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Information on EC 1.14.11.18 - phytanoyl-CoA dioxygenase and Organism(s) Homo sapiens and UniProt Accession O14832
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1.14.11.18 phytanoyl-CoA dioxygenaseIUBMB Comments
Part of the peroxisomal phytanic acid alpha-oxidation pathway. Requires Fe2+ and ascorbate.
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Word Map
- 1.14.11.18
- peroxisomal
- refsum
-
alpha-oxidation
- zellweger
-
pigmentosa
-
beta-oxidation
-
3,7,11,15-tetramethylhexadecanoic
- punctata
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pipecolic
-
rhizomelic
-
pristanic
- 2-hydroxyphytanoyl-coa
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chondrodysplasia
-
2-hydroxylation
-
anosmia
-
3-methyl
- phytol
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3-methyl-branched
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cerebro-hepato-renal
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2-oxoglutarate-dependent
- diagnostics
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
phytanoyl-coa hydroxylase, phyhd1, phytanic acid oxidase, phytanoyl-coa 2-hydroxylase, phytanoyl-coa alpha-hydroxylase, phytanoyl-coa dioxygenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
PAHX
PhyH
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-
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Phytanic acid oxidase
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-
-
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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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PAHX
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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-
-
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oxidation
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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.
CAS REGISTRY NUMBER
COMMENTARY
185402-46-4
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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
3,7-dimethyloctan-6-enoyl-CoA + 2-oxoglutarate + O2
3,7-dimethyl-2-hydroxyocta-7-enoyl-CoA + succinate + CO2
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75.2 of the activity with 3-methylhexadecanoyl-CoA
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-
?
3-ethylnonanoyl-CoA + 2-oxoglutarate + O2
3-ethoxy-2-hydroxyhexadecanoyl-CoA + succinate + CO2
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64.7% of the activity with 3-methylhexadecanoyl-CoA
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-
?
3-methyl-5-phenyl-pentanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methyl-5-phenylpentanoyl-CoA + succinate + CO2
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53% of the activity with 3-methylhexadecanoyl-CoA
-
-
?
3-methyldodecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methyldodecanoyl-CoA + succinate + CO2
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110% of the activity with 3-methylhexadecanoyl-CoA
-
-
?
3-methylheptanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylheptanoyl-CoA + succinate + CO2
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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
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-
-
-
?
3-methylnonanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylnonanoyl-CoA + succinate + CO2
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111% of the activity with 3-methylhexadecanoyl-CoA
-
-
?
3-methylundecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxy-3-methylundecanoyl-CoA + succinate + CO2
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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
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-
-
-
?
decanoyl-CoA + 2-oxoglutarate + O2
2-hydroxydecanoyl-CoA + succinate + CO2
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-
-
-
?
dodecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxydodecanoyl-CoA + succinate + CO2
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-
-
-
?
hexadecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyhexadecanoyl-CoA + succinate + CO2
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-
-
-
?
hexanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyhexanoyl-CoA + succinate + CO2
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-
-
-
?
octadecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyoctadecanoyl-CoA + succinate + CO2
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-
-
-
?
octanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyoctanoyl-CoA + succinate + CO2
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-
-
-
?
tetradecanoyl-CoA + 2-oxoglutarate + O2
2-hydroxytetradecanoyl-CoA + succinate + CO2
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-
-
-
?
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
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-
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ir
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
Refsums 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
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-
-
-
?
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
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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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-
?
phytanoyl-CoA + 2-oxoglutarate + O2
alpha-hydroxyphytanoyl-CoA + succinate + CO2
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-
-
-
?
phytanoyl-CoA + 2-oxoglutarate + O2
alpha-hydroxyphytanoyl-CoA + succinate + CO2
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no activity with octadecanoyl-CoA, lignoceroyl-CoA, 2-methylhexadecanoyl-CoA and 4,8,12-trimethyltridecanoyl-CoA
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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
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?
additional information
?
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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 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
phytanoyl-CoA + 2-oxoglutarate + O2
2-hydroxyphytanoyl-CoA + succinate + CO2
Refsums 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
-
-
?
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
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
COMMENTARY
LITERATURE
Iron
Fe2+
Iron
Fe2+ required. Maximal activity is 0.05-0.1 mM Fe2+ in absence of ATP
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
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
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+
additional information
-
not inhibited by bifonazole, clotrimazole, miconazole, ketoconazole
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
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
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+
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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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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imidazole
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+
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.000002
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in kidney cell line 293, activity can be induced 4fold by phytanic acid
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
infantile-onset Adult Refsum's disease due to phytanoyl-CoA hydroxylase ((PHYH) c.164delT, p.L55fsX12) mutation. The challenges of a successful pregnancy in a patient with Adult Refsums disease due to phytanoyl-CoA hydroxylase deficiency
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). PAHX_HUMAN
338
0
38538
Swiss-Prot
Mitochondrion (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
35400
-
mature protein after cleavage of presumed leader sequence, calculation from cDNA sequence
41200
-
precursor protein with peroxisomal targeting signal type 2, calculation from cDNA sequence
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
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
LITERATURE
hanging drop vapour diffusion method in 21% polyethylene glycol 3350, 0.3 M triammonium citrate, pH 7.1, at 18°C
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D177A
F275S
places a polar side chain in a hydrophobic pocket and possibly interferes with the overall structure or impair protein folding
G204S
H175A
H259A
mutation removes two of the hydrogen bonds and probably destabilizes the beta-turn, which in turn destabilizes the core double stranded beta-helix
N269H
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
clinically observed mutant is fully active, mutation may result in a defective targeting of the protein to peroxisomes
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
R275W
G204S
mutation causes partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation
G204S
disruption of the 2-oxoglutarate binding pocket, uncouples 2-oxoglutarate and phytanoyl-CoA oxidation
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
carboxymethyl-Sepharose cation exchange chromatography and Superdex S75 gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
assays for Refsums 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
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Jansen, G.A.; Mihalik, S.J.; Watkins, P.A.; Moser, H.W.; Jakobs, C.; Denis, C.; Wanders, R.J.A.
Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome: direct, unequivocal evidence for the new, revised pathway of phytanic acid alpha-oxidation in humans
Biochem. Biophys. Res. Commun.
229
205-210
1996
Homo sapiens
Mihalik, S.J.; Morrell, J.C.; Kim, D.; Sacksteder, K.A.; Watkins, P.A.; Gould, S.J.
Identification of PAHX, a Refsum disease gene
Nature Genet.
17
185-189
1997
Homo sapiens
Jansen, G.A.; Mihalik, S.J.; Watkins, P.A.; Jakobs, C.; Moser, H.W.; Wanders, R.J.A.
Characterization of phytanoyl-Coenzyme A hydroxylase in human liver and activity measurements in patients with peroxisomal disorders
Clin. Chim. Acta
271
203-211
1998
Homo sapiens
Jansen, G.A.; Ofman, R.; Ferdinandusse, S.; Ijlst, L.; Muijsers, A.O.; Skjeldal, O.H.; Stokke, O.; Jakobs, C.; Besley, G.T.N.; Wraith, J.E.; Wanders, R.J.A.
Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene
Nature Genet.
17
190-193
1997
Homo sapiens, Rattus norvegicus
Chahal, A.; Khan, M.; Pai, S.G.; Barbosa, E.; Singh, I.
Restoration of phytanic acid oxidation in Refsum disease fibroblasts from patients with mutations in the phytanoyl-CoA hydroxylase gene
FEBS Lett.
429
119-122
1998
Homo sapiens
Jansen, G.A.; Ferdinandusse, S.; Hogenhout, E.M.; Verhoeven, N.M.; Jakobs, C.; Wanders, R.J.A.
Phytanoyl-CoA hydroxylase deficiency. Enzymological and molecular basis of classical Refsum disease
Adv. Exp. Med. Biol.
466
371-376
1999
Homo sapiens
Zomer, A.W.M.; Jansen, G.A.; Van der Burg, B.; Verhoeven, N.M.; Jakobs, C.; Van der Saag, P.T.; Wanders, R.J.A.; Poll-The, B.T.
Phytanoyl-CoA hydroxylase activity is induced by phytanic acid
Eur. J. Biochem.
267
4063-4067
2000
Homo sapiens, Mus musculus, Platyrrhini, Rattus norvegicus
Croes, K.; Foulon, V.; Casteels, M.; Van Veldhoven, P.P.; Mannaerts, G.P.
Phytanoyl-CoA hydroxylase: recognition of 3-methyl-branched acyl-CoAs and requirement for GTP or ATP and Mg2+ in addition to its known hydroxylation cofactors
J. Lipid Res.
41
629-636
2000
Homo sapiens, Rattus norvegicus
Kershaw, N.J.; Mukherji, M.; MacKinnon, C.H.; Claridge, T.D.; Odell, B.; Wierzbicki, A.S.; Lloyd, M.D.; Schofield, C.J.
Studies on phytanoyl-CoA 2-hydroxylase and synthesis of phytanoyl-coenzyme A
Bioorg. Med. Chem. Lett.
11
2545-2548
2001
Homo sapiens
Mukherji, M.; Kershaw, N.J.; Schofield, C.J.; Wierzbicki, A.S.; Lloyd, M.D.
Utilization of sterol carrier protein-2 by phytanoyl-CoA 2-hydroxylase in the peroxisomal alpha oxidation of phytanic acid
Chem. Biol.
9
597-605
2002
Homo sapiens
Mukherji, M.; Chien, W.; Kershaw, N.J.; Clifton, I.J.; Schofield, C.J.; Wierzbicki, A.S.; Lloyd, M.D.
Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum's disease
Hum. Mol. Genet.
10
1971-1982
2001
Homo sapiens (O14832)
Chen, C.; Wang, Q.; Fang, X.; Xu, Q.; Chi, C.; Gu, J.
Roles of phytanoyl-CoA alpha-hydroxylase in mediating the expression of human coagulation factor VIII
J. Biol. Chem.
276
46340-46346
2001
Homo sapiens
Foulon, V.; Asselberghs, S.; Geens, W.; Mannaerts, G.P.; Casteels, M.; van Veldhoven, P.P.
Further studies on the substrate spectrum of phytanoyl-CoA hydroxylase: implications for Refsum disease?
J. Lipid Res.
44
2349-2355
2003
Homo sapiens
Searls, T.; Butler, D.; Chien, W.; Mukherji, M.; Lloyd, M.D.; Schofield, C.J.
Studies on the specificity of unprocessed and mature forms of phytanoyl-CoA 2-hydroxylase and mutation of the iron binding ligands
J. Lipid Res.
46
1660-1667
2005
Homo sapiens (O14832)
McDonough, M.A.; Kavanagh, K.L.; Butler, D.; Searls, T.; Oppermann, U.; Schofield, C.J.
Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease
J. Biol. Chem.
280
41101-41110
2005
Homo sapiens (O14832), Homo sapiens
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