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

Bazzani, Susanna; Hoppe, Andreas; Holzhütter, Hermann-Georg

doi:10.1186/1752-0509-6-118

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]

⁰lethal with block of the alternative reaction Q00007, EC 1.5.7.1.
¹to activate the enzyme in the reference state, the import of dihydroorotate should be blocked.
²lethal with block of thetrahydrofolate recharging. Block of R 01221,Q 00007,R 07168,R 01224,R 01220,R 01218.
³Triacylglycerol is imported, instead to be exported, to compensate the inhibition consequences ( load value=0.063; RF50 inhibited target flux= -0.0032183).
⁴lethal with external depletion of glycerol, 1,2-diacyl glycerol, sn glycerol 3 phosphate, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine.
⁵lethal with external depletion of adenosine, adenine, hypoxanthine, inosine.
⁶acceptors of the respiratory electron chain are ubiquinone and cytochrome C (complex III), lethal if also complex III is blocked.
⁷lethal with external depletion of spermidine.
⁸lethal with external depletion of phosphatidylcholine.
⁹lethal with external depletion of 5’-methylthioinosine, xanthine, hypoxanthine, inosine.
¹⁰lethal with external depletion of spermidine.
¹¹off-target effects due to the enzymatic role during host invasion.
¹²lethal with external depletion of guanine and guanosine.
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).
¹⁴topologically not essential, synthetically lethal with inhibition of glucose 6p isomerase (EC 5.3.1.9).
¹⁵lethal with external depletion of phosphatidylcholine and choline.
¹⁶off-target effects due to cytoskeleton association of the enzyme.
¹⁷RF Score = selectivity score predicted with the concept of reduced fitness.
X = essential enzyme; O=non essential enzyme; ∙=conditional essential enzyme.
HN = HepatoNet1; PN=PlasmoNet; RF50=Reduced Fitness at 50% of enzyme inhibition.

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ISSN: 1752-0509

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