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Table 1 Outcome of the simulated drug target inhibitions

From: Network-based assessment of the selectivity of metabolic drug targets in Plasmodium falciparum with respect to human liver metabolism

EC    HN gene PN gene   RF50 HN perturbed RF50 PN perturbed  
number Enzyme General reaction deletion deletion RF Score metabolites (deviation %) metabolites (deviation %) Sources
  Acyl-CoA Fatty Acid + ATP + CO2 →     Cardiolipin Sphingomyelin  
6.2.1.3 synthetase Fatty Acid CoA + AMP + PPi X X 1.97 (mitochondrion) (-50%) (-97.07%) [17]
  Thymidylate dUMP + 5,10 Methylene THF ↔       
2.1.1.45 synthase dTMP + DHF X X0 1.00 dTTP (-50%) DNA (nucleus) (-50.31%) [12, 14, 17]
4.1.1.23 Orotidine 5P decarboxylase Orotidine 5P →UMP + CO2 X X 0.713 UDP-Glucose (-80.57%) mRNA (nucleus) (-57.44%) [12, 14, 17]
2.4.2.10 Orotate phosphoribosyltransferase Orotidine 5P + PPi ↔ X X 0.713 UDP-Glucose (-80.57%) mRNA (nucleus) (-57.44%) [17]
   Orotate +PRPP       
2.1.3.2 Aspartate carbamoyltransferase Carbamoyl-P + Aspartate → X X1 0.713 UDP-Glucose (-80.57%) mRNA (nucleus) (-57.44%) [17]
   Carbamoyl-Aspartate + Pi       
3.5.2.3 Dihydroorotase N-Carbamoyl-Aspartate → X X1 0.713 UDP-Glucose (-80.57%) mRNA (nucleus) (-57.44%) [14, 17]
   S-Dihydroorotate + H2O       
4.3.2.2 Adenylosuccinate lyase Adenylsuccinate → X X 0.611 NADPH (-91.23%) mRNA (nucleus) (-59.25%) [17]
   Fumarate + AMP       
2.1.2.1 Serine hydroxymethyltransferase 5,10 Methylene THF + Glycine + X X2 0.514 NADPH (-91.92%) DNA (nucleus) (-50.31%) [12, 14, 17]
   H2O ↔ THF + Serine       
1.5.1.3 Dihydrofolate reductase THF + NAD(P)H ↔ DHF + NAD(P) X X 0.50 dTTP (-50%); DNA (nucleus) (-50.31%) [12, 14, 17]
       Tetrahydrofolate (-50%)   
6.4.1.2 Acetyl-CoA carboxylase ATP + Acetyl-CoA + HCO3- → X X 0.47 Triacylglycerol (+105.11 %)3 Protein N6 (lipoyl)lysine [12, 17]
   Malonyl-CoA + ADP + Pi      (apicoplast) (-50%)  
6.3.5.5 & 6.3.4.16 Carbamoyl-P synthetase 2 ATP + Glutamine + HCO3- + H2O → X X1 0.404 UDP-Glucose (-80.56%);Urea (-61.3%) mRNA (nucleus) (-57.43%) [17]
   2 ADP + Pi +Glutamate + Carbamoyl-P       
2.3.1.15 Glycerol 3P acyltransferase Acyl-CoA + glycerol 3P → X X4 0.37 Phosphatidyl ethanol amine (-55.77%); Phosphatidyl choline (-94.53%) [12]
   CoA + 1-acyl-glycerol 3P     Triacylglycerol (-50%);   
       Phosphatidyl inositol (-50%);   
       Phosphatidyl choline (-50%); Cardiolipin (-50%)   
2.3.1.50 Serine C-palmitoyl transferase Serine + Palmitoyl-CoA ↔ O X - - [14]
   3-Dehydrosphinganine + CoA + CO2       
   CoA + CO2       
1.17.4.1 Ribonucleotide reductase dNDP + Ox. Thioredoxin ↔ O X - - [12, 14, 17]
   NDP + Thioredoxin       
2.3.1.37 5-aminolevulinate synthase Glycine + Succinyl-CoA ↔ O X - - [12, 14, 17]
   5-aminolevulinate + CoA + CO2       
2.5.1.6 S-Adenosyl methionine synthase Methionine + ATP ↔ O X - - [17]
   S-Adenosyl-Methionine + PPi + Pi       
2.7.6.1 Phosphoribosyl pyrophosphate synthase ATP + Ribose 5P ↔ O X - - [17]
   PRPP + AMP       
2.7.7.15 Choline phosphate citidyl transferase CTP + Phosphocholine → O X - - [17]
   PPi + CDP-Choline       
1.15.1.1 Superoxide dismutase 2 O2- + 2 H+ → O2 + H2O2 O X - - [12, 14, 17]
2.3.1.24 Sphingosine N-Acyl transferase Acyl-CoA + Sphingosine ↔ CoA + Ceramide O X - - [14]
1.8.1.7 Glutathione reductase 2 GSH + NADP+ ↔ GSSG + NADPH + H+ O X - - [14, 17]
1.8.1.9 Thioredoxin reductase Thioredoxin + NADP+ ↔ Thioredoxin disulfide + NADPH O X - - [14, 17]
4.2.1.24 Delta aminolevulinate dehydratase 2 5-aminolevulinate → porphobilinogen + 2 H2O O X - - [12, 14, 17]
3.3.1.1 S-adenosyl-l-homocysteine hydrolase S-adenosyl-L-homocysteine + H2O → L-homocysteine + Adenosine O X - - [12, 14, 17]
1.10.2.2 mitochondrial Ubiquinone-Cytochrome C reductase QH2 + 2 ferricytochrome c ↔ Q + 2 ferrocytochrome c + 2 H+ O X - - [12, 14, 17]
4.2.1.1 Carbonate dehydratase H2CO3 ↔ CO2 + H2O O X - - [14]
2.7.8.3 Sphingomyelin synthase CDP-choline + a ceramide → CMP + sphingomyelin O X - - [14, 17]
1.1.1.27 L-lactate dehydrogenase (S)-lactate + NAD+ ↔ pyruvate + NADH + H+ O X - - [17]
6.3.2.2 Gamma-glutamylcysteine synthetase ATP + Glutamate + Cysteine → ADP + Pi + gamma-Glutamyl-cysteine O X - - [12, 14, 17]
6.3.4.2 CTP synthase ATP + UTP + Glutamine + H2O → ADP + Pi + Glutamate + CTP O X - - [17]
6.3.4.4 Adenylosuccinate synthase GTP + IMP + Aspartate → GDP + Pi + Adenylosuccinate O X - - [14],[17]
1.9.3.1 Cytochrome c oxidase 4 ferrocytochrome c + O2 + 4 H+ ↔ 4 ferricytochrome c + 2 H2O O X - - [17]
2.4.2.1 Purine nucleoside phosphorylase Inosine + Pi ↔ Ribose 1P + Hypoxanthine O X - - [17]
6.2.1.1 Acetyl-CoA synthase ATP + Acetate + CoA →Acetyl-CoA + AMP + PPi O X - - [17]
2.4.2.8 Hypoxanthine guanine phosphoribosyl transferase Nicotinate D-ribonucleoside + Pi -→Nicotinate + Ribose 1P O X - - [12, 14, 17]
6.3.2.17 Folylpoly glutamate synthase ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate → ADP + phosphate + O X - - [17]
   tetrahydropteroyl-[gamma-Glu]n+1       
1.1.1.205 IMP dehydrogenase IMP + NAD + H2O →Xanthosine 5P + NADH O 5 0 - - [12, 14, 17]
1.6.99.3 NADH dehydrogenase Acceptor + H++ NADH ↔ Reduced Acceptor + NAD+ O 6 0 - - [14]
2.5.1.16 Spermidine synthase S-Adenosylmethioninamine + Putrescine ↔ 5-Methylthioadenosine + Spermidine O 7 0 - - [14] ,[12]
2.7.1.32 Choline kinase Choline + ATP → Phosphocholine + ADP O 8 0 - - [12, 14, 17]
3.5.4.4 Adenosine deaminase Adenosine + H2O ↔ Inosine + NH3 O 9 0 - - [12, 14, 17]
4.1.1.50 S-Adenosyl methionine decarboxylase S-Adenosylmethionine ↔ Adenosylmethioninamine + CO2 O 10 0 - - [12, 14, 17]
4.1.2.13 Aldolase Fructose 1,6 PPi ↔ Glycerone P + Glyceraldehyde P O 11 0 - - [12, 14, 17]
6.3.5.2 GMP syntethase ATP + Xanthosine-5P + Glutamine + H2O → AMP + PPi + GMP + Glutamate O 12 0 - - [14]
4.1.1.17 Ornithine decarboxylase L-ornithine → putrescine + CO2 O 13 0 - - [12, 14]
2.7.1.1 Hexokinase Glucose + ATP → Glucose 6P + ADP O 14 0 - - [17]
2.1.1.103 Phospho ethanolamine N-methyl transferase SAM + Ethanolamine-P ↔ SAH + N-Methylethanolamine-P O 15 0 - - [14]
5.3.1.1 Triose phosphate Isomerase D-glyceraldehyde 3-phosphate ↔ Glycerone phosphate O 16 0 - - [17]
  1. 0lethal with block of the alternative reaction Q00007, EC 1.5.7.1.
  2. 1to activate the enzyme in the reference state, the import of dihydroorotate should be blocked.
  3. 2lethal with block of thetrahydrofolate recharging. Block of R 01221,Q 00007,R 07168,R 01224,R 01220,R 01218.
  4. 3Triacylglycerol is imported, instead to be exported, to compensate the inhibition consequences ( load value=0.063; RF50 inhibited target flux= -0.0032183).
  5. 4lethal with external depletion of glycerol, 1,2-diacyl glycerol, sn glycerol 3 phosphate, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine.
  6. 5lethal with external depletion of adenosine, adenine, hypoxanthine, inosine.
  7. 6acceptors of the respiratory electron chain are ubiquinone and cytochrome C (complex III), lethal if also complex III is blocked.
  8. 7lethal with external depletion of spermidine.
  9. 8lethal with external depletion of phosphatidylcholine.
  10. 9lethal with external depletion of 5’-methylthioinosine, xanthine, hypoxanthine, inosine.
  11. 10lethal with external depletion of spermidine.
  12. 11off-target effects due to the enzymatic role during host invasion.
  13. 12lethal with external depletion of guanine and guanosine.
  14. 13lethal with external depletion of putrescine, spermidine and blocked agmatinase (EC 3.5.1.53), in Plasmodium bergheii but not yet charaterized in Plasmodium flaciparum).
  15. 14topologically not essential, synthetically lethal with inhibition of glucose 6p isomerase (EC 5.3.1.9).
  16. 15lethal with external depletion of phosphatidylcholine and choline.
  17. 16off-target effects due to cytoskeleton association of the enzyme.
  18. 17RF Score = selectivity score predicted with the concept of reduced fitness.
  19. X = essential enzyme; O=non essential enzyme; ∙=conditional essential enzyme.
  20. HN = HepatoNet1; PN=PlasmoNet; RF50=Reduced Fitness at 50% of enzyme inhibition.