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Information on EC 1.1.1.170 - 3beta-hydroxysteroid-4alpha-carboxylate 3-dehydrogenase (decarboxylating) and Organism(s) Homo sapiens and UniProt Accession Q15738

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IUBMB Comments
The enzyme participates in the biosynthesis of several important sterols such as ergosterol and cholesterol. It is part of a three enzyme system that removes methyl groups from the C-4 position of steroid molecules. The first enzyme, EC 1.14.18.9, 4alpha-methylsterol monooxygenase, catalyses three successive oxidations of the methyl group, resulting in a carboxyl group; the second enzyme, EC 1.1.1.170, catalyses an oxidative decarboxylation that results in a reduction of the 3beta-hydroxy group at the C-3 carbon to an oxo group; and the last enzyme, EC 1.1.1.270, 3beta-hydroxysteroid 3-dehydrogenase, reduces the 3-oxo group back to a 3beta-hydroxyl. If a second methyl group remains at the C-4 position, this enzyme also catalyses its epimerization from 4beta to 4alpha orientation, so it could serve as a substrate for a second round of demethylation. cf. EC 1.1.1.418, plant 3beta-hydroxysteroid-4alpha-carboxylate 3-dehydrogenase (decarboxylating).
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Homo sapiens
UNIPROT: Q15738
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
nsdhl, erg26, erg26p, sterol-4-alpha-carboxylate 3-dehydrogenase, sterol-4-alpha-carboxylate-3-dehydrogenase, sterol-4alpha-carboxylate 3-dehydrogenase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
sterol-4-alpha-carboxylate-3-dehydrogenase
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3beta-hydroxy-4alpha-methylcholestenecarboxylate 3-dehydrogenase (decarboxylating)
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3beta-hydroxy-4beta-methylcholestenoate dehydrogenase
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C-3 sterol dehydrogenase(C-4 decarboxylase)
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NSDHL
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sterol 4alpha-carboxylic decarboxylase
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sterol-4alpha-carboxylate 3-dehydrogenase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
redox reaction
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
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-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
3beta-hydroxysteroid-4alpha-carboxylate:NAD(P)+ 3-oxidoreductase (decarboxylating)
The enzyme participates in the biosynthesis of several important sterols such as ergosterol and cholesterol. It is part of a three enzyme system that removes methyl groups from the C-4 position of steroid molecules. The first enzyme, EC 1.14.18.9, 4alpha-methylsterol monooxygenase, catalyses three successive oxidations of the methyl group, resulting in a carboxyl group; the second enzyme, EC 1.1.1.170, catalyses an oxidative decarboxylation that results in a reduction of the 3beta-hydroxy group at the C-3 carbon to an oxo group; and the last enzyme, EC 1.1.1.270, 3beta-hydroxysteroid 3-dehydrogenase, reduces the 3-oxo group back to a 3beta-hydroxyl. If a second methyl group remains at the C-4 position, this enzyme also catalyses its epimerization from 4beta to 4alpha orientation, so it could serve as a substrate for a second round of demethylation. cf. EC 1.1.1.418, plant 3beta-hydroxysteroid-4alpha-carboxylate 3-dehydrogenase (decarboxylating).
CAS REGISTRY NUMBER
COMMENTARY hide
71822-23-6
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3beta-hydroxy-cholest-8,24-dien-4alpha-carboxylate + NAD+
4alpha-methyl-cholest-8,24-dien-3-one + CO2 + NADH
show the reaction diagram
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?
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+
a 3-oxosteroid + CO2 + NAD(P)H
show the reaction diagram
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?
4alpha-carboxy-4beta-methyl-5alpha-cholesta-8-en-3beta-ol + NADP+
4alpha-methyl-5alpha-cholesta-8-en-3-one + NADPH + CO2
show the reaction diagram
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enzyme is involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis
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4alpha-carboxy-5alpha-cholesta-8-en-3beta-ol + NADP+
5alpha-cholesta-8-en-3-one + CO2 + NADPH
show the reaction diagram
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enzyme is involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(P)+
a 3-oxosteroid + CO2 + NAD(P)H
show the reaction diagram
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000063 - 0.08
FR171456
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
surface of
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway
physiological function
the sterol-4-alpha-carboxylate-3-dehydrogenase is an essential enzyme in the ergosterol/cholesterol biosynthesis pathway
malfunction
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mutations in NSDHL gene are associated with human CHILD syndrome, congenital hemidysplasia with ichthyosiform nevus and limb defects
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
NSDHL_HUMAN
373
1
41900
Swiss-Prot
other Location (Reliability: 1)
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Caldas, H.; Herman, G.E.
NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets
Hum. Mol. Genet.
12
2981-91
2003
Homo sapiens
Manually annotated by BRENDA team
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
Nat. Commun.
6
8613
2015
Candida albicans (Q5A1B0), Homo sapiens (Q15738), Homo sapiens, Saccharomyces cerevisiae (P53199), Saccharomyces cerevisiae, Saccharomyces cerevisiae BY4743 (P53199)
Manually annotated by BRENDA team