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(15S)-hydroperoxyeicosatetraenoic acid + O2
?
-
-
-
-
?
(15S)-hydroxyeicosatetraenoic acid + O2
?
-
-
-
-
?
(5Z,8Z,11Z,14Z)-nonadeca-5,8,11,14-tetraene-1,19-dioic acid + O2
?
-
8-LOX tolerates a carboxylic group in the substrate-binding pocket
-
-
?
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid + O2
(8S,15S)-dihydroperoxy-5Z,9E,11Z,13E-eicosatetraenoic acid
-
-
-
-
?
(8S)-hydroxyeicosatetraenoic acid + O2
?
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
5-hydroperoxy fatty acid + O2
leukotriene A4
-
leukotriene A synthase activity, reaction rate is approximately 7% of arachidonate 8-lipoxygenation
-
-
?
5-hydroperoxyeicosatetraenoic acid + ?
leukotriene A4
-
-
unstable product
?
alpha-linolenic acid + O2
?
-
-
-
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
arachidonate + O2
(5Z,9E,11Z,14Z)-(8S)-8-hydroperoxyeicosa-5,9,11,14-tetraenoate
-
-
-
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8S)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
-
-
?
arachidonic acid + O2
(5Z,8E,11Z,14Z)-8-hydroperoxyicosa-5,8,11,14-tetraenoic acid + (5Z,8E,11Z,14Z)-8-hydroxyicosa-5,8,11,14-tetraenoic acid
-
arachidonic acid, enzyme activity only detectable after in vivo treatment with the phorbol ester tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate)
-
-
?
arachidonic acid + O2
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
docosahexaenoic acid + O2
?
-
-
-
-
?
eicosapentaenoic acid + O2
?
-
-
-
-
?
gamma-linoleic acid + O2
?
-
-
-
-
?
linoleic acid + O2
?
-
poor substrate
-
-
?
additional information
?
-
2 arachidonic acid + 2 O2

8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
lipoxygenase pathway
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
pathway of epidermal arachidonate oxygenation
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
lipoxygenase pathway
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
arachidonate + O2

(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
-
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
8-H(p)ETE is the major reaction product of 8-LOX independent of the pH
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
-
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
subtle rearrangements, primarily in the side chains of three amino acids, allow binding of arachidonic acid in a catalytically competent conformation
-
-
?
arachidonic acid + O2

(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
-
-
-
-
?
arachidonic acid + O2
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
-
-
-
-
?
arachidonic acid + O2
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
-
-
-
-
?
arachidonic acid + O2
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
-
-
-
-
?
arachidonic acid + O2
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
-
-
-
-
?
arachidonic acid + O2
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
-
-
-
-
?
arachidonic acid + O2
(8R)-8-hydroperoxy-5,9,11,14-eicosatetraenoic acid
-
-
-
-
?
additional information

?
-
-
the inducible expression of 8-lipoxygenase inhibits cell growth, 15-LOX-2 and 8-LOX, although displaying different positional specificity, use common signaling pathways to induce growth inhibition in premalignant epithelial cells, overview
-
-
-
additional information
?
-
-
in the absence of arachidonate, Tyr181 and Arg182 of helix alpha2 participate in an interhelical charge cluster with Glu430 of the arched helix
-
-
-
additional information
?
-
-
usage of a combination of molecular dynamics simulations with quantum mechanics/molecular mechanics calculations to study the hydrogen abstraction step and the molecular oxygen addition step of the hydroperoxidation reaction of arachidonic acid catalyzed by both wild-type Coral 8R-LOX and its Gly427Ala mutant
-
-
-
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2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
arachidonate + O2
(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
arachidonate + O2
(5Z,9E,11Z,14Z)-(8S)-8-hydroperoxyeicosa-5,9,11,14-tetraenoate
-
-
-
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8S)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
-
-
?
additional information
?
-
-
the inducible expression of 8-lipoxygenase inhibits cell growth, 15-LOX-2 and 8-LOX, although displaying different positional specificity, use common signaling pathways to induce growth inhibition in premalignant epithelial cells, overview
-
-
-
2 arachidonic acid + 2 O2

8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
lipoxygenase pathway
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
pathway of epidermal arachidonate oxygenation
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
lipoxygenase pathway
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
2 arachidonic acid + 2 O2
8-hydroxy,9-oxo-eicosa-5Z,11Z,14Z-trienoic acid + 9-oxo-[8,12-cis]-prosta-5Z,10,14Z-trienoic acid + H2O
-
-
-
-
?
arachidonate + O2

(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
-
-
?
arachidonate + O2
(5Z,9E,11Z,14Z)-(8R)-8-hydroperoxyicosa-5,9,11,14-tetraenoate
-
-
-
-
?
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H604F
-
8-LOX mutant, induces strong pH-dependent alterations in the positional specificity but the pH-optimum remains the same. At acidic pH 8S-H(p)ETE is the exclusive arachidonic acid oxygenation product but with more alkaline pH increasing shares of 15S-H(p)ETE, above pH 9 15S-H(p)ETE is the major oxygenation product. Specific activity of 8-LOX mutant with (5Z,8Z,11Z,14Z)-nonadeca-5,8,11,14-tetraene-1,19-dioic acid as substrate continously declines when pH increases
Y603F
-
8-LOX mutant, is relative insensitive towards pH alterations in the near physiological range (pH 6-8), at strong alkaline conditions (pH more than 9) significant shares of 15S-H(p)ETE are formed
Y603F/H604F
-
8-LOX double mutant, induces strong pH-dependent alterations in the positional specificity but the pH-optimum remains the same. At acidic pH 8S-H(p)ETE is the exclusive arachidonic acid oxygenation product but with more alkaline pH increasing shares of 15S-H(p)ETE, above pH 9 15S-H(p)ETE is the major oxygenation product
A417G
-
converts arachidonic acid mainly to 12-hydroxyeicosatetraenoic acid, mutant retains 38% of catalytic efficiency
A417S
-
same oxygenase specificity and similar catalytic activity to wild-type 8S-LOX
A589M
-
site-directed mutagenesis, the mutant shows reduced activity and altered protein fold compared to the wild-type enzyme
A620H
-
site-directed mutagenesis, the mutant shows reduced activity and altered protein fold compared to the wild-type enzyme
D39A
-
118% activity compared to the wild type enzyme, mutant with diminished fluorescence resonance energy transfer properties, consistent with a role for calcium in membrane binding
D39A/E47A
-
106% activity compared to the wild type enzyme, a double mutant with calcium-binding residues from two of the three sites mutated exhibits no fluorescence resonance energy transfer signal
E47A
-
65% of the activity of the wild type enzyme, mutant with diminished fluorescence resonance energy transfer properties, consistent with a role for calcium in membrane binding
G427A
-
site-directed mutagenesis. In wild-type, molecular oxygen adds to C8 of arachidonic acid with an R stereochemistry. In the mutant, Ala427 pushes Leu385, blocks the region over C8, and opens an oxygen access channel now directed to C12, where molecular oxygen is added with an S stereochemistry. Thus, the specificity turns out to be dramatically inverted
I433A
-
absence of the Ile side chain destabilizes the roof of the U-shaped channel, measurable activity only in the presence of CaCl2 and the detergent emolphogen
I433W
-
has no measurable activity, presumably because the Trp side chain effectively blocks the arachidonic acid binding site
L432A
-
less than 5% of the activity of the wild-type
L432F
-
less than 5% of the activity of the wild-type
L432I
-
less than 5% of the activity of the wild-type
L432V
-
less than 20% of the activity of the wild-type
R182A
-
site-directed mutagenesis, the mutant shows reduced activity and altered protein fold compared to the wild-type enzyme
W41A
-
140% activity compared to the wild type enzyme, exhibits only less than 2% of the increase in fluorescence at 517 nm upon the addition of CaCl2 of the wild-type signal
W77A
-
44% of the activity of the wild type enzyme, exhibits only 4% of the increase in fluorescence at 517 nm upon the addition of CaCl2 of the wild-type signal
additional information

-
doxycycline-inducible expression in keratinocytes 308 leads to an inhibition of cell growth that is associated with an inhibition of DNA synthesis, as shown by a reduction of 5-bromo-2-deoxy-uridine incorporation up to 46%, doxycycline-induced keratinocytes show increased levels of reactive oxygen species. The antioxidant N-acetyl-L-cysteine and a specific inhibitor of p38 mitogen-activated protein kinase, but not of extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase/stress-activated kinases, completely abolish the LOX-induced growth inhibition
additional information
-
deletion mutant lacks one of the loops, as well as chelating amino acids from two of the three Ca2+ binding sites (the center site and that most distal from the catalytic domain). The Ca2+ site proximal to the catalytic domain, defined primarily by main chain contacts, remains intact and occupied in the mutant structure. Deletion mutant displays wild-type activity in a membrane-free assay, but Ca2+ does not promote membrane binding of the mutant and does not stimulate enzyme activity in a membrane-based assay
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Bundy, G.L.; Nidy, E.G.; Epps, D.E.; Mizsak, S.A.; Wnuk, R.J.
Discovery of an arachidonic acid C-8 lipoxygenase in the gorgonian coral Pseudoplexaura porosa
J. Biol. Chem.
261
747-751
1986
Pseudoplexaura porosa
brenda
Brash, A.R.; Baertschi, S.W.; Ingram, C.D.; Harris, T.M.
On non-cyclooxygenase prostaglandin synthesis in the sea whip coral, Plexaura homomalla: an 8(R)-lipoxygenase pathway leads to formation of an alpha-ketol and a Racemic prostanoid
J. Biol. Chem.
262
15829-15839
1987
Plexaura homomalla
brenda
Fuerstenberger, G.; Hagedorn, H.; Jacobi, T.; Besemfelder, E.; Stephan, M.; Lehman, W.D.; Marks, F.
Characterization of an 8-lipoxygenase activity induced by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin in vivo
J. Biol. Chem.
266
15738-15745
1991
Mus musculus
brenda
Brash, A.R.; Boeglin, W.E.; Chang, M.S.; Shieh, B.H.
Purification and molecular cloning of an 8R-lipoxygenase from the coral Plexaura homomalla reveal the related primary structures of R- and S-lipoxygenases
J. Biol. Chem.
271
20949-20957
1996
Asteroidea, Callista chione, Plexaura homomalla, Strongylocentrotus purpuratus
brenda
Steel, D.J.; Tieman, T.L.; Schwartz, J.H.; Feinmark, S.L.
Identification of an 8-lipoxygenase pathway in nervous tissue of Aplysia californica
J. Biol. Chem.
272
18673-18681
1997
Aplysia californica
brenda
Qiao, N.; Takahashi, Y.; Takamatsu, H.; Yoshimoto, T.
Leukotriene A synthase activity of purified mouse skin arachidonate 8-lipoxygenase expressed in Escherichia coli
Biochim. Biophys. Acta
1438
131-139
1999
Mus musculus
brenda
Schneider, C.; Strayhorn, W.D.; Brantley, D.M.; Nanney, L.B.; Yull, F.E.; Brash, A.R.
Upregulation of 8-lipoxygenase in the dermatitis of IkB-a-deficient mice
J. Invest. Dermatol.
122
691-698
2004
Mus musculus
brenda
Coffa, G.; Brash, A.R.
A single active site residue directs oxygenation stereospecificity in lipoxygenases: Stereocontrol is linked to the position of oxygenation
Proc. Natl. Acad. Sci. USA
101
15579-15584
2004
Plexaura homomalla
brenda
Jisaka, M.; Iwanaga, C.; Takahashi, N.; Goto, T.; Kawada, T.; Yamamoto, T.; Ikeda, I.; Nishimura, K.; Nagaya, T.; Fushiki, T.; Yokota, K.
Double dioxygenation by mouse 8S-lipoxygenase: specific formation of a potent peroxisome proliferator-activated receptor alpha agonist
Biochem. Biophys. Res. Commun.
338
136-143
2005
Mus musculus
brenda
Oldham, M.L.; Brash, A.R.; Newcomer, M.E.
Insights from the X-ray crystal structure of coral 8R-lipoxygenase: calcium activation via a C2-like domain and a structural basis of product chirality
J. Biol. Chem.
280
39545-39552
2005
Plexaura homomalla
brenda
Schweiger, D.; Fuerstenberger, G.; Krieg, P.
Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways
J. Lipid Res.
48
553-564
2007
Mus musculus
brenda
Neau, D.B.; Gilbert, N.C.; Bartlett, S.G.; Boeglin, W.; Brash, A.R.; Newcomer, M.E.
The 1.85 A structure of an 8R-lipoxygenase suggests a general model for lipoxygenase product specificity
Biochemistry
48
7906-7915
2009
Plexaura homomalla (O16025), Plexaura homomalla
brenda
Walther, M.; Roffeis, J.; Jansen, C.; Anton, M.; Ivanov, I.; Kuhn, H.
Structural basis for pH-dependent alterations of reaction specificity of vertebrate lipoxygenase isoforms
Biochim. Biophys. Acta
1791
827-835
2009
Mus musculus
brenda
Saura, P.; Suardiaz, R.; Masgrau, L.; Gonzalez-Lafont, A.; Rosta, E.; Lluch, J.
Understanding the molecular mechanism of the Ala-versus-Gly concept controlling the product specificity in reactions catalyzed by lipoxygenases a combined molecular dynamics and QM/MM study of coral 8R-lipoxygenase
ACS Catal.
7
4854-4866
2017
Plexaura homomalla
-
brenda
Neau, D.B.; Bender, G.; Boeglin, W.E.; Bartlett, S.G.; Brash, A.R.; Newcomer, M.E.
Crystal structure of a lipoxygenase in complex with substrate the arachidonic acid-binding site of 8R-lipoxygenase
J. Biol. Chem.
289
31905-31913
2014
Plexaura homomalla (O16025)
brenda