods known to the person skilled in the art. Systems suitable for this purpose are rabbit reticulocyte and wheat germ extracts and bacterial lysates. In vitro transcribed mRNA may also be translated into Xenopus oocytes.

Oligo- and polypeptides, the sequences of which are derived from the peptide sequence of the enzymes according to the invention, may be obtained by chemical synthesis. Given appropriate selection of the sequences, such peptides have properties which are characteristic of the enzymes according to the invention. Such peptides may be produced in large quantities and are particularly suitable for investigating the kinetics of enzyme activity, regulation of enzyme activity, the threedimensional structure of the enzymes, inhibition of enzyme activity by various chemicals and pharmaceuticals and the binding geometry and binding affinity of various ligands.

DNA with the nucleotides from sequences SEQ ID no. i, 3 and 5 are preferably used for the recombinant production of the enzymes according to the invention.

The invention accordingly moreover relates to a process for screening for compounds which inhibit the deoxy-Dxylulose phosphate metabolic pathway. According to this WO 00/17233 PCT/EP99/07055 -11process, a host organism, which contains a recombinant expression vector, wherein the vector comprises at least a portion of the oligonucleotide sequence according to SEQ ID no. 1, SEQ ID no. 3 or SEQ ID no. 5 or variants or homologues thereof, is provided, as is a compound which is suspected to have antimicrobial, antiparasitic, antibacterial, antiviral and antimycotic action in humans and animals or an antimicrobial, antiviral, bactericidal, herbicidal or fungicidal activity in plants. The host organism is then brought into contact with the compound and the activity of the compound determined.

The present invention also provides methods for determining the enzymatic activity of the gcpE protein.

Said activity may be determined using known methods.

Determination is performed by detecting the phosphorylation of a sugar or of a phosphorus sugar or of a precursor of isoprenoid biosynthesis, in particular the phosphorylation of 2-C-methyl-D-erythritol, 2-C-methyl-Derytritol phosphate, in particular 2-C-methyl-Derythritol 4-phosphate, 2-C-methyl-D-erythrose, 2-Cmethyl-D-erythrose phosphate, in particular 2-C-methyl-Derythrose 4-phosphate. The present invention also provides the use of this measurement method for identifying substances which inhibit the activity of the particular enzymes.

The enzymatic activity of DOXP synthase and DOXP reductoisomerase may be detected in a single step by determining the conversion of glyceraldehyde 3-phosphate into 2-C-methylerythritol 4-phosphate.

WO 00/17233 PCT/EP99/07055 -12- Determination of the activities of DOXP synthase and DOXP reductoisomerase proceeds analogously. Fluorimetric methods described by Querol et al. are also suitable for determining DOXP synthase activity (Querol et al., abstracts, 4 t h European Symposium on Plant Isoprenoids, Barcelona, 21-23 April 1999).

EDITORIAL NOTE APPLICATION NUMBER 61947/99 The following Sequence Listing pages 1 to 22 are part of the description. The claims pages follow on pages 13 to WO 00/17233 PCT/EP99/07055 -1- SEQUENCE LISTING <110> Jomaa, Hassan <120> Genes of the 1-deoxy-D-xylulose biosynthesis pathway <130> 15696 <140> PCT/EP99 <141> 1999-09-22 <150> DE19923567.8 <151> 1999-05-22 <150> DE19843279.8 <151> 1998-09-22 <160> 6 <170> PatentIn Ver. 2.1 <210> 1 <211> 1467 <212> DNA <213> Plasmodium falciparum <220> <221> CDS <222> (1)..(1467) <220> <221> gene <222> (1)..(1467) <220> <221> mRNA <222> (1)..(1467) <400> 1 atg aag aaa tat att Met Lys Lys Tyr Ile 1 5 aat gat tta gta ata Asn Asp Leu Val Ile aga aaa aat aac gca Arg Lys Asn Asn Ala gat aat aaa ata aca Asp Asn Lys Ile Thr tat ata tat ttt ttc ttc atc aca ata act att Tyr Ile Tyr Phe Phe Phe Ile Thr Ile Thr Ile 10 aat aat aca tca aaa tgt gtt tcc att gaa aga Asn Asn Thr Ser Lys Cys Val Ser Ile Glu Arg 25 tat ata aat tat ggt ata gga tat aat gga cca Tyr Ile Asn Tyr Gly Ile Gly Tyr Asn Gly Pro 40 aag agt aga aga tgt aaa aga ata aag tta tgc Lys Ser Arg Arg Cys Lys Arg Ile Lys Leu Cys 55 WO 00/17233 PCT/EP99/07055 -2aaa Lys aaq gat tta ata Lys Asp Leu Ile att ggt gca ata Ile Gly Ala Ile aag Lys aaa cca att aat Lys Pro Ile Asn gca att ttt gga Ala Ile Phe Gly agt Ser act ggt agt ata Thr Gly Ser Ile acg aat gct tta Thr Asn Ala Leu aat ata Asn Ile ata agg gag Ile Arg Glu tat qtg aat Tyr Val Asn 115 aat aaa att gaa Asn Lys Ile Glu aat Asn 105 gtt ttt aat gtt Val Phe Asn Val aaa gca ttg Lys Ala Leu 110 aga gaa ttt Arg Giu Phe aag agt gtg aat Lys Ser Val Asn tta tat gaa caa Leu Tyr Giu Gin gct Ala 125 tta cca Leu Pro 130 gaa tat ttg tgt Glu Tyr Leu Cys ata Ile 135 cat gat aaa agt His Asp Lys Ser tat gaa qaa tta Tyr Giu Giu Leu aaa Lys 145 gaa ctg gta aaa Glu Leu Vai Lys ata aaa gat tat Ile Lys Asp Tyr aaa Lys 155 cct ata ata ttg Pro Ile Ile Leu ggt gat gaa ggg Gly Asp Giu Gly atg Met 165 aaa qaa ata tgt Lys Giu Ile Cys agt aat agt ata Ser Asn Ser Ile gat aaa Asp Lys 175 ata gtt att Ile Val Ile gca att atg Ala Ile Met 195 att gat tct ttt Ile Asp Ser Phe caa Gin 185 gga tta tat tct Gly Leu Tyr Ser act atg tat Thr Met Tyr 190 qaa tcc att Glu Ser Ile 576 624 aat aat aaa ata Asn Asn Lys Ile gcg tta gct aat Ala Leu Aa Asn gtc tct Vai Ser 210 gct ggt ttc ttt Ala Giy Phe Phe tta Leu 215 aag aaa tta tta Lys Lys Leu Leu att cat aaa aat Ile His Lys Asn gca Ala 225 aag ata ata cct Lys Ile Ile Pro gat tca gaa cat Asp Ser Giu His agt Ser 235 gct ata ttt caa Ala Ile Phe Gin tgt Cys 240 672 720 768 tta gat aat aat Leu Asp Asn Asn aag Lys 245 gta tta aaa aca Val Leu Lys Thr aaa Lys 250 tgt tta caa gac Cys Leu Gin Asp aat ttt Asn Phe 255 tct aaa att Ser Lys Ile cca ttt caa Pro Phe Gin 275 aat ata aat aaa Asn Ile Asn Lys ttt tta tgt tca Phe Leu Cys Ser tct gga ggt Ser Giy Gly 270 aca tca gaa Thr Ser Glu 816 864 aat tta act atg Asn Leu Thr Met gac Asp 280 gaa tta aaa aat Glu Leu Lys Asn WO 00/17233 PCT/EP99/07055 aat gct Asn Ala 290 tta aag cat cct Leu Lys His Pro aaa Lys 295 tgg aaa atg ggt Trp Lys Met Gly aaa ata act ata Lys Ile Thr Ile gat Asp 305 tct gca act atg Ser Ala Thr Met aat aaa ggt tta Asn Lys Gly Leu gag Glu 315 gtt ata gaa acc Val Ile Glu Thr 912 960 1008 ttt tta ttt gat Phe Leu Phe Asp gta Val 325 gat tat aat gat Asp Tyr Asn Asp gaa gtt ata gta Glu Val Ile Val cat aaa His Lys 335 gaa tgc att Glu Cys Ile agt caa atg Ser Gin Met 355 cat tct tgt gtt His Ser Cys Val gaa Glu 345 ttt ata gac aaa Phe Ile Asp Lys tca gta ata Ser Val Ile 350 tat tct tta Tyr Ser Leu 1056 1104 tat tat cca gat Tyr Tyr Pro Asp caa ata ccc ata Gin Ile Pro Ile tta Leu 365 aca tgg Thr Trp 370 cct gat aga ata Pro Asp Arg Ile aaa Lys 375 aca aat tta aaa Thr Asn Leu Lys tta gat ttg get Leu Asp Leu Ala cag Gin 385 gtt tca act ctt Val Ser Thr Leu ttt cat aaa cct Phe His Lys Pro tct Ser 395 tta gaa cat ttc Leu Glu His Phe ccg Pro 400 1152 1200 1248 tgt att aaa tta Cys Ile Lys Leu gct Ala 405 tat caa gca ggt Tyr Gin Ala Gly aaa gga aac ttt Lys Gly Asn Phe tat cca Tyr Pro 415 act gta cta Thr Val Leu aat aaa att Asn Lys Ile 435 gcg tca aat gaa Ala Ser Asn Glu ata Ile 425 gct aac aac tta Ala Asn Asn Leu ttt ttg aat Phe Leu Asn 430 caa gtt ctt Gin Val Leu 1296 1344 aaa tat ttt gat Lys Tyr Phe Asp att Ile 440 tec tct ata ata Ser Ser Ile Ile gaa tct Glu Ser 450 ttc aat tct caa Phe Asn Ser Gin aag Lys 455 gtt tcg gaa aat Val Ser Glu Asn gaa gat tta atg Glu Asp Leu Met 1392 1440 aag Lys 465 caa att cta caa Gin Ile Leu Gin cat tct tgg gcc His Ser Trp Ala gat aaa get acc Asp Lys Ala Thr gat Asp 480 ata tac aac aaa Ile Tyr Asn Lys cat His 485 aat tct tca tag Asn Ser Ser 1467 <210> 2 <211> 488 <212> PRT <213> Plasmodium falciparum WO 00/17233 WO 00/ 7233PCT/EP99/07055 <400> 2 Met Lys 1 Asn Asp Arg Lys Asp Asn Lys Lys Ala Ile Ile Arg Tyr Val Leu Pr~o 130 Lys Giu 145 Gly Asp Ile Val Ala Ile Val Ser 210 Ala Lys 225 Leu Asp Ser Lys Pro Phe Asn Ala 290 Lys Leu Asn Lys Asp Phe Glu As n 115 Glu Leu Glu Ile Met 195 Ala Ile Asn Ile Gin 275 Leu Ile 5 Ile Ala Thr Ile Ser Asn Ser Leu Lys Met 165 Ile Asn Phe Pro Lys 245 As n Leu His Tyr Asn Tyr Lys Asp 70 Thr Lys Val Cys Asn 150 Lys Asp Lys Phe Val1 230 Val1 Ile Thr Pro Ile Asn Ile Ser 55 Ile Gly Ile Asn Ile 135 Ile Glu Ser Ile Leu 215 Asp Leu Asn Met Lys 295 T yr Thr Asn 40 Arg Gly Ser Glu Glu 120 His Lys Ile Phe Val1 200 Lys Ser Lys Lys Asp 280 Trp Phe Ser Tyr Arg Al a Ile Asn 105 Leu Asp Asp Cys Gin 185 Ala Lys Giu Thr Ile 265 Giu Lys Phe 10 Lys Gly Cys Ile Gly 90 Val1 Tyr Lys T yr S er 170 Gly Leu Leu His Lys 250 Phe Leu Met Phe Cys Ile Lys Lys 75 Thr Phe Giu Ser Lys 155 Ser Leu Al a Leu Ser 235 Cys Leu Lys Gly Ile Val1 Gly Arg Lys As n As n Gin Val 140 Pro Asn Tyr As n Asn 220 Al a Leu Cys As n Lys 300 Thr Ser T yr Ile Pro Al a Val Ala 125 T yr Ile S er Ser Lys 205 Ile Ile Gin Ser Val1 285 Lys Ile Ile Asn Lys Ile Leu Lys 110 Arg Giu Ile Ile Thr 190 Giu His Phe Asp Ser 270 Thr Ile Thr Giu Gly Leu Asn As n Al a Giu Glu Leu Asp 175 Met Ser Lys Gin As n 255 Gly Ser Thr Ile Arg Pro Cys Val Ile Leu Phe Leu Cys 160 Lys Tyr Ile Asn Cys 240 Phe Gly Glu Ile WO 00/17233 WO 0017233PCT/EP99/07055 Asp 305 Phe Glu Ser Thr Gin 385 Cys Thr As n Glu Lys 465 Thr Asp Ile 340 Tyr Asp Thr Leu Asn 420 Lys Asn Leu Met Val1 325 His T yr Arg Leu Ala 405 Ala Tyr Ser Gin Met 310 Asp Ser Pro Ile Thr 390 Tyr Ser Phe Gin Ile 470 Asn Tyr Cys Asp Lys 375 Phe Gin Asn Asp Lys 455 His Gly Asp Giu 345 Gin Asn Lys Gly Ile 425 Ser Ser T rp Leu Ile 330 Phe Ile Leu Pro Ile 410 Ala Ser Giu Al a Giu 315 Giu Ilie Pro Lys Ser 395 Lys Asn Ile As n Lys 475 Ile Ile Lys Leu 365 Leu Giu Asn Leu Ser 445 Giu Lys Giu Vali Ser 350 Tyr Asp His Phe Phe 430 Gin Asp Ala His 320 Lys Ile Leu Aila Pro 400 Pro Asn Leu Met Asp .480 Ile Tyr Asn Lys His Asn Ser Ser 485 3 <2i1> 3872 <212> DNA <2i3> Piasmodium faiciparum <220> <22i> CDS <222> (i26)..(3740) <220> <221> gene <222> (i)..(3870) <220> <221> mRNA <222> (1)..(3870) <400> 3 ggtaatatac gtataatata tatataatat attcttacgt atgtatcatt tatgaatcat WO 00/17233 PCT/EP99/07055 -6aataatattc taaatttacc ttccgttttt gctcgatctt ctcattttcg tttcagcttt 120 tatca atg att ttt aat tat gtg ttt ttt aag aac ttt gta cca gtt gtt 170 Met Ile Phe Asn Tyr Val Phe Phe Lys Asn Phe Val Pro Val Val cta tac att ctc Len Tyr Ile Leu ata ata tat att Ile Ile Tyr Ile aac Asn tta aat ggc atg Len Asn Gly Met aat aat Asn Asn 218 aaa aat caa Lys Asn Gin ttg tca agq Len Ser Arq aaa aca gaa aaa Lys Thr Giu Lys tat ata aag aaa- Tyr Ile Lys Lys ttg aat agq Len Asn Arg ata gca tgc Ile Ala Cys 266 314 aaa aat tcg tta Lys Asn Ser Leu tgt Cys agt tct aaa aat Ser Ser Lys Asn ttg ttc Leu Phe gat ata gqa aat Asp Ile Gly Asn gat aat aga aat Asp Asn Arg Asn acg Thr aca tat ggc tat Thr Tyr Gly Tyr aat Asn gtg aat gtt aaa Val Asn Vai Lys aat Asn gat gat att aat Asp Asp Ile Asn tta cta aaa aat Len Leu Lys Asn 362 410 458 tat agt aat aaa Tyr Ser Asn Lys ttg Leu 100 tac atg gat aag Tyr Met Asp Lys agg Arg 105 aaa aat att aat Lys Asn Ile Asn aat gta Asn Val 110 att agt act Ile Ser Thr aat caa aaa Asn Gin Lys 130 aaa ata tct ggg Lys Ile Ser Gly att tca aat att Ile Ser Asn Ile tgt agt aga Cys Ser Arg 125 tgt tta act Cys Len Thr gaa aat gaa caa Glu Asn Giu Gin aaa Lys 135 aga aat aaa caa Arg Asn Lys Gin caa tgt Gin Cys 145 cac act tat aat His Thr Tyr Asn atg Met 150 tca cat gaa cag Ser His Glu Gin gac Asp 155 aaa cta gct aat Lys Leu Ala Asn gat Asp 160 aat aat agg aat Asn Asn Arg Asn aaa aag aat ttt Lys Lys Asn Phe tta tta ttt ata Leu Leu Phe Ile 602 650 698 tat ttt aat ttg Tyr Phe Asn Len aaa Lys 180 cga atg aaa aat Arg Met Lys Asn tct Ser 185 ctt cta aat aaa Leu Len Asn Lys gac aat Asp Asn 190 ttc ttt tac Phe Phe Tyr aaa aaa aaa Lys Lys Lys 210 aaa gaa aaa aaa Lys Giu Lys Lys ttg Leu 200 tca ttt ctg cat Ser Phe Leu His aag gcc tat Lys Ala Tyr 205 aga aaa tct Arg Lys Ser 746 794 aat tgc act ttt Asn Cys Thr Phe caa Gin 215 aat tat agt tta Asn Tyr Ser Len -WO 00/17233 PCT/EP99/07055 -7aat cgt gat tca cat aaa ttg ttt tct gga gaa ttt Asn Arg Asp Ser His Lys Leu Phe Ser Gly Glu Phe 225 230 235 gac gat tat aca Asp Asp Tyr Thr aat Asn 240 aat aat get tta Asn Asn Ala Leu gaa tcc gaa aaa Glu Ser Glu Lys aaa Lys 250 gaa tac att aca Glu Tyr Ile Thr aat aat aat aat Asn Asn Asn Asn aaa Lys 260 aat aat aat aat Asn Asn Asn Asn aat aat gat aat Asn Asn Asp Asn aaa aat Lys Asn 270 aat gat aat Asn Asp Asn gag aga tec Glu Arg Ser 290 gat tat aat aat Asp Tyr Asn Asn aat Asn 280 aat agt tgt aat Asn Ser Cys Asn aat tta gga Asn Leu Gly 285 aat aat cca Asn Asn Pro 986 1034 aat cat tat gat Asn His Tyr Asp tat ggt gga gat Tyr Gly Gly Asp aat Asn 300 tgt aat Cys Asn 305 aat aat aat gac Asn Asn Asn Asp aaa Lys 310 tat gat ata gga Tyr Asp Ile Gly tat ttc aaa cag Tyr Phe Lys Gin att Ile 320 aat acc ttt att Asn Thr Phe Ile att gat gaa tat Ile Asp Glu Tyr aaa Lys 330 act ata tat ggt Thr Ile Tyr Gly gat Asp 335 1082 1130 1178 gaa ata tat aaa Glu Ile Tyr Lys gaa Glu 340 ata tat gaa cta Ile Tyr Glu Leu gta gaa aga aat Val Glu Arg Asn att cct Ile Pro 350 gaa tat tat Glu Tyr Tyr cta ttt gat Leu Phe Asp 370 cga aaa tat ttt Arg Lys Tyr Phe tca Ser 360 gaa gat att aaa Glu Asp Ile Lys aag agt gtc Lys Ser Val 365 aaa gct ata Lys Ala Ile 1226 1274 ata gat aaa tat Ile Asp Lys Tyr gat gtc gaa ttt Asp Val Glu Phe gaa Glu 380 aaa gaa Lys Glu 385 gaa ttt ata aat Glu Phe Ile Asn aat Asn 390 gga gtt tat att Gly Val Tyr Ile aat ata gat aat Asn Ile Asp Asn aca Thr 400 tat tat aaa aaa Tyr Tyr Lys Lys aat att tta ata Asn Ile Leu Ile atg Met 410 aaa aag ata tta Lys Lys Ile Leu 1322 1370 1418 tat ttc cca tta Tyr Phe Pro Leu tta Leu 420 aaa tta att aat Lys Leu Ile Asn cca tca gat tta Pro Ser Asp Leu aaa aag Lys Lys 430 tta aaa aaa Leu Lys Lys caa Gin 435 tat tta cct tta Tyr Leu Pro Leu tta Leu 440 gca cat gaa tta Ala His Glu Leu aaa ata ttt Lys Ile Phe 445 1466 WO 00/17233 PCT/EP99/07055 tta ttt ttt Leu Phe Phe 450 att gta aat ata Ile Val Asn Ile aca Thr 455 gga ggt cat ttt Gly Gly His Phe tct gtt tta Ser Val Leu 1514 agc tct Ser Ser 465 tta gaa att caa Leu Giu Ile Gin tta tta ttg tat Leu Leu Leu Tyr ttt aat caa cca Phe Asn Gin Pro tat Tyr 480 gat aat qtt ata Asp Asn Val Ile tat Tyr 485 gat ata gga cat Asp Ile Gly His caa Gin 490' gca tat gta cat Ala Tyr Vai His aaq Lys 495 1562 1610 1658 ata ttq acc gga Ile Leu Thr Gly aga Arg 500 aaa cta tta ttt Lys Leu Leu Phe cta Leu 505 tca tta aga aat Ser Leu Arg Asn aaa aaa Lys Lys 510 ggt att agt Gly Ile Ser ggg gct ggt Gly Ala Gly 530 gga Gly 515 ttc cta aat att Phe Leu Asn Ile ttt Phe 520 gaa agt att tat Glu Ser Ile Tyr gat aaa ttt Asp Lys Phe 525 gga tat tat Gly Tyr Tyr 1706 1754 cac aqt tcc act His Ser Ser Thr tta agt gct ata Leu Ser Ala Ile gaa gcc Glu Ala 545 gag tgg caa gtg Glu Trp Gin Val aag Lys 550 aat aaa gaa aaa Asn Lys Giu Lys gga aat qga gat Gly Asn Gly Asp ata Ile 560 gaa ata agt gat Glu Ile Ser Asp gca aat gtc acg Ala Asn Val Thr aat gaa agg ata Asn Glu Arg Ile 1802 1850 1898 caa aaa gga ata Gin Lys Gly Ile cac His 580 aat gat aat aat Asn Asp Asn Asn aac aat aat att Asn Asn Asn Ile aat aat Asn Asn 590 aat aat tat Asn Asn Tyr gta cca aat Val Pro Asn 610 aat cct tca gat Asn Pro Ser Asp gtg Va1 600 gta gga aga gaa Val Gly Arg Glu aat acg aat Asn Thr Asn 605 gta cac att Val His Ile 1946 1994 gta cga aat gat Val Arg Asn Asp cat aac gtg gat His Asn Vai Asp aaa Lys 620 gct att Ala Ile 625 ata gga gat ggt Ile Giy Asp Gly ggt Gly 630 tta aca ggt gga Leu Thr Gly Gly gca tta qaa gcg Ala Leu Giu Ala tta aat tat att tca Leu Asn Tyr Ile Ser 640 gat aac gga caa gtt Asp Asn Giy Gin Val 660 ttc Phe 645 ttg aat tct aaa Leu Asn Ser Lys tta att att tat Leu Ile Ile Tyr 2042 2090 2138 tct tta cca aca Ser Leu Pro Thr aat gcc Asn Ala 665 gta agt ata Val Ser Ile tca ggt Ser Gly 670 WO 00/17233 PCT/EP99/07055 aat aga cct Asn Arg Pro aat ata gaa Asn Ile Glu 690 ggt tct ata tca Gly Ser Ile Ser gat Asp 680 cat tta cat tat His Leu His Tyr ttt gtt tct Phe Val Ser 685 aat gca aaa Asn Ala Lys 2186 2234 gca aat gct ggt Ala Asn Ala Gly aat aaa tta tcg Asn Lys Leu Ser aaa Lys 700 gag aat Glu Asn 705 aac att ttt gaa Asn Ile Phe Glu aat Asn 710 ttg aat tat gat Leu Asn Tyr Asp att ggt gtt gtg Ile Gly Val Val aat Asn 720 ggt aat aat aca Gly Asn Asn Thr gag ctc ttt aaa Glu Leu Phe Lys gta Val 730 tta aat aat ata Leu Asn Asn Ile 2282 2330 2378 gaa aat aaa tta Glu Asn Lys Leu aaa Lys 740 aga gct act gtt Arg Ala Thr Val cat gta cgt aca His Val Arg Thr aaa aaa Lys Lys 750 tcg aat gat Ser Asn Asp ata aag aaa Ile Lys Lys 770 ata aat tca aag Ile Asn Ser Lys agt Ser 760 cca ata agt ata Pro Ile Ser Ile ttg cac tct Leu His Ser 765 tta aat gga Leu Asn Gly 2426 2474 aat gag att ttc Asn Glu Ile Phe ttc gat acc act Phe Asp Thr Thr aat att Asn Ile 785 cat aag gag aac His Lys Glu Asn aag Lys 790 ata gaa gaa gag Ile Glu Glu Glu aat gtg tct tca Asn Val Ser Ser tct Ser 800 aca aag tat gat Thr Lys Tyr Asp aat aat aag aat Asn Asn Lys Asn aat Asn 810 aaa aat aat gat Lys Asn Asn Asp 2522 2570 2618 agt gaa att ata Ser Glu Ile Ile aaa Lys 820 tat gaa gat atg Tyr Glu Asp Met tca aaa gag acg Ser Lys Glu Thr ttc aca Phe Thr 830 gat ata tat Asp Ile Tyr ata ata ttc Ile Ile Phe 850 aca Thr 835 aat gaa atg tta Asn Glu Met Leu aaa Lys 840 tat tta aag aaa Tyr Leu Lys Lys gat aga aat Asp Arg Asn 845 ttg gtt aaa Leu Val Lys 2666 2714 cta tct ccc get Leu Ser Pro Ala tta gga gga tca Leu Gly Gly Ser att agt Ile Ser 865 gag cgt tat cca Glu Arg Tyr Pro aat Asn 870 aat gta tat gat Asn Val Tyr Asp ggt ata gca gaa Gly Ile Ala Glu 2762 2810 cat tct gta act His Ser Val Thr gca gca gct atg Ala Ala Ala Met gca Ala 890 atg aat aag aaa Met Asn Lys Lys WO 00/17233 PCT/EP99/07055 aaa ata caa tta Lys Ile Gin Leu tgt Cys 900 ata tat tcg acc Ile Tyr Ser Thr tta caa aga gca Leu Gin Arg Ala tat gat Tyr Asp 910 2858 caa att ata Gin Ile Ile att gga aga Ile.Gly Arg 930 gat ctt aat tta Asp Leu Asn Leu caa Gin 920 aat ata cct tta Asn Ile Pro Leu aag gtt ata Lys Val Ile 925 cat caa ggt His Gin Gly 2906 2954 agt gga tta gta Ser Gly Leu Val gag gat ggg gca Glu Asp Gly Ala ata tat Ile Tyr 945 gat tta tct tat Asp Leu Ser Tyr ctt Leu 950 ggg aca ctt aac Gly Thr Leu Asn gca tat ata ata Ala Tyr Ile Ile tct Ser 960 cca agt aat caa Pro Ser Asn Gin gat ttg aaa aga Asp Leu Lys Arg gct Ala 970 ctt agg ttt gct Leu Arg Phe Ala tat Tyr 975 3002 3050 3098 tta gat aag gac Leu Asp Lys Asp cat His 980 tct gtg tat ata Ser Val Tyr Ile ata ccc aga atg Ile Pro Arg Met aac ata Asn Ile 990 tta agt gat Leu Ser Asp gag age aaa Glu Ser Lys 1010 aag Lys 995 tac atg aaa gga tat Tyr Met Lys Gly Tyr 1000 ttg aac att cat Leu Asn Ile His atg aaa aat Met Lys Asn 1005 gat gta gat Asp Val Asp 3146 3194 aat atc gat gta aac Asn Ile Asp Val Asn 1015 gtg gat ata aac Val Asp Ile Asn gat Asp 1020 aaa tat Lys Tyr 1025 att gga Ile Gly 1040 agt gaa gaa tat atg Ser Glu Glu Tyr Met 1030 gac gat gat aat ttt Asp Asp Asp Asn Phe 1035 ata aaa tcg ttt Ile Lys Ser Phe 3242 3290 aaa tct aga att Lys Ser Arg Ile 1045 att aaa atg gat aat Ile Lys Met Asp Asn 1050 gaa aat aat aat aca Glu Asn Asn Asn Thr 1055 aat gaa cat tat tca Asn Glu His Tyr Ser 1060 age aga gga gat aca cag aca aaa aaa Ser Arg Gly Asp Thr Gin Thr Lys Lys aaa aaa Lys Lys 1070 1065 gtt tgt atc ttt aac atg ggt agt atg ctt ttt aat gta att aat get Val Cys Ile Phe Asn Met Gly Ser Met Leu Phe Asn Val Ile Asn Ala 1075 1080 1085 3338 3386 3434 3482 ata aaa gaa att gaa aaa gaa caa tat att tca cat aat tat tct ttt Ile Lys Glu Ile Glu Lys Glu Gin Tyr Ile Ser His Asn Tyr Ser Phe 1090 1095 1100 tca att gtt gat atg ata ttt tta aat cct tta gat aaa aat atg ata Ser Ile Val Asp Met Ile Phe Leu Asn Pro Leu Asp Lys Asn Met Ile 1105 1110 1115 WO 00/17233 PCT/EP99/07055 -11gat cat gta.ata aaa caa aat aaa cat caa tat tta att act tat gaa 3530 Asp His Val Ile Lys Gin Asn Lys His Gin Tyr Leu Ile Thr Tyr Glu 1120 1125 1130 1135 gat aat act ata ggt ggt ttt tct aca cat ttc aat aat tat tta ata 3578 Asp Asn Thr Ile Gly Gly Phe Ser Thr His Phe Asn Asn Tyr Leu Ile 1140 1145 1150 gaa aat aat tat att aca aaa cat aac tta tat gtt cat aat att tat 3626 Glu Asn Asn Tyr Ile Thr Lys His Asn Leu Tyr Val His Asn Ile Tyr 1155 1160 1165 tta tct aat gag cca att gaa cat gca tct ttt aag gat caa caa gaa 3674 Leu Ser Asn Glu Pro Ile Glu His Ala Ser Phe Lys Asp Gin Gin Glu 1170 1175 1180 gtc gtc aaa atg gat aaa tgt agt ctt gtc aat aga att aaa aat tat 3722 Val Val Lys Met Asp Lys Cys Ser Leu Val Asn Arg Ile Lys Asn Tyr 1185 1190 1195 ctt aaa aat aat cct aca tgatgtaaga taaatatata tttctaaaat 3770 Leu Lys Asn Asn Pro Thr 1200 1205 tatttttttt ttatacttta atgtgtacaa taaaatatat atctaaatat attttatttg 3830 tacgcttttt tttttttttt tttaattgtt atttttgtat at 3872 <210> 4 <211> 1205 <212> PRT <213> Plasmodium falciparum <400> 4 Met Ile Phe Asn Tyr Val Phe Phe Lys Asn Phe Val Pro Val Val Leu 1 5 10 Tyr Ile Leu Leu Ile Ile Tyr Ile Asn Leu Asn Gly Met Asn Asn Lys 25 Asn Gin Ile Lys Thr Glu Lys Ile Tyr Ile Lys Lys Leu Asn Arg Leu 40 Ser Arg Lys Asn Ser Leu Cys Ser Ser Lys Asn Lys Ile Ala Cys Leu 55 Phe Asp Ile Gly Asn Asp Asp Asn Arg Asn Thr Thr Tyr Gly Tyr Asn 70 75 Val Asn Val Lys Asn Asp Asp Ile Asn Ser Leu Leu Lys Asn Asn Tyr 90 Ser Asn Lys Leu Tyr Met Asp Lys Arg Lys Asn Ile Asn Asn Val Ile 100 105 110 Ser Thr Asn Lys Ile Ser Gly Ser Ile Ser Asn Ile Cys Ser Arg Asn 115 120 125 WID 00/17233 WO 00/ 7233PCT/EP99/07055 12 Gin Lys Giu Asn Glu Gin Lys Arg Asn 130 135 Cys 145 Asn Phe Phe Lys Arg 225 Asn Asn Asp Arg As n 305 Asn Ile Tyr Phe Giu 385 Tyr His Asn Asin Tyr Lys 210 Asp Asn Asn As n Ser 290 Asn Thr Tyr Tyr Asp 370 Glu Tyr Tyr Asn Lys 180 Lys Cys His Leu Lys 260 Asp His Asn Ile Giu 340 Arg Asp Ile Lys Asn Asn 165 Arg Giu Thr Lys Tyr 245 As n Tyr Tyr Asp Asn 325 Ile Lys Lys Asn Giu 405 Met 150 Lys Met Lys Phe Leu 230 Giu Asn Asn Asp Lys 310 Ile T yr Tyr Tyr As n 390 Asn Ser Lys Lys Lys Gin 215 Phe Ser As n Asn Asn 295 Tyr Asp Giu Phe As n 375 Giy Ile His Asn Asn Leu 200 Asn Ser Glu Asn Asn 280 T yr Asp Giu Leu Ser 360 Asp Vai Leu Giu Phe Ser 185 Ser Tyr Gly Lys Lys 265 Asn Giy Ile Tyr Tyr 345 Giu Vali Tyr Ile Lys Gin Asn 170 Leu Phe Ser Giu Lys 250 Asn Ser Gly Giy Lys 330 Val1 Asp Giu Ile Met 410 Gin Asp 155 Leu Leu Leu Leu Phe 235 Giu As n Cys Asp Lys 315 Thr Giu Ile Phe Asn 395 Lys Arg 140 Lys Leu As n His Lys 220 Asp Tyr Asp As n As n 300 Tyr Ie Ar g Lys Giu 380 As n Lys Cys Leu Phe Lys Lys 205 Arg Asp Ile As n As n 285 Asn Phe Tyr As n Lys 365 Lys Ile Ile Leu Aia Ile Asp 190 Aia Lys Tyr Thr Lys 270 Leu Asn Lys Giy Ile 350 Ser Aila Asp Leu Thr Asn As n 175 Asn Tyr Ser Thr Leu 255 Asn Giy Pro Gin Asp 335 Pro Vai Ile Asn His 415 Gin Asp 160 T yr Phe Lys Asn Asn 240 As n Asn Giu Cys Ile 320 Giu* Giu Leu Lys Thr 400 T yr Phe Pro Leu Leu Lys Leu Ile Asn Asn Pro Ser Asp Leu Lys Lys Leu 00/17233 WO 0017233PCT/EP99/07055 13 Lys Phe Ser 465 Asp Leu Ile Al a Al a 545 Giu Lys As n Pro Ile 625 Asn As n Arg Ile Asn 705 Gly Lys Phe 450 Leu Asn Thr Ser Gly 530 Giu Ile Gly Tyr Asn 610 Ile Tyr Gly Pro Glu 690 Asn As n Gin 435 Ile Glu Val Giy Gly 515 His Trp Ser Ile Ile 595 Val1 Gly Ile Gin Ile 675 Ala Ile As n Tyr Vali Ile Ile Arq 500 Phe Ser Gin Asp His 580 Asn Arg Asp Ser Val1 660 Giy As n Phe Thr Leu Asn Gin Tyr 485 Lys Leu Ser Vai Asn 565 Asn Pro Asn Giy Phe 645 Ser Ser Ala Giu Giu 725 Leu Thr 455 Leu Ile Leu Ile Ser 535 As n Asn As n Asp Asn 615 Leu As n Pro Ser Asp 695 Leu Leu Leu 440 Giy Leu Gly Phe Phe 520 Leu Lys Val Asn Vai 600 His Thr Ser Thr Asp 680 Asn As n Phe Al a Gly Leu His Leu 505 Giu Ser Giu Thr Ile 585 Val Asn Giy Lys Asn 665 His Lys Tyr Lys Giu Phe Ile 475 Aia Leu Ile Ile Tyr 555 As n As n Arg Asp Met 635 Leu Vai His Ser T yr 715 Leu Leu Ser 460 Phe Tyr Ar g Tyr Gin 540 Gly Giu As n Giu Lys 620 Al a Ile Ser Tyr Lys 700 Ile Asn Lys 445 Ser As n Val1 Asn Asp 525 Giy As n Arg Ile As n 605 Val1 Leu Ile Ile Phe 685 As n Gly Asn Phe Leu Pro Lys 495 Lys Phe Tyr Asp Phe 575 Asn Asn Ile Ala Asn 655 Gly Ser Lys Val1 Lys 735 WO 00/17233 PCT/EP99/07055 -14- Asn Lys Leu Lys Arg Ala Thr Val Leu His Val Arg Thr Lys Lys Ser 740 745 750 Asn Asp Phe Ile Asn Ser Lys Ser Pro Ile Ser Ile Leu His Ser Ile 755 760 765 Lys Lys Asn Glu Ile Phe Pro Phe Asp Thr Thr Ile Leu Asn Gly Asn 770 775 780 Ile His Lys Glu Asn Lys Ile Glu Glu Glu Lys Asn Val Ser Ser Ser 785 790 795 800 Thr Lys Tyr Asp Val Asn Asn Lys Asn Asn Lys Asn Asn Asp Asn Ser 805 810 815 Glu Ile Ile Lys Tyr Glu Asp Met Phe Ser Lys Glu Thr Phe Thr Asp 820 825 830 Ile Tyr Thr Asn Glu Met Leu Lys Tyr Leu Lys Lys Asp Arg Asn Ile 835 840 845 Ile Phe Leu Ser Pro Ala Met Leu Gly Gly Ser Gly Leu Val Lys Ile 850 855 860 Ser Glu Arg Tyr Pro Asn Asn Val Tyr Asp Val Gly Ile Ala Glu Gin 865 870 875 880 His Ser Val Thr Phe Ala Ala Ala Met Ala Met Asn Lys Lys Leu Lys 885 890 895 Ile Gin Leu Cys Ile Tyr Ser Thr Phe Leu Gin Arg Ala Tyr Asp Gin 900 905 910 Ile Ile His Asp Leu Asn Leu Gin Asn Ile Pro Leu Lys Val Ile Ile 915 920 925 Gly Arg Ser Gly Leu Val Gly Glu Asp Gly Ala Thr His Gin Gly Ile 930 935 940 Tyr Asp Leu Ser Tyr Leu Gly Thr Leu Asn Asn Ala Tyr Ile Ile Ser 945 950 955 960 Pro Ser Asn Gin Val Asp Leu Lys Arg Ala Leu Arg Phe Ala Tyr Leu 965 970 975 Asp Lys Asp His Ser Val Tyr Ile Arg Ile Pro Arg Met Asn Ile Leu 980 985 990 Ser Asp Lys Tyr Met Lys Gly Tyr Leu Asn Ile His Met Lys Asn Glu 995 1000 1005 Ser Lys Asn Ile Asp Val Asn Val Asp Ile Asn Asp Asp Val Asp Lys 1010 1015 1020 Tyr Ser Glu Glu Tyr Met Asp Asp Asp Asn Phe Ile Lys Ser Phe Ile 1030 1035 1040 WO 00/17233 PCT/EP99/07055 Gly Lys Ser Arg Ile Ile Lys Met Asp Asn Glu Asn Asn Asn Thr Asn 1045 1050 1055 Glu His Tyr Ser Ser Arg Gly Asp Thr Gin Thr Lys Lys Lys Lys Val 1060 1065 1070 Cys Ile Phe Asn Met Gly Ser Met Leu Phe Asn Val Ile Asn Ala Ile 1075 1080 1085 Lys Glu Ile Glu Lys Glu Gin Tyr Ile Ser His Asn Tyr Ser Phe Ser 1090 1095 1100 Ile Val Asp Met Ile Phe Leu Asn Pro Leu Asp Lys Asn Met Ile Asp 105 1110 1115 1120 His Val Ile Lys Gin Asn Lys His Gin Tyr Leu Ile Thr Tyr Glu Asp 1125 1130 1135 Asn Thr Ile Gly Gly Phe Ser Thr His Phe Asn Asn Tyr Leu Ile Glu 1140 1145 1150 Asn Asn Tyr Ile Thr Lys His Asn Leu Tyr Val His Asn Ile Tyr Leu 1155 1160 1165 Ser Asn Glu Pro Ile Glu His Ala Ser Phe Lys Asp Gin Gin Glu Val 1170 1175 1180 Val Lys Met Asp Lys Cys Ser Leu Val Asn Arg Ile Lys Asn Tyr Leu 185 1190 1195 1200 Lys Asn Asn Pro Thr 1205 <210> <211> 3147 <212> DNA <213> Plasmodium falciparum <220> <221> CDS <222> (199)..(2670) <400> tttcattttt ctttacccac atatatatat atatatatat aatatatata tataatatta tatatttgat atatgattta aaattgtaac ataaaaaaaa taattatatt aaatatgtgt 120 atacatctcc aacatataaa tattattttt tattattatt tttttttttt tttttcataa 180 tgcctgaata accacaaa atg agt tat ata aaa aga ctg att ctt ttt atg 231 Met Ser Tyr Ile Lys Arg Leu Ile Leu Phe Met 1 5 tta ctg ttt tat tct cat gta aaa att aaa aaa tta ttt att aaa att 279 Leu Leu Phe Tyr Ser His Val Lys Ile Lys Lys Leu Phe Ile Lys Ile 20 WO 00/17233 PCT/EP99/07055 -16tct aat gta Ser Asn Val aac ata ttt ttt Asn Ile Phe Phe gaa qca aag aaa Glu Ala Lys Lys qga aaa aaq Gly Lys Lys gaa ttc Glu Phe ttt ctt ttt tta Phe Leu Phe Leu cta Leu 50 aat ata aaa aaa Asn Ile Lys Lys aat Asn agc caa cag aaa Ser Gin Gin Lys act tat cat att Thr Tyr His Ile acc Thr aaa agg aat acc Lys Arg Asn Thr ata Ile aat aaa agt gat Asn Lys Ser Asp tta tat tct tta Leu Tyr Ser Leu aat qaa gaa ggg Asn Glu Giu Gly tct tca aaa aag Ser Ser Lys Lys gaa tat Glu Tyr aaa aat tta Lys Asn Leu aaa tat tgt Lys Tyr Cys 110 aaa Lys gat gaa gaa aaa Asp Giu Giu Lys tat Tyr 100 aat atc ata caa Asn Ile Ile Gin aat ata aaa Asn Ile Lys 105 aca cga gaa Thr Arg Glu gaa tgt act aaa Glu Cys Thr Lys tat aaa agg ctc Tyr Lys Arg Leu gta gtt Vai Val 125 att gga aat gtt Ile Gly Asn Val att qga gga aat Ile Giy Giy Asn aat Asn 135 aaa ata gct att Lys Ile Ala Ile act atg gct agc Thr Met Ala Ser tgt Cys 145 gat aca aga aat gta gaa gaa tgt gta Asp Thr Arg Asn Vai Glu Giu Cys Val 150 caa att aga aaa Gin Ile Arg Lys aaa qat ttg ggt Lys Asp Leu Gly gac att gta agg Asp Ile Vai Arg ttg act Leu Thr 170 qtt caa gga Val Gin Gly tta tta tct Leu Leu. Ser 190 gtt Va1 175 caa gaa gca caa Gin Giu Ala Gin gct Ala 180 agt tat cat att Ser Tyr His Ile aaa gaa aaa Lys Giu Lys 185 att cat ttt Ile His Phe gaa aat gta aat Glu Asn Val Asn cca tta gta gca Pro Leu Val Ala gat Asp 200 aat cct Asn Pro 205 aaa ata gct tta Lys Ile Ala Leu atg Met 210 gca gct gat gtg Ala Ala Asp Val ttt Phe 215 gaa aaa att cga Glu Lys Ile Arg aat cca gga aat Asn Pro Gly Asn tat Tyr 225 gtt gat gqa aga Val Asp Gly Arg aaa Lys 230 aaa tgg ata gat Lys Trp Ile Asp gtt tat aaa act Val Tyr Lys Thr gaa gaa ttt gat Glu Giu Phe Asp ggg aaa tta ttt Gly Lys Leu Phe ata aaa Ile Lys 250 00/17233 WO 0017233PCT/EP99/07055 17 gaa aaa ttt Glu Lys Phe ata aga att Ile Arg Ile 270 gta Val 255 coa tta att gaa Pro Leu Ile Glu aaa tgt aaa aga tta *aat aga goa Lys Cys Lys Arg Leu Asn Arg Ala 260 265 gga aca aat cat Gly Thr Asn His gga Gly 275 tcc ctt tca tct Ser Leu Ser Ser cga Arg 280 gta tta tca Val Leu Ser 1047 tat tat Tyr Tyr 285 gga gat aca cca Gly Asp Thr Pro tta Leu 290 ggt atg gta gaa Gly Met Val Glu gct ttt gag ttt Ala Phe Glu Phe tot Ser 300 gat tta tgt att Asp Leu Cys Ile gaa Glu 305 aac aat ttt tac Asn Asn Phe Tyr aat Asn 310 ctt gtt ttt tot Leu Val Phe Ser 1095 1143 1191 aaa got tot aat Lys Ala Ser Asn tat. gtt atg ata Tyr Val Met Ile tot tat aga tta Ser Tyr Arg Leu tta gta Leu Val 330 tot aaa oaa Ser Lys Gin aca gaa goa Thr Glu Ala 350 tat Tyr 335 gaa aga aat Giu Arg Asn atg atg Met Met 340 tto oot ata oat Phe Pro Ile His tta gga gtt Leu Gly Vai 345 tat tta ggt Tyr Leu Gly 1239 1287 gga ttt ggt gat Gly Phe Gly Asp gga aga ata aaa Gly Arg Ile Lys tot Ser 360 ata gga Ile Gly 365 tot tta tta tat Ser Leu Leu Tyr gat Asp 370 ggt ata gga gat Gly Ile Gly Asp att ogt ata too Ile Arg Ile Ser aoa gaa gat oot Thr Giu Asp Pro gaa gag tta aot Giu Glu Leu Thr oot Pro 390 tgt aaa aaa tta Cys Lys Lys Leu 1335 1383 1431 gaa aat tta aag Giu Asn Leu Lys aaa Lys 400 aga ata ttt tat Arg Ile Phe Tyr gaa aat ttt aaa Glu Asn Phe Lys gaa gat Giu Asp 410 aat gaa tta Asn Glu Leu gaa gaa aat Giu Giu Asn 430 aaa Lys 415 aat aat gaa atg Asn Asn Glu Met gat Asp 420 aoo aaa aat ota Thr Lys Asn Leu tta aat ttt Leu Asn Phe 425 aat gta gaa Asn Vai Glu 1479 1527 tat oga aat ttt Tyr Arg Asn Phe aat ata aaa aaa Asn Ile Lys Lys aaa aat Lys Asn 445 aat aat gta tta Asn Asn Vai Leu oat His 450 gaa gag tgo aot Glu Glu Cys Thr ggt aat gta gta Gly Asn Val Val 1575 1623 ata aaa gag tta Ile Lys Glu Leu gat tot otg oaa Asp Ser Leu Gin att Ile 470 ttt aaa gat tta Phe Lys Asp Leu aat As n 475 WO 00/17233 PCT/EP99/07055 18tta gaa gta gat Leu Glu Val Asp tca Ser 480 aat gga aat ttg Asn Gly Asn Leu aag gga gc aaa Lys Gly Ala Lys aca act Thr Thr 490 1671 gat atg gtt Asp Met Val aaa act gtg Lys Thr Val 510 ata aat qat ttt Ile Asn Asp Phe cat His 500 aat ata aca aat Asn Ile Thr Asn tta gga aaa Leu Gly Lys 505 gta gtt caa Val Val Gin 1719 1767 gat aaa tta atg Asp Lys Leu Met gtg gga att aat Vai Giy Ile Asn ata Ile 520 tat gaa Tyr Glu 525 cca cat aat ata Pro His Asn Ile gaa Glu 530 ttt ata gaa aaa Phe Ile Giu Lys gaa cca aat aat Glu Pro Asn Asn gat Asp 540 aat aat aat aat Asn Asn Asn Asn aat aat aat aat Asn Asn Asn Asn ata Ile 550 tta ttt tat gtg Leu Phe Tyr Val 1815 1863 1911 ata aaa aat att Ile Lys Asn Ile atg Met 560 aac agt tca gaa Asn Ser Ser Glu aat att aaa tta Asn Ile Lys Leu agt aat Ser Asn 570 tct aaa gga Ser Lys Gly ata aaa aaa Ile Lys Lys 590 gga tta att tta Gly Leu Ile Leu aac Asn 580 gga aaa gaa gat Gly Lys Giu Asp ata caa acc Ile Gin Thr 585 att cta tta Ile Leu Leu 1959 2007 ata aaa gaa tta Ile Lys Giu Leu cgt cgt cct tta Arg Arg Pro Leu ttc Phe 600 aaa tca Lys Ser 605 gat aac ata tat Asp Asn Ile Tyr gaa Glu 610 cat gta tta ata His Val Leu Ile aga aga att aat Arg Arg Ile Asn gaa Glu 620 ctt tta caa tcc Leu Leu Gin Ser aat ata aat ata Asn Ile Asn Ile cct Pro 630 tat ata cat tat Tyr Ile His Tyr 2055 2103 2151 gat att aat tca Asp Ile Asn Ser aac Asn 640 aat tat gat gat Asn Tyr Asp Asp tta gtt aat tca Leu Val Asn Ser aca tta Thr Leu 650 tat gca gga Tyr Ala Gly aac gta act Asn Val Thr 670 tgt ttg atg gat Cys Leu Met Asp tta Leu 660 atg ggg gat ggt Met Gly Asp Gly ctt att gtt Leu Ile Val 665 gaa aca aaa Glu Thr Lys 2199 2247 aat gat gtt ctt Asn Asp Val Leu aat aaa aaa aag Asn Lys Lys Lys tat gat Tyr Asp 685 gaa aaa gaa gaa Glu Lys Glu Glu gta Va1 690 gag gaa gag gga Glu Giu Giu Gly aac Asn 695 aat aaa gat att Asn Lys Asp Ile 2295 WO 00/17233 WO 0017233PCT/EP99/07055 19 aga ctt ttg agc Arg Leu Leu Ser aga Arg 705 aga Arg gtt gca tta aat Val Ala Leu Asm tca Ser 710 aaa Lys ttt tta aca tta Phe Leu Thr Leu aat Asn 715 tta caa gat Leu Gin Asp aca Thr 720 gga Gly ata cgt tta Ile Arg Leu aca gat tat Thr Asp Tyr ata gcc Ile Ala 730 tgc cca tct Cys Pro Ser aaa att atg Lys Ile Met 750 atg gga tgt Met Gly Cys aga act tta Arg Thr Leu ttt Phe 740 tta Leu ata caa gaa Ile Gin Giu tta aca ggg Leu Thr Giy aaa ggc gtt Lys Gly Val act act aaa Thr Thr Lys 745 att gca gtc Ile Aia Vai gca cat ttt Ala His Phe 2343 2391 2439 2487 2535 2583 2631 2680 att gtt aat Ile Val Asn 765 ggt tat Giy Tyr ggt Gly 770 cct Pro gga gaa atg Gly Giu Met gca Aila 775 tta Leu gtt ggt agt Val Gly Ser aaa aaa att Lys Lys Ile 780 gag Glu gat Asp 790 gaa Glu tat tat ggt Tyr Tyr Gly aaa Lys 795 tta gta gaa Leu Vai Giu a ga Arg 800 aaa Lys ata cct gag Ile Pro Giu gct tgt Ala Cys gat aaa tt Asp Lys Le' 810 taaattgaat g uata gaa tta att Ile Giu Leu Ile 815 aaa cat aac aaa Lys His Asn Lys 820 aaa gat cca.

Lys Asp Pro atggacaagt tatttttcct tgcatacata gactaatacc tatatatata aaaatataat atatgttaat atatatatat atttatttat tttaaaattt atattaaaat aagaacaatt tatttattta aatttaaaag ggaaaaggag actgaatgag ttatttatct tatttttttt gtgtattata ttttaataat tttatattta tatttacaaa aaaataaata aaagaaaaaa tatatataat ttattttttt taataatatc cattcttata tatttattta ataaataata aataaaacaa aaaagaaaag atattataaa ttttgaagta attttattgt acttgttaaa tttttggtat ttatatatct acaaaataac gatacga tttttcgatg atatttataa tattttaaaa tatatatata atgaaaagta gtttttatat atatatatat 2740 2800 2860 2920 2980 3040 3100 3147 <210> 6 <211> 824 <212> PRT <213> Plasmodium faiciparum <400> 6 Met Ser Tyr Ile Lys Arg Leu Ile Leu Phe Met Leu Leu Phe Tyr Ser 1 5 10 WO 00/17233 WO 0017233PCTIEP99/07055 20 His Phe Leu Thr Asn Giu Thr Val Cys 145 Lys Glu Val1 Leu Tyr 225 Giu Leu Asn Pro Glu 305 Val1 Phe Leu Lys Giu Giu Lys Lys 130 Asp Asp Ala As n Met 210 Val1 Glu Ile His Leu 290 Asn Lys Al a Asn Arg Glu Lys Lys 115 Ile Thr Leu Gin Ile 195 Ala Asp Phe Glu Gly 275 Gly As n Ile Giu Ile Asn Gly Tyr 100 Tyr Gly Arg Gly Al a 180 Pro Al a Gly Asp Lys 260 Ser Met Phe Lys Ala Lys Thr Asn Asn Lys Gly As n Al a 165 Ser Leu Asp Arg Giu 245 Cys Leu Val1 Tyr Lys Lys Lys Ile 70 Ser Ile Arg Asn Val 150 Asp T yr Val1 Val Lys 230 Gly Lys Ser Giu Asn 310 Leu Lys Asn As n Ser Ile Leu Asn 135 Giu Ile His Ala Phe 215 Lys Lys Arg Ser Ser 295 Leu Phe Asn 40 Ser Lys Lys Gin Pro 120 Lys Giu Val1 Ile Asp 200 Giu T rp Leu Leu Arg 280 Al a Val1 Ile 25 Gly Gin Ser Lys Asn 105 Thr I le Cys Arg Lys 185 Ile Lys Ile Phe Asn 265 Val Phe Phe Lys Lys Gln Asp Giu Ile Arg Ala Val Leu 170 Glu His Ile Asp Ile 250 Arg Leu Giu Ser Ile Lys Lys Phe T yr Lys Giu Ile Tyr 155 Thr Lys Phe Arg Lys 235 Lys Ala Ser Phe Met 315 As n Phe Thr T yr Asn Tyr Val 125 Thr Ile Gin Leu Pro 205 Asn Tyr Lys Arg Tyr 285 Asp Al a Val1 Phe Tyr Ser Leu Cys 110 Ile Met Arg Gly Ser 190 Lys Pro Lys Phe Ile 270 Gly Leu Ser Tyr Val Met Ile Gin Ser Tyr Arq Leu Leu Val Ser Lys Gin Tyr Glu WO 00/17233 PCT/EP99/07055 -21- 325 330 335 Arg Asn Met Met Phe Pro Ile His Leu Gly Val Thr Glu Ala Gly Phe 340 345 350 Gly Asp Asn Gly Arg Ile Lys Ser Tyr Leu Gly Ile Gly Ser Leu Leu 355 360 365 Tyr Asp Gly Ile Gly Asp Thr Ile Arg Ile Ser Leu Thr Glu Asp Pro 370 375 380 Trp Glu Glu Leu Thr Pro Cys Lys Lys Leu Val Glu Asn Leu Lys Lys 385 390 395 400 Arg Ile Phe Tyr Asn Glu Asn Phe Lys Glu Asp Asn Glu Leu Lys Asn 405 410 415 Asn Glu Met Asp Thr Lys Asn Leu Leu Asn Phe Glu Glu Asn Tyr Arg 420 425 430 Asn Phe Asn Asn Ile Lys Lys Arg Asn Val Glu Lys Asn Asn Asn Val 435 440 445 Leu His Glu Glu Cys Thr Ile Gly Asn Val Val Thr Ile Lys Glu Leu 450 455 460 Glu Asp Ser Leu Gin Ile Phe Lys Asp Leu Asn Leu Glu Val Asp Ser 465 470 475 480 Asn Gly Asn Leu Lys Lys Gly Ala Lys Thr Thr Asp Met Val Ile Ile 485 490 495 Asn Asp Phe His Asn Ile Thr Asn Leu Gly Lys Lys Thr Val Asp Lys 500 505 510 Leu Met Gin Val Gly Ile Asn Ile Val Val Gin Tyr Glu Pro His Asn 515 520 525 Ile Glu Phe Ile Glu Lys Met Glu Pro Asn Asn Asp Asn Asn Asn Asn 530 535 540 Asn Asn Asn Asn Asn Ile Leu Phe Tyr Val Asp Ile Lys Asn Ile Met 545 550 555 560 Asn Ser Ser Glu Lys Asn Ile Lys Leu Ser Asn Ser Lys Gly Tyr Gly 565 570 575 Leu Ile Leu Asn Gly Lys Glu Asp Ile Gin Thr Ile Lys Lys Ile Lys 580 585 590 Glu Leu Asn Arg Arg Pro Leu Phe Ile Leu Leu Lys Ser Asp Asn Ile 595 600 605 Tyr Glu His Val Leu Ile Thr Arg Arg Ile Asn Glu Leu Leu Gin Ser 610 615 620 Leu Asn Ile Asn Ile Pro Tyr Ile His Tyr Val Asp Ile Asn Ser Asn 625 630 635 640 WO 00/1 7233 PCT/EP99/07055 22 Asn Leu Val1 Giu Arg 705 Arg Arg Thr Asn Al a 785 Asn Lys Tyr Met Leu Val1 690 Val Ile Thr Gly Gly 770 Pro Ile His Asp Leu 660 Asn Giu Leu Leu Phe 740 Leu Gly Lys Glu Lys 820 Leu Gly Lys Gly Ser 710 Lys Ile Gly Met Asp 790 Glu Lys As n Gly Ile 680 Asn Leu Asp Giu Lys 760 Asp Tyr Cys Pro Ser Leu 665 Giu Lys Thr Tyr Thr 745 Ile Al a T yr Asp Thr 650 Ile Thr Asp Leu Ile 730 Thr Al a His Gly Lys 810 Tyr Asn Tyr His 700 Ile Cys Lys Met Gly 780 Glu Ile Ala Val Asp 685 Arg Leu Pro Ile Gly 765 Tyr Leu Giu Gly Thr 670 Giu Leu Gin Ser Met 750 Cys Val1 Val Leu Ser 655 Asn Lys Leu Asp Cys 735 Lys Ile Gly Giu Ile 815 C ys Asp Giu Ser Thr 720 Gly Leu Val1 Ser Arg 800 Lys

Claims

22. SEP. 2003 11:00 SPRUSON FERGUSuN NU. JU41 r. r' -13- The claims defining the invention are as follows: 1. Isolated, purified or recombinant DNA sequences which code for a polypeptide with the amino acid sequence shown in SEQ ID No. 6 or for an analogue or derivative of the polypeptide according to SEQ ID No. 6, in which one or more amino s acids have been deleted, added or replaced by other amino acids wherein the catalytic function of the polypeptide is retained. 2. DNA sequences according to claim 1, characterised in that it also comprises functional regulation signals. 3. The DNA sequences according to claim 2, wherein said functional regulation signals include operators, enhancers and/or ribosomal binding sites. 4. DNA sequence with the following sub-sequences i) promoter which is active in viruses, eukaryotes and prokaryotes and ensures the formation of an RNA in the intended target tissue or target cells, ii) DNA sequences according to any one of claims 1 to 3, iii) 3 untranslated sequence which, in viruses, eukaryotes and prokaryotes, results in the addition of poly residues onto the 3 end of the RNA. A process for the production of transgenic viruses, eukaryotes and prokaryotes for modifying the isoprenoid content, characterised in that a DNA sequence according to any one of claims 2 to 4 is transferred and incorporated into the genome of viruses, eukaryotic and prokaryotic cells with or without use of a vector. 6. Transgenic systems which contain one or more DNA sequences according to any one of claims 1 to 4 as "foreign" or "additional" DNA, which sequences are expressed, wherein said systems exclude human beings. 2 7. The transgenic systems according to claim 6, wherein said systems are selected from whole plants and plant cells. 8. Expression vector containing one or more DNA sequences according to any one of claims 1 to 4. 9. Isolated, purified or recombinant protein which is involved in the 1-deoxy-D- xylulose-5-phosphate metabolic pathway and is coded by DNA sequence SEQ ID No. or is coded by DNA sequences which hybridise under stringent conditions with DNA sequence SEQ ID No. 5 or fragments of these DNA sequences in the DNA region which codes for the mature protein. (R:\BUU]Qo2651.doc:jin 22/09 '03 MON 10:53 [TX/RX NO 9754] 22. SEP. 2003 11:00 SPRUSON FERGUSON NO. 3941 P. U -14- Protein according to claim 9, obtainable from the culture supernatants of parasites or from the disrupted parasites and purification by chromatographic and electrophoretic methods. 11. Protein according to claim 9 or claim 10 characterised in that it is the product of viral, prokaryotic or eukaryotic expression of exogenous DNA, is coded by sequence SEQ ID No. 5 or is coded by DNA sequences which hybridise under stringent conditions with DNA sequence SEQ ID No. 5 or fragments of these DNA sequences in the DNA region which codes for the mature protein, or is coded by DNA sequences which would hybridise without degeneration of the genetic code with the sequences to defined in and which code for a polypeptide with a corresponding amino acid sequence. 12. Protein according to any one of claims 9 to 11, comprising the amino acid sequence SEQ ID No. 6. 13. Process for screening a compound for the treatment of infectious processes in is humans and animals, wherein the process comprises: a provision of a host cell which contains a recombinant expression vector which codes for proteins according to any one of claims 9 to 12, wherein the vector comprises at least a portion of the oligonucleotide sequence according to SEQ ID No. 5 or variants or analogues thereof, and moreover of a compound suspected to have antimycotic, antibiotic, antiparasitic or antiviral action in humans and animals; b) bringing the host cell into contact with the compound; and c determining the antimicrobial, antimycotic, antibiotic, antiparasitic or antiviral action of the compound 25 14. Process for screening for compounds for treating plants, wherein the process comprises: a) provision of a host cell which contains a recombinant expression vector which codes for proteins according to any one of claims 9 to 12, wherein the vector comprises at least a portion of the oligonucleotide sequence according to SEQ ID No. 1, SEQ ID No. 3 or SEQ ID No. 5 or variants or analogues thereof, and moreover of a compound suspected to have antimicrobial, antiviral, antiparasitic, bactericidal, fungicidal or herbicidal action in plants; b) bringing the host cell into contact with the compound; and [R:ULeuU102651.dojin 22/09 '03 MON 10:53 [TX/RX NO 9754] 22. SEP. 2003 11:01 SPRUSON FERGUSON NU. JU41 L U -I c) determining the antimicrobial, antiviral, antiparasitic, bactericidal, fungicidal or herbicidal action of the compound. Use of DNA according to one of claims 1 to 4 or of proteins according to any One Of claims 9 to 12 or of transgenic systems according to claim 6 or claim 7 for the s prevention or treatment of diseases in humans and animals. 16. Use of the proteins according to any one of claims 9 to 12 as a target for herbicides. 17. Isolated, purified or recombinant DNA sequences substantially as hercinbefore described with reference to any one of the examples. 18. A process for the production of transgenic viruses, eukaryotes and prokaryotes, said process substantially as hereinibefore described with reference to any one of the examples. 19. Protein selected from DOX? synthase, DOXP reductoisomerase and GcpE kinase substantially as hereinbefore described with reference to any one of the examples. Dated 22 September 2003 Jomaa Pharmaka GmbH *0 0090 4090 .9 @9 9 9@*990 9 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 90 9. 0 9 9* 0 9. 9. 9* VLAL15UU10243 Ldot.iri 22/09 '03 MON 10:53 [TX/RX NO 9754]