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Information on EC 1.1.1.178 - 3-hydroxy-2-methylbutyryl-CoA dehydrogenase and Organism(s) Homo sapiens
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1.1.1.178 3-hydroxy-2-methylbutyryl-CoA dehydrogenaseIUBMB Comments
Also acts, more slowly, on (2S,3S)-2-hydroxy-3-methylpentanoyl-CoA.
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Word Map
- 1.1.1.178
- l-3-hydroxyacyl-coa
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2-methyl-3-hydroxybutyric
- hyperinsulinism
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tiglylglycine
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hydroxyacyl-coas
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choreoathetosis
- medicine
- lchad
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kcnj11
- 2-methylacetoacetate
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Reaction Schemes
Synonyms
hsd10, schad, 17beta-hsd10, 2-methyl-3-hydroxybutyryl-coa dehydrogenase, 17beta-hydroxysteroid dehydrogenase type 10, short chain 3-hydroxyacyl-coa dehydrogenase, 3-hydroxyacyl-coa dehydrogenase type ii, 3-hydroxy-2-methylbutyryl-coa dehydrogenase, hadii, short-chain l-3-hydroxy-2-methylacyl-coa dehydrogenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
2-methyl-3-hydroxy-butyryl CoA dehydrogenase
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-
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2-methyl-3-hydroxybutyryl coenzyme A dehydrogenase
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-
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dehydrogenase, 2-methyl-3-hydroxybutyryl coenzyme A
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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-
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redox reaction
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-
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reduction
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PATHWAY SOURCE
PATHWAYS
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-, -, -
SYSTEMATIC NAME
IUBMB Comments
(2S,3S)-3-hydroxy-2-methylbutanoyl-CoA:NAD+ oxidoreductase
Also acts, more slowly, on (2S,3S)-2-hydroxy-3-methylpentanoyl-CoA.
CAS REGISTRY NUMBER
COMMENTARY
52227-66-4
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH + H+
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-
-
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
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-
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
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isoleucine metabolism
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?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
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isoleucine metabolism
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?
additional information
?
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genetic deficiency of enzyme activity leads to neurodegenerative disease, that can be lessened by dietary isoleucine restriction, detection of high urinary levels of 2-methyl-3-hydroxybutyryl-CoA and tiglyl-glycine
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?
additional information
?
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inborn X-linked deficiency in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase, MHBD, causes lethal neurodegenerative disease due to an error in isoleucine metabolism, overview
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?
additional information
?
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acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl-branched acyl-CoAs
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
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isoleucine metabolism
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
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isoleucine metabolism
-
?
additional information
?
-
-
genetic deficiency of enzyme activity leads to neurodegenerative disease, that can be lessened by dietary isoleucine restriction, detection of high urinary levels of 2-methyl-3-hydroxybutyryl-CoA and tiglyl-glycine
-
-
?
additional information
?
-
-
inborn X-linked deficiency in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase, MHBD, causes lethal neurodegenerative disease due to an error in isoleucine metabolism, overview
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-azepan-1-yl-2-phenyl-2-(4-thioxo-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl)-ethanone
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specific inhibitor of SCHAD, forms a covalent adduct with NAD+ by a catalytic suicide mechanism
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
remaining enzyme activity in genetic deficient fibroblast is 0.02 nmol per min and mg protein
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional 17beta-hydroxysteroid dehydrogenase type 10/2-methyl-3-hydroxybutyryl-CoA dehydrogenase
Uniprot
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). HCD2_HUMAN
261
0
26923
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D86G
28% residual activity. Mutation causes severe disruption of mitochondrial morphology
L122V
N274S
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nucleotide substitution A740G, inborn mutation involved in lethal X-linked MHBD deficiency
R130C
additional information
L122V
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nucleotide substitution C364G, inborn mutation involved in X-linked MHBD deficiency
R130C
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nucleotide substitution C388T, inborn mutation involved in lethal X-linked MHBD deficiency
R130C
64% residual activity, mutant is unstable at room temperature and steadily loses enzyme activity. Mutation causes severe disruption of mitochondrial morphology
additional information
-
10 X-linked MHBD deficiency patient phenotypes, overview
additional information
mutation p.D86G c.257A>G in exon 3 was diagnosed in one child with a very severe neonatal presentation, absent neurological development and death from progressive hypertrophic cardiomyopathy at the age of 7 months. MHBD activity in fibroblasts was only partially reduced to approximately 30% of normal. Mutation p.Q165H c.495A>C in exon 5 was diagnosed in a boy who presented with pre- and postnatal failure to thrive but normal cognitive and motor development. Neurological examination in this boy and two affected relatives has been entirely normal up to the present age of 8 years. There is no measurable MHBD activity in fibroblasts, molecular studies identified hemizygosity for the mutation
additional information
-
mutation p.D86G c.257A>G in exon 3 was diagnosed in one child with a very severe neonatal presentation, absent neurological development and death from progressive hypertrophic cardiomyopathy at the age of 7 months. MHBD activity in fibroblasts was only partially reduced to approximately 30% of normal. Mutation p.Q165H c.495A>C in exon 5 was diagnosed in a boy who presented with pre- and postnatal failure to thrive but normal cognitive and motor development. Neurological examination in this boy and two affected relatives has been entirely normal up to the present age of 8 years. There is no measurable MHBD activity in fibroblasts, molecular studies identified hemizygosity for the mutation
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
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used for coupled enzyme assay to detect 3-oxothiolase deficiency in L-isoleucine degrading pathway
medicine
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important in brain development and aging, SCHAD deficiency is an inherited defect in mitochondrial fatty acid oxidation, reported cases of SCHAD deficiency are actually due to a deficiency of HAD, abnormal levels may contribute to the pathogenesis of some neural disorders, potential target for intervention in Alzheimer's disease, Parkinson's disease, and an X-linked mental retardation
medicine
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MHBD deficiency is a X-linked inborn error in the metabolism of isoleucine. Impairment of energy metabolism seems to play a role in the pathogenesis of MHBD deficiency. Males are more severely affected than females by MHBD deficiency. Male patients with MHBD deficiency before 10 months of age show neurodegeneration, while female carriers show a variety of symptoms (borderline learning difficulties to psychomotor and speech delay)
medicine
mutation p.D86G c.257A>G in exon 3 was diagnosed in one child with a very severe neonatal presentation, absent neurological development and death from progressive hypertrophic cardiomyopathy at the age of 7 months. MHBD activity in fibroblasts was only partially reduced to approximately 30% of normal. Mutation p.Q165H c.495A>C in exon 5 was diagnosed in a boy who presented with pre- and postnatal failure to thrive but normal cognitive and motor development. Neurological examination in this boy and two affected relatives has been entirely normal up to the present age of 8 years. There is no measurable MHBD activity in fibroblasts, molecular studies identified hemizygosity for the mutation. There is no correlation between enzyme activity and clinical presentation. HSD10 is essential for structural and functional integrity of mitochondria independently of its enzymatic activity. Impairment of this function in neural cells causes apoptotic cell death whilst the enzymatic activity of HSD10 is not required for cell survival
medicine
mutant loses most or all catalytic functions, and the males with this mutation have a severe clinical phenotype. The mutation eliminates several hydrogen bonds and reduces the van der Waals interaction between HSD10 subunits. The resulting disruption of protein structure impairs some if not all of the catalytic and non-enzymatic functions of HSD10. Eight patients with the R130C mutation show an average 2-methyl-3-hydroxybutyryl-CoA dehydrogenase activity of only 6% of the normal control level
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Gibson, K.M.; Lee, C.F.; Kamali, V.; Soevik, O.
A coupled assay detecting defects in fibroblasts isoleucine degradation distal to enoyl-CoA hydratase: application to 3-oxothiolase deficiency
Clin. Chim. Acta
205
127-135
1992
Homo sapiens
Zschocke, J.; Ruiter, J.P.N.; Brand, J.; Lindner, M.; Hoffmann, G.F.; Wanders, R.J.A.; Mayatepek, E.
Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism
Pediatr. Res.
48
852-855
2000
Homo sapiens
Garcia-Villoria, J.; Ofman, R.; Sala, P.R.; Merinero, B.; Ramos, J.; Garcia-Silva, M.T.; Beseler, B.; Dalmau, J.; Wanders, R.J.; Ugarte, M.
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: an X-linked inborn error of isoleucine metabolism that may mimic a mitochondrial disease
Pediatr. Res.
58
488-491
2005
Homo sapiens
Yang, S.Y.; He, X.Y.; Schulz, H.
3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease
FEBS J.
272
4874-4883
2005
Homo sapiens, Mus musculus, Rattus norvegicus
Garcia-Villoria, J.; Navarro-Sastre, A.; Fons, C.; Perez-Cerda, C.; Baldellou, A.; Fuentes-Castello, M.A.; Gonzalez, I.; Hernandez-Gonzalez, A.; Fernandez, C.; Campistol, J.; Delpiccolo, C.; Cortes, N.; Messeguer, A.; Briones, P.; Ribes, A.
Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis
Clin. Biochem.
42
27-33
2009
Homo sapiens
Rauschenberger, K.; Schoeler, K.; Sass, J.O.; Sauer, S.; Djuric, Z.; Rumig, C.; Wolf, N.I.; Okun, J.G.; Koelker, S.; Schwarz, H.; Fischer, C.; Grziwa, B.; Runz, H.; Nuemann, A.; Shafqat, N.; Kavanagh, K.L.; Haemmerling, G.; Wanders, R.J.; Shield, J.P.; Wendel, U.; Stern, D.; Nawroth, P.; Hoffmann, G.F.; Bartram, C.R.
A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival
EMBO Mol. Med.
2
51-62
2010
Homo sapiens (Q99714), Homo sapiens, Mus musculus, Xenopus laevis
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