Literature summary for 1.1.1.267 extracted from

Haymond, A.; Dowdy, T.; Johny, C.; Johnson, C.; Ball, H.; Dailey, A.; Schweibenz, B.; Villarroel, K.; Young, R.; Mantooth, C.J.; Patel, T.; Bases, J.; Dowd, C.S.; Couch, R.D.
A high-throughput screening campaign to identify inhibitors of DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD) (2018), Anal. Biochem., 542, 63-75 .

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Application

Application	Comment	Organism
drug development	the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues, including enzymes DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD)	Mycobacterium tuberculosis
drug development	the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues, including enzymes DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD)	Yersinia pestis
drug development	the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues, including enzymes DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD)	Francisella tularensis subsp. novicida

Cloned(Commentary)

Cloned (Comment)	Organism
gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL	Mycobacterium tuberculosis
gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL	Yersinia pestis
gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL	Francisella tularensis subsp. novicida

Inhibitors

Inhibitors	Comment	Organism
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole	i.e. PPT, lead molecule as inhibitor of IspC	Francisella tularensis subsp. novicida
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole	i.e. PPT, lead molecule as inhibitor of IspC	Mycobacterium tuberculosis
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole	i.e. PPT, lead molecule as inhibitor of IspC	Yersinia pestis
13-methyl-[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium chloride	i.e. sanguinarine chloride, lead molecule as inhibitor of IspC	Francisella tularensis subsp. novicida
13-methyl-[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium chloride	i.e. sanguinarine chloride, lead molecule as inhibitor of IspC	Mycobacterium tuberculosis
13-methyl-[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium chloride	i.e. sanguinarine chloride, lead molecule as inhibitor of IspC	Yersinia pestis
3'-[(8-cinnamoyl-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-2',4',6'-trihydroxy-5'-methylacetophenone	i.e. rottlerin, lead molecule as inhibitor of IspC	Francisella tularensis subsp. novicida
3'-[(8-cinnamoyl-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-2',4',6'-trihydroxy-5'-methylacetophenone	i.e. rottlerin, lead molecule as inhibitor of IspC	Mycobacterium tuberculosis
3'-[(8-cinnamoyl-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-2',4',6'-trihydroxy-5'-methylacetophenone	i.e. rottlerin, lead molecule as inhibitor of IspC	Yersinia pestis
3-(3,5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one)	i.e. GW5074, lead molecule as inhibitor of IspC	Francisella tularensis subsp. novicida
3-(3,5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one)	i.e. GW5074, lead molecule as inhibitor of IspC	Mycobacterium tuberculosis
3-(3,5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one)	i.e. GW5074, lead molecule as inhibitor of IspC	Yersinia pestis
catechin	-	Francisella tularensis subsp. novicida
catechin	-	Mycobacterium tuberculosis
catechin	3.35% inhibition	Yersinia pestis
EDTA	-	Francisella tularensis subsp. novicida
EDTA	-	Mycobacterium tuberculosis
EDTA	-	Yersinia pestis
fosmidomycin	-	Francisella tularensis subsp. novicida
fosmidomycin	-	Mycobacterium tuberculosis
fosmidomycin	-	Yersinia pestis
additional information	the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues. MEP pathway inhibitors (collectively called MEPicides) are most often rationally designed on the fosmidomycin scaffold, balancing target specificity with bioavailability. Pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Analysis of mechanism of inhibition, most compounds function through aggregation. The method is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation. Screening using Yersinia pestis subsp. A1122, Mycobacterium tuberculosis, and Francisella tularensis subsp. novicida strain Utah 112, overview. Inhibition is attenuated in the presence of Triton X-100 for all inhibitors except sanguinarine chloride and suramin hexasodium	Francisella tularensis subsp. novicida
additional information	the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues. MEP pathway inhibitors (collectively called MEPicides) are most often rationally designed on the fosmidomycin scaffold, balancing target specificity with bioavailability. Pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Analysis of mechanism of inhibition, most compounds function through aggregation. The method is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation. Screening using Yersinia pestis subsp. A1122, Mycobacterium tuberculosis, and Francisella tularensis subsp. novicida strain Utah 112, overview. Inhibition is attenuated in the presence of Triton X-100 for all inhibitors except sanguinarine chloride and suramin hexasodium	Mycobacterium tuberculosis
additional information	the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues. MEP pathway inhibitors (collectively called MEPicides) are most often rationally designed on the fosmidomycin scaffold, balancing target specificity with bioavailability. Pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Analysis of mechanism of inhibition, most compounds function through aggregation. The method is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation. Screening using Yersinia pestis strain A1122, Mycobacterium tuberculosis, and Francisella tularensis subsp. novicida strain Utah 112, overview. Inhibition is attenuated in the presence of Triton X-100 for all inhibitors except sanguinarine chloride and suramin hexasodium	Yersinia pestis
quercetin	-	Francisella tularensis subsp. novicida
quercetin	-	Mycobacterium tuberculosis
quercetin	95.17% inhibition	Yersinia pestis
quercetin 3-beta-D-glucoside	-	Francisella tularensis subsp. novicida
quercetin 3-beta-D-glucoside	-	Mycobacterium tuberculosis
quercetin 3-beta-D-glucoside	23.75% inhibition	Yersinia pestis
quercetin 3-D-galactoside	-	Francisella tularensis subsp. novicida
quercetin 3-D-galactoside	-	Mycobacterium tuberculosis
quercetin 3-D-galactoside	23.21% inhibition	Yersinia pestis
quercitrin	-	Francisella tularensis subsp. novicida
quercitrin	-	Mycobacterium tuberculosis
quercitrin	21.79% inhibition	Yersinia pestis
suramin hexasodium	-	Francisella tularensis subsp. novicida
suramin hexasodium	-	Mycobacterium tuberculosis
suramin hexasodium	-	Yersinia pestis

Metals/Ions

Metals/Ions	Comment	Organism
Mg2+	required	Mycobacterium tuberculosis
Mg2+	required	Yersinia pestis
Mg2+	required	Francisella tularensis subsp. novicida

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	Mycobacterium tuberculosis	-	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	Yersinia pestis	-	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	Francisella tularensis subsp. novicida	-	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	Francisella tularensis subsp. novicida U112	-	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	Yersinia pestis A1122	-	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	Mycobacterium tuberculosis H37Rv	-	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	Mycobacterium tuberculosis ATCC 25618	-	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?

Organism

Organism	UniProt	Comment	Textmining
Francisella tularensis subsp. novicida	A0Q7Y5	-	-
Francisella tularensis subsp. novicida U112	A0Q7Y5	-	-
Mycobacterium tuberculosis	P9WNS1	-	-
Mycobacterium tuberculosis ATCC 25618	P9WNS1	-	-
Mycobacterium tuberculosis H37Rv	P9WNS1	-	-
Yersinia pestis	Q8ZH62	-	-
Yersinia pestis A1122	Q8ZH62	-	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration	Mycobacterium tuberculosis
recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration	Yersinia pestis
recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration	Francisella tularensis subsp. novicida

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	-	Mycobacterium tuberculosis	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	-	Yersinia pestis	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	-	Francisella tularensis subsp. novicida	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	-	Francisella tularensis subsp. novicida U112	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	-	Yersinia pestis A1122	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	-	Mycobacterium tuberculosis H37Rv	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+	-	Mycobacterium tuberculosis ATCC 25618	2-C-methyl-D-erythritol 4-phosphate + NADP+	-	?

Synonyms

Synonyms	Comment	Organism
DXP reductoisomerase	-	Mycobacterium tuberculosis
DXP reductoisomerase	-	Yersinia pestis
DXP reductoisomerase	-	Francisella tularensis subsp. novicida
DXR	-	Mycobacterium tuberculosis
DXR	-	Yersinia pestis
DXR	-	Francisella tularensis subsp. novicida
FtIspC	-	Francisella tularensis subsp. novicida
IspC	-	Mycobacterium tuberculosis
IspC	-	Yersinia pestis
IspC	-	Francisella tularensis subsp. novicida
MtbIspC	-	Mycobacterium tuberculosis
YpIspC	-	Yersinia pestis

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Mycobacterium tuberculosis
37	-	assay at	Yersinia pestis
37	-	assay at	Francisella tularensis subsp. novicida

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.8	-	assay at	Mycobacterium tuberculosis
7.8	-	assay at	Yersinia pestis
7.8	-	assay at	Francisella tularensis subsp. novicida

Cofactor

Cofactor	Comment	Organism
NADP+	-	Mycobacterium tuberculosis
NADP+	-	Yersinia pestis
NADP+	-	Francisella tularensis subsp. novicida
NADPH	-	Mycobacterium tuberculosis
NADPH	-	Yersinia pestis
NADPH	-	Francisella tularensis subsp. novicida

General Information

General Information	Comment	Organism
metabolism	the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway	Mycobacterium tuberculosis
metabolism	the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway	Yersinia pestis
metabolism	the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway	Francisella tularensis subsp. novicida