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Information on EC 5.1.99.6 - NAD(P)H-hydrate epimerase
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5.1.99.6 NAD(P)H-hydrate epimeraseIUBMB Comments
The enzyme can use either (R)-NADH-hydrate or (R)-NADPH-hydrate as a substrate. Its physiological role is to convert the (R) forms to the (S) forms, which could then be restored to active dinucleotides by EC 4.2.1.93, ATP-dependent NAD(P)H-hydrate dehydratase.
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Word Map
- 5.1.99.6
-
nadphx
- dehydratase
-
epimerization
-
neurometabolic
- probands
-
moonlighting
-
coma
-
febrile
-
exome
-
edema
-
cerebrospinal
-
ataxia
- pyridoxal
- leukoencephalopathy
- medicine
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
=
=
Synonyms
apoa1bp, nad(p)hx epimerase, ynl200c, nad(p)h-hydrate epimerase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
AIBP
epimerase-PPOX
NAD(P)HX epimerase
NAD(P)HX epimerase
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide = (6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(1)
-
-
-
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate = (6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(2)
-
-
-
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PATHWAY SOURCE
PATHWAYS
-
, , ,
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SYSTEMATIC NAME
IUBMB Comments
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide 6-epimerase
The enzyme can use either (R)-NADH-hydrate or (R)-NADPH-hydrate as a substrate. Its physiological role is to convert the (R) forms to the (S) forms, which could then be restored to active dinucleotides by EC 4.2.1.93, ATP-dependent NAD(P)H-hydrate dehydratase.
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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
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
-
i.e. NADHX
-
-
r
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
-
i.e. NADPHX
-
-
r
(R)-NADPH-hydrate
(S)-NADPH-hydrate
-
higher catalytic efficiency with (R)-NADPH-hydrate compared to(R)-NADH-hydrate
-
-
?
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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
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
i.e. NADHX
-
-
r
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
-
i.e. NADHX
-
-
r
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
(6R)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
i.e. NADPHX
-
-
r
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
the hydratase is dependent on ATP, but the epimerase ist not
-
additional information
the hydratase is dependent on ATP, but the epimerase ist not
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
NaCl does not affect activity up to a concentration of 5 mM
-
additional information
-
NaCl does not affect activity up to a concentration of 5 mM
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Atherosclerosis
The APOA1bp-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients.
Brain Diseases
A novel homozygous missense variant in the NAXE gene in an Iranian family with progressive encephalopathy with brain edema and leukoencephalopathy.
Brain Edema
A novel homozygous missense variant in the NAXE gene in an Iranian family with progressive encephalopathy with brain edema and leukoencephalopathy.
Carcinoma, Hepatocellular
NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1? signaling in hepatocellular carcinoma.
Dehydration
Homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy.
Leukoencephalopathies
A novel homozygous missense variant in the NAXE gene in an Iranian family with progressive encephalopathy with brain edema and leukoencephalopathy.
Leukoencephalopathies
Homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy.
Neoplasms
NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1? signaling in hepatocellular carcinoma.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0006
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
pH and temperature not specified in the publication
0.00115
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
pH and temperature not specified in the publication
0.0016
(R)-NADH-hydrate
-
in the presence of 5 mM KCl, at 30°C in 25 mM Tris-HCl, pH 8.0, 2 mM MgCl2, 0.2 mM ATP
0.00033
(R)-NADPH-hydrate
-
in the presence of 5 mM KCl, at 30°C in 25 mM Tris-HCl, pH 8.0, 2 mM MgCl2, 0.2 mM ATP
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.38
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide
pH and temperature not specified in the publication
0.26
(6S)-6beta-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide phosphate
pH and temperature not specified in the publication
82
(R)-NADH-hydrate
-
in the presence of 5 mM KCl, at 30°C in 25 mM Tris-HCl, pH 8.0, 2 mM MgCl2, 0.2 mM ATP
1827
(R)-NADPH-hydrate
-
in the presence of 5 mM KCl, at 30°C in 25 mM Tris-HCl, pH 8.0, 2 mM MgCl2, 0.2 mM ATP
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.1
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional NAD(P)H-hydrate repair enzyme Nnr, catalyzes both reactions of EC 5.1.99.6 and 4.2.1.136
UniProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
a truncated form of the Arabidopsis epimerase lacking the PPOX domain is also fully active in the interconversion
physiological function
additional information
physiological function
hydration of NAD(P)H to NAD(P)HX, which inhibits several dehydrogenases, is corrected by an ATP-dependent dehydratase and an epimerase recently identified as the products of the vertebrate Carkd (carbohydrate kinase domain) and Aibp (apolipoprotein AI-binding protein) genes, respectively
physiological function
hydration of NAD(P)H to NAD(P)HX, which inhibits several dehydrogenases, is corrected by an ATP-dependent dehydratase and an epimerase recently identified as the products of the vertebrate Carkd (carbohydrate kinase domain) and Aibp (apolipoprotein AI-binding protein) genes, respectively
physiological function
hydration of NAD(P)H to NAD(P)HX, which inhibits several dehydrogenases, is corrected by an ATP-dependent dehydratase and an epimerase recently identified as the products of the vertebrate Carkd (carbohydrate kinase domain) and Aibp (apolipoprotein AI-binding protein) genes, respectively
physiological function
-
NADH and NADPH undergo spontaneous and enzymatic reactions that produce R and S forms of NAD(P)H hydrates, which are not electron donors and inhibit various dehydrogenases. The highly conserved epimerase repairs the hydrates formed from NADH and NADPH in plants together with a highly conserved dehydratase targeted to multiple compartments
physiological function
NADH and NADPH undergo spontaneous and enzymatic reactions that produce R and S forms of NAD(P)H hydrates, which are not electron donors and inhibit various dehydrogenases. The highly conserved epimerase repairs the hydrates formed from NADH and NADPH in plants together with a highly conserved dehydratase targeted to multiple compartments
additional information
-
the epimerase homologue is fused to the vitamin B6 salvage enzyme pyridoxine 5'-phosphate oxidase, PPOX. Plant epimerase homologs have an extra C-terminal domain that belongs to the pyridoxine/pyridoxamine phosphate oxidase (PPOX) family
additional information
the epimerase homologue is fused to the vitamin B6 salvage enzyme pyridoxine 5'-phosphate oxidase, PPOX. Plant epimerase homologs have an extra C-terminal domain that belongs to the pyridoxine/pyridoxamine phosphate oxidase (PPOX) family
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K192A
mutation decreases in vitro epimerase activity by more than 95% but does not affect dehydratase activity, reaction of EC 4.2.1.136. Mutant cells have essentially normal NAD(P)HX dehydratase activity and NAD(P)HX levels. Cells show metabolome changes, particularly in amino acids, which exceed those in cells lacking the entire yjeF gene. Mutant cells also have reduced levels of free (i.e. weakly bound or unbound) pyridoxal 5'-phosphate
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni2+- or Co2+-charged column chromatography and Q-Sepharose column chromatography
recombinant N-terminally His-tagged enzyme from Escherichia coli by nickel affinity chromatography
Ni2+- or Co2+-charged column chromatography and Q-Sepharose column chromatography
-
Ni2+- or Co2+-charged column chromatography and Q-Sepharose column chromatography
-
recombinant N-terminally His-tagged enzyme from Escherichia coli by nickel affinity chromatography
-
recombinant N-terminally His-tagged enzyme from Escherichia coli by nickel affinity chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
expression of N-terminally His-tagged enzyme in Escherichia coli
gene Aibp, expression of GFP-fused or Myc-tagged mAIBP in CHO cells and in HEK-293 cells, in vitro transcription-translation assays, full-length coding sequences of the mouse mAIBP
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
pathogenic biallelic mutations in NAXE in children from four families lead to (sub-)acute-onset ataxia, cerebellar edema, spinal myelopathy, and skin lesions. Lactate is elevated in cerebrospinal fluid of all affected individuals. Disease onset is during the second year of life and clinical signs as well as episodes of deterioration are triggered by febrile infections. Disease course is rapidly progressive, leading to coma, global brain atrophy, and finally to death in all affected individuals. NAXE levels are undetectable in fibroblasts from affected individuals of two families. These fibroblasts show highly elevated concentrations of the toxic metabolite cyclic-NADHX
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Marbaix, A.; Nol, G.; Detroux, A.; Vertommen, D.; Van Schaftingen, E.; Linster, C.
Extremely conserved ATP- or ADP-dependent enzymatic system for nicotinamide nucleotide
J. Biol. Chem.
286
41246-41252
2011
Saccharomyces cerevisiae, Mus musculus
brenda
Marbaix, A.Y.; Tyteca, D.; Niehaus, T.D.; Hanson, A.D.; Linster, C.L.; Van Schaftingen, E.
Occurrence and subcellular distribution of the NAD(P)HX repair system in mammals
Biochem. J.
460
49-58
2014
Rattus norvegicus (B0BNM1), Mus musculus (Q8K4Z3), Homo sapiens (Q8NCW5)
brenda
Niehaus, T.D.; Richardson, L.G.; Gidda, S.K.; Elbadawi-Sidhu, M.; Meissen, J.K.; Mullen, R.T.; Fiehn, O.; Hanson, A.D.
Plants utilize a highly conserved system for repair of NADH and NADPH hydrates
Plant Physiol.
165
52-61
2014
Zea mays, Arabidopsis thaliana (Q9LTX3)
brenda
Kremer, L.S.; Danhauser, K.; Herebian, D.; Petkovic Ramadza, D.; Piekutowska-Abramczuk, D.; Seibt, A.; Mueller-Felber, W.; Haack, T.B.; Ploski, R.; Lohmeier, K.; Schneider, D.; Klee, D.; Rokicki, D.; Mayatepek, E.; Strom, T.M.; Meitinger, T.; Klopstock, T.; Pronicka, E.; Mayr, J.A.; Baric, I.; Distelmaier, F.; Prokisch, H.
NAXE mutations disrupt the cellular NAD(P)HX repair system and cause a lethal neurometabolic disorder of early childhood
Am. J. Hum. Genet.
99
894-902
2016
Homo sapiens (Q8NCW5), Homo sapiens
brenda
Niehaus, T.D.; Elbadawi-Sidhu, M.; Huang, L.; Prunetti, L.; Gregory, J.F.; de Crecy-Lagard, V.; Fiehn, O.; Hanson, A.D.
Evidence that the metabolite repair enzyme NAD(P)HX epimerase has a moonlighting function
Biosci. Rep.
38
BSR20180223
2018
Escherichia coli (P31806), Escherichia coli
brenda
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