New Drug Targets. Sean T. Prigge, PhD

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1 This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License. Your use of this material constitutes acceptance of that license and the conditions of use of materials on this site. Copyright 2006, The Johns Hopkins University and Sean T. Prigge. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided AS IS ; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed.

2 New Drug Targets Sean T. Prigge, PhD

3 MMV

4 Attritrion

5 Attrition There are several reasons for the high dropout rate: a biologically poor target lack of activity against the target or parasite toxicity tolerability cost of goods

6 MMV

7 Malaria Parasite

8 Mitochondrial rigin Bacterium Malaria Mitochondion Endosymbiosis

9 Apicoplast rigin Cyanobacterium Algal Cell Malaria Apicoplast Endosymbiosis Secondary Endosymbiosis

10 ranellar Genomes Mitochondrion (6 Kbp) cytochrome oxidase I cytochrome oxidase I cytochrome oxidase III Apicoplast (35 Kbp) Full set of trnas Clp protease Elongation Factor TU ABC transport involved in Fe-S assembly 6 RFs of less than 100 AA

11 Nuclear Genome 5300 genes Mitochondial Import Apicoplast Import 246 possible 148 likely 551 possilbe 126 likely (<1000 plastid proteins in A. thal)

12 Metabolic Pathways Human Plant Malaria Tricarboxylic Acid Cycle Mito Mito Porphyrin Biosynthesis Mito Mito + Chlor Shikimate Pathway No Chlor Isoprenoid Biosyntheis Mevalonate DXP No Chlor Fatty Acid Biosynthesis Type I Type II No Chlor

14 TCA Cycle

15 No Pyruvate Dehydrogenase Complex TCA Cycle

16 No Pyruvate Dehydrogenase Complex TCA Cycle Lys

17 No Pyruvate Dehydrogenase Complex TCA Cycle Porphyrin Biosynthesis Lys

18 Metabolic Pathways Human Plant Malaria Tricarboxylic Acid Cycle Mito Mito Mito Porphyrin Biosynthesis Mito Mito + Chlor Shikimate Pathway No Chlor Isoprenoid Biosyntheis Mevalonate DXP No Chlor Fatty Acid Biosynthesis Type I Type II No Chlor

19 Porphyrin TCA Cycle Biosynthesis 4 4 2H Heme

20 Porphyrin TCA Cycle Biosynthesis Apicoplast 4 4 2H Heme

21 Apicoplast TCA Cycle Mitochondrion TCA Cycle Zn or Mn 4 Dipyrromethane 4 2H FAD 2Fe-2S

22 Metabolic Pathways Human Plant Malaria Tricarboxylic Acid Cycle Mito Mito Mito Porphyrin Biosynthesis Mito Mito + Chlor ½Mito ½Apico Shikimate Pathway No Chlor Isoprenoid Biosyntheis Mevalonate DXP No Chlor Fatty Acid Biosynthesis Type I Type II No Chlor

23 Shikimate Pathway Pentose Phospate Cycle Glycolysis Chorismate Ubiquinone p-aminobenzoate aromatic AAs

24 Shikimate Pathway Pentose Phospate Cycle Glycolysis - No predicted oranellar targeting. -CS localized to cytosol by immunomicroscopy Ubiquinone p-aminobenzoate aromatic AAs

25 Metabolic Pathways Human Plant Malaria Tricarboxylic Acid Cycle Mito Mito Mito Porphyrin Biosynthesis Mito Mito + Chlor ½Mito ½Apico Shikimate Pathway No Chlor Isoprenoid Biosyntheis Mevalonate DXP No Chlor Fatty Acid Biosynthesis Type I Type II No Chlor

26 Isoprenoid Biosynthesis Mevalonate-dependent 4 steps from 3-hydroxy methylglutaryl-coa to Isopentenyl-PP (V,L,I degradation) Typically supports terpenoid and sterol biosynthesis Mevalonate-independent DXP (1-deoxy D-xylulose 5-phosphate)

27 Isoprenoid Biosynthesis PEP / phosphate translocator Triose phosphate / phosphate translocator

28 Metabolic Pathways Human Plant Malaria Tricarboxylic Acid Cycle Mito Mito Mito Porphyrin Biosynthesis Mito Mito + Chlor ½Mito ½Apico Shikimate Pathway No Chlor Isoprenoid Biosyntheis Mevalonate No DXP No Chlor Apico Fatty Acid Biosynthesis Type I Type II No Chlor

29 Fatty Acid Biosynthesis Type I Fatty Acid Synthase Multifuctional enzyme (one or two polypeptides) Found in most eukaryotic cells Type II Fatty Acid Synthase Enzymes expressed as separate proteins Found in plants and microorganisms

30 Fatty Acid Biosynthesis Type I Fatty Acid Synthase Multifuctional enzyme (one or two polypeptides) Found in most eukaryotic cells 7 genes found Type II Fatty Acid Synthase Enzymes expressed as separate proteins Found in plants and microorganisms

31 Type II FAS Kyoto Encyclopedia of Genes and Genomes

32 Type II FAS ACP MCAT ACP KASIII ACP KASI/II ACP ENR ACP BKR H HAD ACP

33 Type II FAS ACP Fluorescent tagged proteins are localized to the apicoplast MCAT ACP KASIII ACP KASI/II ACP ENR ACP BKR H HAD ACP

34 Type II FAS phospho pantethiene ACP Malonyl MCAT -CoA CoA - ACP KASIII Acetyl -CoA CoA ACP KASI/II ACP NAD+ ENR NADH ACP NADPH BKR H HAD NADP+ ACP

35 Type II FAS Acetyl-CoA CoA Malonyl-CoA Dims, Fops

36 Type II FAS Phosphoenolpyruvate/phosphate translocator

37 Type II FAS Phosphoenolpyruvate/phosphate translocator TCA Cycle Type II FAS

38 Metabolic Pathways Human Plant Malaria Tricarboxylic Acid Cycle Mito Mito Mito Porphyrin Biosynthesis Mito Mito + Chlor ½Mito ½Apico Shikimate Pathway No Chlor Isoprenoid Biosyntheis Mevalonate No DXP No Chlor Apico Fatty Acid Biosynthesis Type I No Type II No Chlor Apico

39 Two Conclusions 1. Apicoplast = reducing environment Reactions sensitive to oxidizing environment 2. Close association between mitochondrion and apicoplast Heme biosynthesis Sharing of: Acetyl-CoA trna-ligases Fe-S Lipoate

Glycolysis - Plasmodium

Glycolysis - Plasmodium Apicomplexan Biochemistry Basics Toxoplasma Good cell biology model Genome sequencing not completed Virtual pathways Cryptosporidium The strange one Genome sequence completed Virtual pathways Plasmodium