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Literature summary for 1.1.1.170 extracted from

  • Helliwell, S.B.; Karkare, S.; Bergdoll, M.; Rahier, A.; Leighton-Davis, J.R.; Fioretto, C.; Aust, T.; Filipuzzi, I.; Frederiksen, M.; Gounarides, J.; Hoepfner, D.; Hofmann, A.; Imbert, P.E.; Jeker, R.; Knochenmuss, R.; Krastel, P.; Margerit, A.; Memmert, K.; Miault, C.V.; Movva, N.R.; Muller, A.; Naegeli, H.-U.; Oberer, L.; Prindle, V.; Riedl, R.; Schuierer, S.; Sexton, J.A.; Tao; J.; Wagner, T.; Yin, H.; Zhang, J.; Roggo, S.; Reinker, S.; Parker, C.N.
    FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p (2015), Nat. Commun., 6, 8613.
    View publication on PubMedView publication on EuropePMC

Protein Variants

Protein Variants Comment Organism
Gly90Ser naturally occuring mutation of ERG26 that confers resistance to inhibitor FR171456 Saccharomyces cerevisiae
additional information multiple mutations in ERG26 confer resistance to inhibitor FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a structure model of Erg26 Saccharomyces cerevisiae

Inhibitors

Inhibitors Comment Organism Structure
FR171456 a natural specific inhibitor of yeast Erg26p from Monodictys sp.. FR171456 is a natural product with cholesterol-lowering properties in animal models. FR171456 significantly alters the levels of cholesterol pathway intermediates in yeast cells. FR171456 causes significant growth inhibition of strain SC5314 at. Erg26p inhibition requires the 4alpha-carboxyl group of FR171456, substitution of the 4alpha-carboxylic group of FR171456 by a carbobenzylamido group (Compound-1) decreases inhibition Candida albicans
FR171456 a natural specific inhibitor of mammalian NSDHL from Monodictys sp.. FR171456 is a natural product with cholesterol-lowering properties in animal models. FR171456 significantly alters the levels of cholesterol pathway intermediates in human cells. R171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. In a screen to profile compound activity against 503 cancer cell lines only five cell lines are sensitive to FR171456 with IC50 values below 0.005 mM. Calcidiol, a cholesterol metabolite situated downstream of NSDHL, is decreased in a FR171456 dose-dependent manner, consistent with a reduction of cholesterol synthesis, and new derivatives of NSDHL substrates are deteremined in the cells that are no longer effective as substrates Homo sapiens
FR171456 a natural specific inhibitor of yeast Erg26p from Monodictys sp.. Genomic profiling identifies Erg26p as the FR171456 target, the ERG26 heterozygous strain (erg26DELTA/ERG26) shows the most significant hypersensitivity to FR171456. FR171456 is a natural product with cholesterol-lowering properties in animal models. FR171456 significantly alters the levels of cholesterol pathway intermediates in yeast cells. FR171456 causes significant growth inhibition of strain BY4743 at concentrations up to 0.2 mM. Multiple mutations, e.g. Gly90Ser, in enzyme ERG26 confer resistance to FR171456 in growth and enzyme assays. FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. Erg26p inhibition requires the 4a-carboxyl group of FR171456, substitution of the 4alpha-carboxylic group of FR171456 by a carbobenzylamido group (Compound-1) decreases inhibition by 300fold. FR171456 docking into a homology model of Erg26p. Modelling FR171456 resistance mutations on Erg26p, overview Saccharomyces cerevisiae

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
additional information Michaelis-Menten kinetics Homo sapiens
additional information
-
additional information Michaelis-Menten kinetics Saccharomyces cerevisiae
0.55
-
3beta-hydroxy-cholest-8,24-dien-4alpha-carboxylate pH 7.5, 30°C Saccharomyces cerevisiae

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+ Homo sapiens
-
a 3-oxosteroid + CO2 + NAD(P)H
-
?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+ Saccharomyces cerevisiae
-
a 3-oxosteroid + CO2 + NAD(P)H
-
?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+ Candida albicans
-
a 3-oxosteroid + CO2 + NAD(P)H
-
?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+ Saccharomyces cerevisiae BY4743
-
a 3-oxosteroid + CO2 + NAD(P)H
-
?

Organism

Organism UniProt Comment Textmining
Candida albicans Q5A1B0
-
-
Homo sapiens Q15738
-
-
Saccharomyces cerevisiae P53199
-
-
Saccharomyces cerevisiae BY4743 P53199
-
-

Source Tissue

Source Tissue Comment Organism Textmining
Huh-7 cell
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3beta-hydroxy-cholest-8,24-dien-4alpha-carboxylate + NAD+
-
Homo sapiens 4alpha-methyl-cholest-8,24-dien-3-one + CO2 + NADH
-
?
3beta-hydroxy-cholest-8,24-dien-4alpha-carboxylate + NAD+
-
Saccharomyces cerevisiae 4alpha-methyl-cholest-8,24-dien-3-one + CO2 + NADH
-
?
3beta-hydroxy-cholest-8,24-dien-4alpha-carboxylate + NAD+
-
Saccharomyces cerevisiae BY4743 4alpha-methyl-cholest-8,24-dien-3-one + CO2 + NADH
-
?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+
-
Homo sapiens a 3-oxosteroid + CO2 + NAD(P)H
-
?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+
-
Saccharomyces cerevisiae a 3-oxosteroid + CO2 + NAD(P)H
-
?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+
-
Candida albicans a 3-oxosteroid + CO2 + NAD(P)H
-
?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+
-
Saccharomyces cerevisiae BY4743 a 3-oxosteroid + CO2 + NAD(P)H
-
?

Subunits

Subunits Comment Organism
More ERG26p structure homology modeling based on the crystal structure of Pseudomonas aeruginosa UDP-N-acetylglucosamine 4-epimerase complexed with UDP-N-acetylgalactosamine, PDB ID 1SB8 Saccharomyces cerevisiae

Synonyms

Synonyms Comment Organism
Erg26
-
Saccharomyces cerevisiae
Erg26
-
Candida albicans
Erg26p
-
Saccharomyces cerevisiae
Erg26p
-
Candida albicans
NSDHL
-
Homo sapiens
sterol-4-alpha-carboxylate-3-dehydrogenase
-
Homo sapiens
sterol-4-alpha-carboxylate-3-dehydrogenase
-
Saccharomyces cerevisiae
sterol-4-alpha-carboxylate-3-dehydrogenase
-
Candida albicans

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
30
-
assay at Homo sapiens
30
-
assay at Saccharomyces cerevisiae

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.5
-
assay at Homo sapiens
7.5
-
assay at Saccharomyces cerevisiae

Cofactor

Cofactor Comment Organism Structure
NAD(P)+
-
Candida albicans
NAD+
-
Homo sapiens
NAD+
-
Saccharomyces cerevisiae

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.00135
-
FR171456 in vitro inhibition, pH 7.5, 30°C Saccharomyces cerevisiae

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0000063
-
in a Huh-7 cell-based assay, pH 7.5, 30°C Homo sapiens FR171456
0.0022
-
in vitro inhibition, pH 7.5, 30°C Saccharomyces cerevisiae FR171456
0.036
-
in a K-562 cell-based assay, pH 7.5, 30°C Homo sapiens FR171456
0.08
-
in a Hep-G2 cell-based assay, pH 7.5, 30°C Homo sapiens FR171456

General Information

General Information Comment Organism
metabolism the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway Homo sapiens
metabolism the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway Saccharomyces cerevisiae
metabolism the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway Candida albicans
additional information ERG26p structure homology modeling based on the crystal structure of Pseudomonas aeruginosa UDP-N-acetylglucosamine 4-epimerase complexed with UDP-N-acetylgalactosamine, PDB ID 1SB8 Saccharomyces cerevisiae
physiological function the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway Homo sapiens
physiological function the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway Saccharomyces cerevisiae
physiological function the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway Candida albicans