Information on EC 1.14.11.18 - phytanoyl-CoA dioxygenase

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The expected taxonomic range for this enzyme is: Euarchontoglires

EC NUMBER
COMMENTARY
1.14.11.18
-
RECOMMENDED NAME
GeneOntology No.
phytanoyl-CoA dioxygenase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
phytanoyl-CoA + 2-oxoglutarate + O2 = 2-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
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-
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REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
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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SYSTEMATIC NAME
IUBMB Comments
phytanoyl-CoA, 2-oxoglutarate:oxygen oxidoreductase (2-hydroxylating)
Part of the peroxisomal phytanic acid alpha-oxidation pathway. Requires Fe2+ and ascorbate.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
PAHX
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-
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PhyH
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-
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Phytanic acid oxidase
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-
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phytanoyl-CoA 2-hydroxylase
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Phytanoyl-CoA alpha-hydroxylase
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-
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phytanoyl-CoA hydroxylase
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-
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CAS REGISTRY NUMBER
COMMENTARY
185402-46-4
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ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
26 T4-like myoviruses, including 10 from non-cyanobacterial myoviruses and 16 from marine cyanobacterial myoviruses, isolated from Prochlorococcus sp. and Synechococcus sp.
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-
Manually annotated by BRENDA team
mouse
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
role of 2-oxoglutarate during cyanophage infection, overview
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3,7-dimethyloctan-6-enoyl-CoA + 2-oxoglutarate + O2
3,7-dimethyl-2-hydroxyocta-7-enoyl-CoA + succinate + CO2
show the reaction diagram
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75.2 of the activity with 3-methylhexadecanoyl-CoA
-
-
?
3-ethylnonanoyl-CoA + 2-oxoglutarate + O2
3-ethoxy-2-hydroxyhexadecanoyl-CoA + succinate + CO2
show the reaction diagram
-
64.7% of the activity with 3-methylhexadecanoyl-CoA
-
-
?
3-methyl-5-phenyl-pentanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methyl-5-phenylpentanoyl-CoA + succinate + CO2
show the reaction diagram
-
53% of the activity with 3-methylhexadecanoyl-CoA
-
-
?
3-methyldodecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methyldodecanoyl-CoA + succinate + CO2
show the reaction diagram
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110% of the activity with 3-methylhexadecanoyl-CoA
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-
?
3-methylheptanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylheptanoyl-CoA + succinate + CO2
show the reaction diagram
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16.2% of the activity with 3-methylhexadecanoyl-CoA
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-
?
3-methylhexadecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylhexadecanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
3-methylhexadecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylhexadecanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
3-methylnonanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylnonanoyl-CoA + succinate + CO2
show the reaction diagram
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111% of the activity with 3-methylhexadecanoyl-CoA
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-
?
3-methylundecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylundecanoyl-CoA + succinate + CO2
show the reaction diagram
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110% of the activity with 3-methylhexadecanoyl-CoA
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-
?
butanoyl-CoA + 2-oxoglutarate + O2
2-hydroxybutanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
decanoyl-CoA + 2-oxoglutarate + O2
2-hydroxydecanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
dodecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxydodecanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
hexadecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyhexadecanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
hexanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyhexanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
octadecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyoctadecanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
octanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyoctanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
phytanoyl-CoA + 2-oxoglutarate
2-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
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ir
phytanoyl-CoA + 2-oxoglutarate + O2
alpha-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
phytanoyl-CoA + 2-oxoglutarate + O2
alpha-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
phytanoyl-CoA + 2-oxoglutarate + O2
alpha-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
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no activity with octadecanoyl-CoA, lignoceroyl-CoA, 2-methylhexadecanoyl-CoA and 4,8,12-trimethyltridecanoyl-CoA
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-
?
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
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-
-
-
?
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
O14832
Refsum‘s disease ia a neurological syndrome characterized by adult-onset retinitis pigmentosa, anosemia, sensory neuropathy and phytanic acidaemia. Many cases are caused by mutations in peroxidomal oxygenase phytanoyl-CoA 2-hydroxylase
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-
?
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
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3R and 3S epimers are hydroxylated with approximately equal efficiency. Both unprocessed proenzyme and mature form of PAHX are fully active
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-
?
tetradecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxytetradecanoyl-CoA + succinate + CO2
show the reaction diagram
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-
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-
?
isovaleryl-CoA + 2-oxoglutarate + O2
?
show the reaction diagram
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-
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-
?
additional information
?
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interaction between PAHX and the A2 domain of the coagulation factor VIII is a part responsible for the low-level expression of factor VIII
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additional information
?
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Resum disease might be characterized by an accumulation of not only phytanic acid but also ther 3-alkyl-branched fatty acids, no activity with isovaleryl-CoA, 4-phenyl-3-methylbutanoyl-CoA, 3-methylpentanoyl-CoA, hexadecanoyl-CoA, octanoyl-CoA, prostanoyl-CoA or 4-methylnonaoyl-CoA. Chain length of at least seven carbon atoms is a prerequisite for PAHX-dependent hydroxylation. The optimal chain length appears to be 9-12 carbon atoms. The branch at position 3 is a prerequisite for the activity of PAHX
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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
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
show the reaction diagram
O14832
Refsum‘s disease ia a neurological syndrome characterized by adult-onset retinitis pigmentosa, anosemia, sensory neuropathy and phytanic acidaemia. Many cases are caused by mutations in peroxidomal oxygenase phytanoyl-CoA 2-hydroxylase
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-
?
additional information
?
-
-
interaction between PAHX and the A2 domain of the coagulation factor VIII is a part responsible for the low-level expression of factor VIII
-
-
-
additional information
?
-
-
Resum disease might be characterized by an accumulation of not only phytanic acid but also ther 3-alkyl-branched fatty acids
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COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
additional information
-
UTP, CTP, ITP, AMP, ADP, NAD+ and FAD can not act as cofactors, ATP and GTP can be replaced by adenosine-5'-O-(3-thiotriphosphate), adenylylimidodiphosphate, adenylyl-(beta,gamma-methylene)-diphosphonate and guanylyl-imidodiphosphate
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METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Fe2+
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optimal activity at 0.5 mM; requirement
Fe2+
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requirement
Fe2+
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Iron
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required
Iron
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Fe2+ required. Maximal activity is 0.05-0.1 mM Fe2+ in absence of ATP
additional information
-
Cu2+, Mn2+ or Zn2+ can not replace Fe2+
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
2-methylhexadecanoyl-CoA
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56% of control activity
ATP
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at 0.1 mM Fe2+ 4 mM ATP inhibits enzyme activity. At increased Fe2+ concentrations ATP stimulates with a maximum at 64 mM ATP for 1.0 mM Fe2+
GTP
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at 0.1 mM Fe2+ 4 mM ATP inhibits enzyme activity. At increased Fe2+ concentrations ATP stimulates with a maximum at 64 mM ATP for 1.0 mM Fe2+
propyl gallate
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no activity with 1 mM, interacts with iron binding
hexadecanoyl-CoA
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74% of control activity
additional information
-
not inhibited by bifonazole, clotrimazole, miconazole, ketoconazole
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ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
2-hydroxyphytanoyl-CoA
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Albumin
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0.05 mM 3-methylhexadecanoyl-CoA, no hydroxylation in absence of albumin. Hydroxylation of 3-methylnonanoyl-CoA or 3-methyldodecanoyl-CoA is much less dependent on the presence of albumin
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ascorbate
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2.5fold induction at 5 mM
ATP
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at 0.1 mM Fe2+ 4 mM ATP inhibits enzyme activity. At increased Fe2+ concentrations ATP stimulates with a maximum at 64 mM ATP for 1.0 mM Fe2+
GTP
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at 0.1 mM Fe2+ 4 mM GTP inhibits enzyme activity. At increased Fe2+ concentrations ATP stimulates with a maximum at 64 mM GTP for 1.0 mM Fe2+
imidazole
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at 0.1 mM Fe2+ 4 mM ATP inhibits enzyme activity. At increased Fe2+ concentrations ATP stimulates with a maximum at 64 mM ATP for 1.0 mM Fe2+; stimulates at 1.0 mM Fe2+
SCP-2
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phytanoylis efficiently 2-hydroxylated by PAHX in vitro in the presence of mature SCO-2. SCP-2 increases discrimination between straight-chain and branched-chain substrates, i.e. it decreases activity with straight chain substrates and increase activity with branched-chain substrates. In vivo substrates for PAHX may be SCP-2 complexes
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KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.049
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2-oxoglutarate
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-
0.0408
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3-methylhexadecanoyl-CoA
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SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.000001
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in kidney cell line COS-1, activity can be induced 4fold by phytanic acid
0.0000018
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in embryonic carcinoma cell line P19-EC, activity can be induced 4fold by phytanic acid
0.000002
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in kidney cell line 293, activity can be induced 4fold by phytanic acid
0.0000022
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in fibroblast homogenate
0.0000031
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in hepatoma cell line HepG2, no induction by phytanic acid
0.000024
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in hepatoma cell line FaO, activity can be induced 2.5fold by phytanic acid
0.000041
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in liver homogenate
0.0001
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in purified peroxisomes
0.00026
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in purified liver peroxisomes
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.5
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pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6.5
8.5
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at pH 6.5 over 80%, at pH 8.5 50% of control activity
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
33000
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-
purified protein, SDS-PAGE
35000
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purified protein, SDS-PAGE
35400
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mature protein after cleavage of presumed leader sequence, calculation from cDNA sequence
35440
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calculated from amino acid sequence without N-terminal methionine
38600
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calculated from amino acid sequence
41200
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precursor protein with peroxisomal targeting signal type 2, calculation from cDNA sequence
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
proteolytic modification
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unprocessed proenzyme contains a N-terminal peroxisomal targeting sequence that is cleaved to give mature PAHX. Both forms are able to hydroxylate a range of CoA derivatives, but under the same assay conditions, the N-terminal Hexa-His-tagged unprocessed form is less active than the nontagged mature form
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
hanging drop vapour diffusion method in 21% polyethylene glycol 3350, 0.3 M triammonium citrate, pH 7.1, at 18°C
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Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
carboxymethyl-Sepharose cation exchange chromatography and Superdex S75 gel filtration
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Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
T4-like cyanopohage, marine cyanobacterial and non-cyanobacterial, genotyping, overview
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expressed in Escherichia coli
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in bacterial expression vector pMALc2
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in bacterial expression vector pQE-31
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in mammalian expression vector pcDNA3
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in yeast expression vector
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wild-type and mutant enzymes, expression in Escherichia coli
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in yeast expression vector pEL26 and pEL30
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ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
D177A
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mutant enzyme does not catalyze hydroxylation of phytanoyl-CoA
D177A
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no activity with phytanoyl-CoA
E197Q
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disruption of the 2-oxoglutarate binding pocket
F275S
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places a polar side chain in a hydrophobic pocket and possibly interferes with the overall structure or impair protein folding
G204S
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mutation causes partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation
G204S
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disruption of the 2-oxoglutarate binding pocket, uncouples 2-oxoglutarate and phytanoyl-CoA oxidation
H175A
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mutant enzyme does not catalyze hydroxylation of phytanoyl-CoA
H175A
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no activity with phytanoyl-CoA
H213A
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insoluble mutant enzyme
H259A
-
mutation removes two of the hydrogen bonds and probably destabilizes the beta-turn, which in turn destabilizes the core double stranded beta-helix
H264A
-
activity with phytanoyl-CoA is 7.5 of the wild-type activity
I199F
-
disruption of the 2-oxoglutarate binding pocket
N269H
-
mutation causes partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation
N269H
-
disruption of the 2-oxoglutarate binding pocket, uncouples 2-oxoglutarate and phytanoyl-CoA oxidation
N83Y
-
disruption of protein-protein interactions proposed to involve PAHX, such as that with sterol carrier protein-2, proposed to be responsible for solubilization and presentation of phytanoyl-CoA to PAHX
P29S
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clinically observed mutant is fully active, mutation may result in a defective targeting of the protein to peroxisomes
Q176A
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activity with phytanoyl-CoA is 16.3% of the wild-type activity
Q176K
-
mutation causes partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation
R245Q
-
disruption of protein-protein interactions proposed to involve PAHX, such as that with sterol carrier protein-2, proposed to be responsible for solubilization and presentation of phytanoyl-CoA to PAHX
R275Q
-
mutation results in impaired 2-oxoglutarate binding
R275Q
-
very low catalytic activity
R275W
-
mutation results in impaired 2-oxoglutarate binding
R275W
-
very low catalytic activity
W193R
-
disruption of the 2-oxoglutarate binding pocket
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
diagnostics
-
the substrate phytanoyl-CoA is difficult to handle because of its amphipathic properties. Commercially available alternative substrates, such as hexadecanoyl-CoA or isovaleryl-CoA are potentially usefull
diagnostics
-
assays for Refsum‘s disease should not be based on PAHX activity alone. At least four different types of mutation cause loss of PAHX activity in vivo. Mutations to the peroxisomal targeting sequence do not affect catalytic function but probably affect targeting or degradation of the enzyme. A second group of mutations, including truncation and missense mutations, results in total loss of activity. A third group of mutations results in uncoupling of substrate oxidation from that of 2-oxoglutarate. A fourth group of mutations causes partial inactivation by hindering binding/utilization of the 2-oxoglutarate cosubstrate and/or iron(II) cofactor. From the therapeutic and biochemical view-point the latter two groups are particularly interesting since it may be possible to restore their activity with modified cosubstrates
medicine
-
treatment of Refsum disease