Information on EC 1.1.1.178 - 3-hydroxy-2-methylbutyryl-CoA dehydrogenase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY
1.1.1.178
-
RECOMMENDED NAME
GeneOntology No.
3-hydroxy-2-methylbutyryl-CoA dehydrogenase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
(2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD+ = 2-methylacetoacetyl-CoA + NADH + H+
show the reaction diagram
inducible by tiglate
-
(2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD+ = 2-methylacetoacetyl-CoA + NADH + H+
show the reaction diagram
inducible by tiglate
Pseudomonas putida PpG2
-
-
(2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD+ = 2-methylacetoacetyl-CoA + NADH + H+
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
2-methylbutyrate biosynthesis
-
Biosynthesis of secondary metabolites
-
isoleucine degradation I
-
Metabolic pathways
-
Valine, leucine and isoleucine degradation
-
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.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
17beta-HSD10
Q99714
-
2-methyl-3-hydroxy-butyryl CoA dehydrogenase
-
-
-
-
2-methyl-3-hydroxybutyryl coenzyme A dehydrogenase
-
-
-
-
2-methyl-3-hydroxybutyryl-CoA dehydrogenase
-
-
3-hydroxyacyl-CoA dehydrogenase type II
Q99714
-
dehydrogenase, 2-methyl-3-hydroxybutyryl coenzyme A
-
-
-
-
short-chain L-3-hydroxy-2-methylacyl-CoA dehydrogenase
-
-
CAS REGISTRY NUMBER
COMMENTARY
52227-66-4
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
bifunctional 17beta-hydroxysteroid dehydrogenase type 10/2-methyl-3-hydroxybutyryl-CoA dehydrogenase
Uniprot
Manually annotated by BRENDA team
bifunctional 17beta-hydroxysteroid dehydrogenase type 10/2-methyl-3-hydroxybutyryl-CoA dehydrogenase
-
-
Manually annotated by BRENDA team
Pseudomonas putida PpG2
PpG2
-
-
Manually annotated by BRENDA team
Sprague-Dawley rats
-
-
Manually annotated by BRENDA team
bifunctional 17beta-hydroxysteroid dehydrogenase type 10/2-methyl-3-hydroxybutyryl-CoA dehydrogenase
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
physiological function
-
generation of conditional Hsd17b10 knock-out mouse lines by elimination of Hsd17b10 in endothelial cells and cells of the immune system. These mice are viable and fertile, but have defects in spleen and vasculature. The animals die rapidly around week 25. Conditional knock-out lines with elimination of the Hsd17b10 gene in noradrenergic neurons are viable and fertile but die around week 26. In the loci coerulei of HSD10 deficient mice in noradrenergic neurons, almost 30% of the mitochondria show depletion of cristae and appeared empty, more than 50% of the mitochondria are loosely packed and have swollen cristae, while normal morphology is only found in 20%
physiological function
-
enzyme knock-down by antisense-oligonucleotides results in a 40% reduction in pyruvate turnover compared to the uninjected or control injected tissue. The morphology of mitochondria in animal cap explants is changed after HSD10 knock-down. Mitochondria show severe reduction of cristae and a generally irregular shape
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2-hydroxy-3-methylpentanoyl-CoA + NAD+
3-methyl-2-oxopentanoyl-CoA + NADH
show the reaction diagram
Pseudomonas putida, Pseudomonas putida PpG2
-
-
-
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
-
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
-
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
-
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
isoleucine metabolism
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
isoleucine metabolism
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
isoleucine metabolism
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
Pseudomonas putida PpG2
-
-, isoleucine metabolism
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH + H+
show the reaction diagram
-
-
-
-
?
3-hydroxybutyryl-CoA + NAD+
acetoacetyl-CoA + NADH
show the reaction diagram
-
-
-
-
?
3-hydroxybutyryl-CoA + NAD+
acetoacetyl-CoA + NADH
show the reaction diagram
Pseudomonas putida, Pseudomonas putida PpG2
-
-
-
-
?
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
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
-
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
isoleucine metabolism
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
-
isoleucine metabolism
-
?
2-methyl-3-hydroxybutyryl-CoA + NAD+
2-methylacetoacetyl-CoA + NADH
show the reaction diagram
Pseudomonas putida, Pseudomonas putida PpG2
-
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 ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
NAD+
-
cannot be replaced by NADP+
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.037
-
2-methyl-3-hydroxybutyryl-CoA
-
-
0.5
-
3-hydroxybutyryl-CoA
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
16.2
-
-
2-methyl-3-hydroxybutyryl-CoA
21.7
-
-
3-hydroxybutyryl-CoA
additional information
-
-
remaining enzyme activity in genetic deficient fibroblast is 0.02 nmol per min and mg protein
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
30
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
27000
-
-
immunoblot analysis
66000
-
-
gel filtration
130000
-
-
gel filtration, sucrose density gradient centrifugation
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
-
2 * 28000, SDS-PAGE
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
6-step procedure with yield of only 6%
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
D86G
Q99714
28% residual activity. Mutation causes severe disruption of mitochondrial morphology
N274S
-
nucleotide substitution A740G, inborn mutation involved in lethal X-linked MHBD deficiency
Q165H
Q99714
complete loss of activity, no binding of cofactor NAD+ or NADH
R130C
-
nucleotide substitution C388T, inborn mutation involved in lethal X-linked MHBD deficiency
R130C
Q99714
64% residual activity, mutant is unstable at room temperature and steadily loses enzyme activity. Mutation causes severe disruption of mitochondrial morphology
L122V
-
nucleotide substitution C364G, inborn mutation involved in X-linked MHBD deficiency
additional information
-
10 X-linked MHBD deficiency patient phenotypes, overview
additional information
Q99714
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
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
used for coupled enzyme assay to detect 3-oxothiolase deficiency in L-isoleucine degrading pathway
medicine
-
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
Q99714
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
Q99714
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