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Information on EC 1.14.11.4 - procollagen-lysine 5-dioxygenase and Organism(s) Homo sapiens and UniProt Accession O60568
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1.14.11.4 procollagen-lysine 5-dioxygenaseIUBMB Comments
Requires Fe2+ and ascorbate.
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Word Map
- 1.14.11.4
-
prolyl
- ehlers-danlos
- hydroxylysine
-
jumonji
- fibrosis
- procollagens
-
fragility
-
domain-containing
- hydroxylases
-
osteogenesis
-
4-hydroxylase
-
kyphoscoliosis
- imperfecta
- demethylase
-
glucosyltransferase
-
pyridinoline
-
hypermobl
-
galactosyltransferase
- contractures
- minoxidil
- hypotonia
-
hydroxylysyl
-
hypermobility
-
bruck
- fkbp10
-
hyperelasticity
-
underhydroxylated
-
sclera
- scoliosis
-
laxity
-
chick-embryo
-
hyperextensibility
-
2-oxoglutarate-dependent
-
serpinh1
-
galactosylhydroxylysyl
- ppib
- medicine
-
crtap
- diagnostics
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
Reaction Schemes
Synonyms
jmjd6, plod2, lysyl hydroxylase, plod1, plod3, lysyl hydroxylase 2, lysyl hydroxylase 3, lysyl hydroxylase 1, procollagen-lysine 2-oxoglutarate 5-dioxygenase 2, procollagen-lysine 2-oxoglutarate 5-dioxygenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
lysyl hydroxylase
lysyl hydroxylase 3
2-oxoglutarate 5-dioxygenase 2
collagen lysine hydroxylase
-
-
-
-
Jmjd6
LH
LH2
lysine hydroxylase
-
-
-
-
lysine, 2-oxoglutarate 5-dioxygenase
-
-
-
-
lysine-2-oxoglutarate dioxygenase
-
-
-
-
lysyl hydroxylase
lysyl hydroxylase 2
lysylprotocollagen dioxygenase
-
-
-
-
oxygenase, protocollagen lysine, di-
-
-
-
-
peptidyl-lysine, 2-oxoglutarate: oxygen oxidoreductase
-
-
-
-
peptidyllysine, 2-oxoglutarate:oxygen 5-oxidoreductase
-
-
-
-
protocollagen lysine hydroxylase
-
-
-
-
protocollagen lysyl hydroxylase
-
-
-
-
additional information
-
the enzyme is a member of the 2-oxoglutarate-dependent dioxygenase family
lysyl hydroxylase 3
with lysyl hydroxylase, collagen galactosyltransferase and glucosylransferase activities
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
decarboxylation
-
-
-
-
redox reaction
-
-
-
-
hydroxylation
hydroxylation
-
-
-
-
hydroxylation
-
the enzyme catalyzes the formation of hydroxylysine by acting on -X-Lys-Gly- triplets in the collagenous domains of proteins of the collagen superfamily and also in -X-Lys-Ala- or -X-Lys-Ser- sequences in the telopeptides located at the ends of the polypeptide chains in some fibril-forming collagens
SYSTEMATIC NAME
IUBMB Comments
L-lysine-[procollagen],2-oxoglutarate:oxygen oxidoreductase (5-hydroxylating)
Requires Fe2+ and ascorbate.
CAS REGISTRY NUMBER
COMMENTARY
9059-25-0
-
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
(Ile-Lys-Gly)3 + 2-oxoglutarate + O2
(Ile-5-hydroxylyseine-Gly)3 + succinate + CO2
-
-
?
2-oxoglutarate + O2 + ascorbate
succinate + CO2 + dehydroascorbate + H2O
-
-
-
?
Ala-Arg-Gly-Ile-Lys-Gly-Ile-Arg-Gly-Phe-Ser-Gly + 2-oxoglutarate + O2
Ala-Arg-Gly-Ile-5-hydroxylysine-Gly-Ile-Arg-Gly-Phe-Ser-Gly + succinate + CO2
-
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
enzyme required during collagen biosynthesis
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
-
-
-
?
peptidyl-L-lysine + 2-oxoglutarate + O2
peptidyl-5-hydroxy-L-lysine + succinate + CO2
synthetic peptides
hydroxy-L-lysine
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
(Ile-Lys-Gly)3 + 2-oxoglutarate + O2
(Ile-5-hydroxylyseine-Gly)3 + succinate + CO2
-
-
-
?
2-oxoglutarate + O2 + ascorbate
succinate + CO2 + dehydroascorbate + H2O
-
-
-
-
?
L-lysine containing nonapeptides + 2-oxoglutarate + O2
5-hydroxy-L-lysine containing nonapeptides + succinate + CO2
-
diverse nonapeptides, synthetic substrates
-
-
?
L-lysine-[collagen] + 2-oxoglutarate + O2
5-hydroxy-L-lysine-[collagen] + succinate + CO2
-
-
-
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
luc7like2(267-278) + 2-oxoglutarate
? + succinate + CO2
substrate is a Luc7like2 protein fragment
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
[procollagen] L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
r
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
human lysyl hydroxylase 3 (LH3/PLOD3) is a multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3. Two distinct catalytic sites at the N- and C-terminal boundaries of each monomer are separated by an accessory domain. Collagen glucosyltransferase (EC 2.4.1.66) and procollagen galactosyltransferase (EC 2.4.1.50) activities localize at the N-terminus of the enzyme, whereas the lysyl hydroxylase activity (EC 1.14.11.4) is segregated at the LH3 C-terminus
-
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
-
-
-
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
-
enzyme required during collagen biosynthesis
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
-
enzyme required during collagen biosynthesis
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
enzyme required during collagen biosynthesis
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
-
influence the integrity and stability of collagen
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
influence the integrity and stability of collagen
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
-
-
-
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
-
PLOD2 specifically hydroxylates lysines in the telopeptide of procollagens, whereas PLOD1 is responsible for lysine hydroxylation in the alpha-helical or central domain
-
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
-
the hydroxylysyl residues are located in Y positions of X-Y-Gly repeats of collagenous sequences
-
-
?
L-lysine-[U2AF65] + 2-oxoglutarate + O2
5-hydroxy-L-lysine-[U2AF65] + succinate + CO2
-
U2AF65 is the splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 65-kDa subunit, which undergoes posttranslational lysyl-5-hydroxylation catalyzed by the Fe2+ and 2-oxoglutarate-dependent dioxygenase Jumonji domain-6 protein Jmjd6, a nuclear protein that has an important role in vertebrate development and is a human homologue of the HIF asparaginyl-hydroxylase
-
-
?
L-lysine-[U2AF65] + 2-oxoglutarate + O2
5-hydroxy-L-lysine-[U2AF65] + succinate + CO2
-
U2AF65 is the splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 65-kilodalton subunit
-
-
?
peptidyl-L-lysine + 2-oxoglutarate + O2
peptidyl-5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
peptidyl-L-lysine + 2-oxoglutarate + O2
peptidyl-5-hydroxy-L-lysine + succinate + CO2
-
-
hydroxy-L-lysine
?
peptidyl-L-lysine + 2-oxoglutarate + O2
peptidyl-5-hydroxy-L-lysine + succinate + CO2
-
minimum sequence required: Xaa-Lys-Gly
-
-
?
peptidyl-L-lysine + 2-oxoglutarate + O2
peptidyl-5-hydroxy-L-lysine + succinate + CO2
-
synthetic peptides
-
-
?
peptidyl-L-lysine + 2-oxoglutarate + O2
peptidyl-5-hydroxy-L-lysine + succinate + CO2
synthetic peptides
hydroxy-L-lysine
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
enzyme is important in fibrosis because its hydroxylation activity of lysine residues in telopeptides leads to increased cross-linking of accumulated collagen with pyrolidine in fibrotic tissues, enzyme expression in increased in systemic sclerosis
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
-
hydroxylation of lysine residues in collagenous sequences
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
some hydroxylated L-lysine residues are precursors for the cross-link formation essential for the tensile strength of collagen, the 2 splicing variants exhibit different specificity for hydroxylation of either telopeptide or helical collagen domain lysine residues, so that their relative expression level determines the type of cross-links formed and affecting collagen strength
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
additional information
?
-
-
lysyl hydroxylase catalyzes the posttranslational formation of hydroxylysines in -X-Lys-Gly- sequences in collagens and other proteins with collagen-like domains
-
-
?
additional information
?
-
lysyl hydroxylase catalyzes the posttranslational formation of hydroxylysines in -X-Lys-Gly- sequences in collagens and other proteins with collagen-like domains
-
-
?
additional information
?
-
-
LH3 differs from the other lysyl hydroxylase isoforms in that it possesses, in addition to lysyl hydroxylase activity, hydroxylysyl galactosyltransferase and galactosylhydroxylysyl glucosyltransferase activities, thus LH3 is able to catalyze the formation of glucosylgalactosylhydroxylysine residues
-
-
?
additional information
?
-
LH3 differs from the other lysyl hydroxylase isoforms in that it possesses, in addition to lysyl hydroxylase activity, hydroxylysyl galactosyltransferase and galactosylhydroxylysyl glucosyltransferase activities, thus LH3 is able to catalyze the formation of glucosylgalactosylhydroxylysine residues
-
-
?
additional information
?
-
-
Ehlers-Danlos syndrome type VIA patients show highly reduced enzyme activity
-
-
?
additional information
?
-
the long splicing variant of isozyme LH2 is the major ubiquitously-expressed form that is spliced into the short form, which is expressed together with the long form only in some tissues, e.g. kidney, spleen, liver, and placenta, alternative splicing can be regulated by both cell density and cycloheximide, regulation of LH2long transcript and of expression of both splicing variants in kidney via cycloheximide that suppress a factor taht inhibits exclusion of exon 13A thereby promoting expression of LH2short, and vice versa also via cycloheximide in fibroblasts, overview, perturbation of LH2 regulation can influence the stability of the extracellular matrix and contribute to connective tissue disorders
-
-
?
additional information
?
-
-
the long splicing variant of isozyme LH2 is the major ubiquitously-expressed form that is spliced into the short form, which is expressed together with the long form only in some tissues, e.g. kidney, spleen, liver, and placenta, alternative splicing can be regulated by both cell density and cycloheximide, regulation of LH2long transcript and of expression of both splicing variants in kidney via cycloheximide that suppress a factor taht inhibits exclusion of exon 13A thereby promoting expression of LH2short, and vice versa also via cycloheximide in fibroblasts, overview, perturbation of LH2 regulation can influence the stability of the extracellular matrix and contribute to connective tissue disorders
-
-
?
additional information
?
-
-
isozymes show no strict substrate specificity concerning the synthetic peptide substrates, but preferences for sequences, analysis of the different isozymes' binding affinities for the peptides whose net charges are very important, partly the peptides bind to the active site, overview
-
-
?
additional information
?
-
-
LH2 hydroxylates the N telopeptide of the full-length procollagen alpha type I chain when coexpressed with this isoenzyme
-
-
?
additional information
?
-
-
Jmjd6 changes alternative RNA splicing of some, but not all, of the endogenous and reporter genes, supporting a specific role for Jmjd6 in the regulation of RNA splicing, overview
-
-
?
additional information
?
-
-
LH3 is responsible for hydroxylysine formation and also for hydroxylysine glycosylations in polypeptides, enzyme mutations cause a severe phenotype, detailed overview
-
-
?
additional information
?
-
LH3 is responsible for hydroxylysine formation and also for hydroxylysine glycosylations in polypeptides, enzyme mutations cause a severe phenotype, detailed overview
-
-
?
additional information
?
-
-
the enzyme is responsible for the hydroxylation of collagen telopeptides
-
-
?
additional information
?
-
-
LH3 differs from the other lysyl hydroxylase isoforms in that it possesses, in addition to lysyl hydroxylase activity, hydroxylysyl galactosyltransferase and galactosylhydroxylysyl glucosyltransferase activities, thus LH3 is able to catalyze the formation of glucosylgalactosylhydroxylysine residues
-
-
?
additional information
?
-
LH3 differs from the other lysyl hydroxylase isoforms in that it possesses, in addition to lysyl hydroxylase activity, hydroxylysyl galactosyltransferase and galactosylhydroxylysyl glucosyltransferase activities, thus LH3 is able to catalyze the formation of glucosylgalactosylhydroxylysine residues
-
-
?
additional information
?
-
JMJD6 catalyses the iron- and 2-oxoglutarate-dependent hydroxylation of lysyl residues in arginine-serine-rich domains of RNAsplicing-related proteins. It catalyses C5 hydroxylation rather than Nepsilon demethylation
-
-
?
additional information
?
-
-
JMJD6 undergoes self-hydroxylation in the presence of Fe(II) and 2-oxoglutarate, in absence of substrate or in presence of substrates like U2AF65, resulting in production of (5S)<-hydroxylysine residues. JMJD6 in human cells is hydroxylated
-
-
?
additional information
?
-
-
lysyl hydroxylase 3 is a multifunctional enzyme of collagen biosynthesis, with glycosyltransferase activity and lysyl hydroxylase activity
-
-
?
additional information
?
-
-
in absence of substrate JMJD6 catalyses turnover of 2-oxoglutarate to succinate
-
-
?
additional information
?
-
an enzyme activity assay for detection of succinate is evaluated: the succinate-Glo assay, employing a luciferase-based luminescence system, is superior from the standpoint of stability and signal-to-noise ratio. Luciferase activity is detected over a wide range of concentrations of LH2, and the luminescence signal was proportional to the concentration of LH2. Method development and evaluation, overview
-
-
?
additional information
?
-
-
an enzyme activity assay for detection of succinate is evaluated: the succinate-Glo assay, employing a luciferase-based luminescence system, is superior from the standpoint of stability and signal-to-noise ratio. Luciferase activity is detected over a wide range of concentrations of LH2, and the luminescence signal was proportional to the concentration of LH2. Method development and evaluation, overview
-
-
?
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
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
enzyme required during collagen biosynthesis
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
L-lysine-[collagen] + 2-oxoglutarate + O2
5-hydroxy-L-lysine-[collagen] + succinate + CO2
-
-
-
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
L-lysine-[U2AF65] + 2-oxoglutarate + O2
5-hydroxy-L-lysine-[U2AF65] + succinate + CO2
-
U2AF65 is the splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 65-kDa subunit, which undergoes posttranslational lysyl-5-hydroxylation catalyzed by the Fe2+ and 2-oxoglutarate-dependent dioxygenase Jumonji domain-6 protein Jmjd6, a nuclear protein that has an important role in vertebrate development and is a human homologue of the HIF asparaginyl-hydroxylase
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
-
enzyme required during collagen biosynthesis
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
-
enzyme required during collagen biosynthesis
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
enzyme required during collagen biosynthesis
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
-
influence the integrity and stability of collagen
-
?
collagen + 2-oxoglutarate + O2
5-hydroxylysyl-collagen + succinate + CO2
influence the integrity and stability of collagen
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
-
-
-
-
?
L-lysine-[procollagen] + 2-oxoglutarate + O2
(2S,5R)-5-hydroxy-L-lysine-[procollagen] + succinate + CO2
-
PLOD2 specifically hydroxylates lysines in the telopeptide of procollagens, whereas PLOD1 is responsible for lysine hydroxylation in the alpha-helical or central domain
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
enzyme is important in fibrosis because its hydroxylation activity of lysine residues in telopeptides leads to increased cross-linking of accumulated collagen with pyrolidine in fibrotic tissues, enzyme expression in increased in systemic sclerosis
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
-
hydroxylation of lysine residues in collagenous sequences
-
-
?
procollagen L-lysine + 2-oxoglutarate + O2
procollagen 5-hydroxy-L-lysine + succinate + CO2
some hydroxylated L-lysine residues are precursors for the cross-link formation essential for the tensile strength of collagen, the 2 splicing variants exhibit different specificity for hydroxylation of either telopeptide or helical collagen domain lysine residues, so that their relative expression level determines the type of cross-links formed and affecting collagen strength
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
[procollagen]-L-lysine + 2-oxoglutarate + O2
[procollagen]-(2S,5R)-5-hydroxy-L-lysine + succinate + CO2
-
-
-
?
additional information
?
-
-
lysyl hydroxylase catalyzes the posttranslational formation of hydroxylysines in -X-Lys-Gly- sequences in collagens and other proteins with collagen-like domains
-
-
?
additional information
?
-
lysyl hydroxylase catalyzes the posttranslational formation of hydroxylysines in -X-Lys-Gly- sequences in collagens and other proteins with collagen-like domains
-
-
?
additional information
?
-
-
Ehlers-Danlos syndrome type VIA patients show highly reduced enzyme activity
-
-
?
additional information
?
-
the long splicing variant of isozyme LH2 is the major ubiquitously-expressed form that is spliced into the short form, which is expressed together with the long form only in some tissues, e.g. kidney, spleen, liver, and placenta, alternative splicing can be regulated by both cell density and cycloheximide, regulation of LH2long transcript and of expression of both splicing variants in kidney via cycloheximide that suppress a factor taht inhibits exclusion of exon 13A thereby promoting expression of LH2short, and vice versa also via cycloheximide in fibroblasts, overview, perturbation of LH2 regulation can influence the stability of the extracellular matrix and contribute to connective tissue disorders
-
-
?
additional information
?
-
-
the long splicing variant of isozyme LH2 is the major ubiquitously-expressed form that is spliced into the short form, which is expressed together with the long form only in some tissues, e.g. kidney, spleen, liver, and placenta, alternative splicing can be regulated by both cell density and cycloheximide, regulation of LH2long transcript and of expression of both splicing variants in kidney via cycloheximide that suppress a factor taht inhibits exclusion of exon 13A thereby promoting expression of LH2short, and vice versa also via cycloheximide in fibroblasts, overview, perturbation of LH2 regulation can influence the stability of the extracellular matrix and contribute to connective tissue disorders
-
-
?
additional information
?
-
-
Jmjd6 changes alternative RNA splicing of some, but not all, of the endogenous and reporter genes, supporting a specific role for Jmjd6 in the regulation of RNA splicing, overview
-
-
?
additional information
?
-
-
LH3 is responsible for hydroxylysine formation and also for hydroxylysine glycosylations in polypeptides, enzyme mutations cause a severe phenotype, detailed overview
-
-
?
additional information
?
-
LH3 is responsible for hydroxylysine formation and also for hydroxylysine glycosylations in polypeptides, enzyme mutations cause a severe phenotype, detailed overview
-
-
?
additional information
?
-
-
the enzyme is responsible for the hydroxylation of collagen telopeptides
-
-
?
additional information
?
-
JMJD6 catalyses the iron- and 2-oxoglutarate-dependent hydroxylation of lysyl residues in arginine-serine-rich domains of RNAsplicing-related proteins. It catalyses C5 hydroxylation rather than Nepsilon demethylation
-
-
?
additional information
?
-
-
JMJD6 undergoes self-hydroxylation in the presence of Fe(II) and 2-oxoglutarate, in absence of substrate or in presence of substrates like U2AF65, resulting in production of (5S)<-hydroxylysine residues. JMJD6 in human cells is hydroxylated
-
-
?
additional information
?
-
-
lysyl hydroxylase 3 is a multifunctional enzyme of collagen biosynthesis, with glycosyltransferase activity and lysyl hydroxylase activity
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
NaCl
-
reduces the activity of the isozymes LH1, LH2a, LH2b, and LH3 with most of the synthetic nonpeptide substrates tested, in some cases the isozyme is activated or completely inhibited, overview
Fe2+
-
a peptide fold in the iron-binding site, within the 40 amino acid residues at the C-terminus, is responsible for KDEL-receptor-independent localization in the endoplasmic reticulum
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
L-alpha-hydroxyglutarate
the enzyme activity is inhibited by L-alpha-hydroxyglutarate but not its enantiomer D-alpha-hydroxyglutarate
minoxidil
-
0.4 mM inhibits LH1 completely, 1 mM inhibits LH2b and LH3 incompletely
NaCl
-
reduces the activity of the isozymes LH1, LH2a, LH2b, and LH3 with most of the synthetic nonpeptide substrates tested, in some cases the isozyme is activated or completely inhibited, overview
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
comparison of Km of 2-oxoglutarate, ascorbate, Fe2+ and type I, type II and type IV protocollagen as substrate with type I, type II and type IV enzyme
-
additional information
additional information
-
Km of recombinant isozymes LH1, LH2a, LH2b, and LH3 for diverse synthetic nonpeptide substrates, overview
-
additional information
additional information
steady-state kinetics of LH2
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
isoform LH3, possessing lysyl hydroxylase, collagengalactosyltransferase and glucosyltransferase activities
UniProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
the expression of all PLOD family members is higher in astrocytoma than in oligoastrocytoma and oligodendroglioma
PLOD2 is mainly expressed within the tunica media of the blood vessels
increased LH2 enzyme activity in lung carcinoma compared to healthy lung
the expression of all PLOD family members is higher in astrocytoma than in oligoastrocytoma and oligodendroglioma
additional information
additional information
the long splicing variant of isozyme LH2 is the major ubiquitously-expressed form that is spliced into the short form, which is expressed together with the long form only in some tissues, e.g. kidney, cartilage, spleen, liver, and placenta, not in skin, lung, aorta, and dura
additional information
-
the long splicing variant of isozyme LH2 is the major ubiquitously-expressed form that is spliced into the short form, which is expressed together with the long form only in some tissues, e.g. kidney, cartilage, spleen, liver, and placenta, not in skin, lung, aorta, and dura
additional information
PLOD2 expression determination by immunhistochemic analysis
additional information
-
PLOD2 expression determination by immunhistochemic analysis
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
LH3 found on the cell surface bypasses the Golgi complex
LH3 is the only secreted LH isoform, LH3 is secreted by two pathways, one through the Golgi complex leading to EndoH resistant LH3, and the other by-passing the Golgi complex and leading to EndoH sensitive LH3
-
additional information
while the lysyl hydroxylase active site mediates retention of LH3 in the endoplasmic reticulum, the glucosyltransferase active site is required for the secretion of LH3 into the extracellular space
-
additional information
lysyl hydroxylase 3 is a multifunctional protein that localizes to the endoplasmic reticulum but is also secreted into the extracellular space and is associated with collagenous proteins on the cell surface
-
additional information
-
a peptide fold in the iron-binding site, within the 40 amino acid residues at the C-terminus, is responsible for KDEL-receptor-independent localization in the endoplasmic reticulum
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
the expression level of the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in lower-grade glioma (LGG)
malfunction
physiological function
drug target
evolution
the enzyme belongs to the 2-oxoglutarate/Fe2+-dependent oxygenase family
malfunction
metabolism
-
in osteoarthritic human synovial fibroblasts, the enzyme expression is induced by TGF-beta via kinase ALK5, not ALK1, and Smad2/3P
physiological function
additional information
-
heterocomplex formation between mouse and human LH3, between human LH1 and LH3 and between human LH2 and LH3, low amount of complexes formed in vivo
malfunction
reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix. Mutations in the human LH3 gene cause a severe connective tissue disorder with features that overlap with a number of collagen disorders
malfunction
disorders of LH3 with a unique phenotype causing severe morbidity as a result of feauters that overlap with collagen disorders
malfunction
enzyme LH3 downregulation decreases MMP-9 recruitment to MRC-5 and thus MMP-9/LH3 interaction
physiological function
the enzyme LH3 has an important role in the organization of the extracellular matrix and the cytoskeleton
physiological function
forms part of the many posttranslational modifications required during collagen biosynthesis
physiological function
lysyl hydroxylase 3 (LH3) is a post-translational modification enzyme with lysyl hydroxylase, collagen galactosyltransferase EC 2.4.1.50, and glucosyltransferase, EC 2.4.1.66, activities, LH3 is able to catalyze the three consecutive reactions required for the formation of unique hydroxylysine-linked carbohydrates, galactosylhydroxylysine and glucosylgalactosyl hydroxylysine, found in collagens and a few other proteins. The active sites for the different activities of the mutifunctional enzyme are localized separately in the C- and the N-terminal parts of the molecule. While the lysyl hydroxylase active site mediates retention of LH3 in the endoplasmic reticulum, the glucosyltransferase active site is required for the secretion of LH3 into the extracellular space
physiological function
recruitment of matrix metalloproteinase-9 (MMP-9) to the fibroblast cell surface by lysyl hydroxylase 3 triggers transforming growth factor-beta (TGF-beta) activation and fibroblast differentiation. LH3 provides the docking mechanism for MMP-9 cell surface association via the MMP-9 FN domain. Recruitment of MMP-9 to fibroblast cell surface does not depend merely on LH3 expression at the cell membrane. LH3 provides a mechanism for deployment of MMP-9 catalytic activity at the fibroblast cell surface that promotes TGF-beta activation and the corresponding enhancement of alpha-SMA expression. MMP-9-induced TGF-beta activation promotes alpha-SMA expression in fibroblasts is consistent with a function that supports tumor progression. LH3 expressed in a variety of tumor cell types fails to recruit MMP-9 to their cell surface
physiological function
procollagen-lysine,2-oxoglutarate 5-dioxygenase (PLOD) family is involved in processes, such as tumor formation and cancer metastasis. A high expression of the PLOD family relates to poor prognosis and high infiltration of immune cells within the tumor microenvironment (TME)
drug target
normalizing the cross-link pattern by selectively inhibiting LH2 (and thus hydroxy-alpha-aminoadipic acid-delta-semialdehyde cross-linking) alters the balance of collagen degradation. It is expected that this results in reversible fibrosis. Since the up-regulation of LH2 is seen in all organs, a drug that specifically inhibits LH2 activity can be used in a wide range of fibrotic disorders. Since LH2 catalyzes only a single reaction downstream in the fibrogenic cascade (namely the formation of unwanted cross-links in collagen of the fibrotic lesions), little (if any) side-effects are expected, as the deposited collagen in the wound area is expected to be normally modified, and thus have the properties (e.g. with respect to tensile strength) required for a normal function of the repaired tissue
drug target
PLOD2 is a gene of clinical relevance with implications in glioblastoma invasion and treatment strategies. PLOD2 expression is positively correlated with tumor grade and inversely associated with glioblastoma patient prognosis
drug target
the expression level of the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in lower-grade glioma (LGG)
malfunction
-
although differential expression of LH2 (long) is associated with fibrotic conditions, there is no direct evidence that the increased Pyr cross-links in the overaccumulated collagen contribute definitively to fibrosis
malfunction
reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix
malfunction
-
PLOD2 knockdown prevents fibrillar collagen formation in breast tumors, decreased PLOD2 expression in breast cancer cells inhibits metastasis, also lung metastasis is significantly impaired by PLOD2 knockdown
malfunction
patients with Bruck syndrome, a recessively inherited disorder with inactivating mutations in the gene encoding LH2 (PLOD2/LH2), have traits of osteogenesis imperfecta with congenital contractures of the large joints. Conversely, skin fibroblasts from patients with systemic sclerosis, a fibrotic disease involving skin and other organs, have elevated LH2 expression and increased production of HLCCs
malfunction
knockdown of PLOD2 in glioma cell lines leads to decreases in migration and invasion under normoxia and hypoxia
physiological function
-
the enzyme is responsible for the hydroxylation of collagen telopeptides
physiological function
the enzyme LH3 has an important role in the organization of the extracellular matrix and the cytoskeleton
physiological function
-
in hypoxic breast cancer cells, hypoxia-inducible factor 1 activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the extracellular matrix. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs
physiological function
-
lysyl hydroxylases are enzymes that catalyze the hydroxylation of lysine into hydroxylysine and, therefore, fulfill a crucial role in collagen modification and cross-linking. Lysyl hydroxylase 2b increases pyridinoline cross-links, making collagen less susceptible to enzymatic degradation
physiological function
-
the lysyl 5S-hydroxylase, JMJD6 acts on proteins involved in RNA splicin. JMJD6 in human cells is self-hydroxylated at Lys111JMJD6 and Lys167JMJD6 to give lysyl 5S-hydroxylase. Self-hydroxylation of JMJD6 may play a regulatory role in modulating the hydroxylation status of proteins involved in RNA splicing
physiological function
hydroxylysine aldehyde-derived collagen cross-links (HLCCs) accumulate in fibrotic tissues and certain types of cancer and are thought to drive the progression of these diseases. HLCC formation is initiated by lysyl hydroxylase 2 (LH2), an Fe(II) and 2-oxoglutarate-dependent oxygenase that hydroxylates telopeptidyl lysine residues on collagen
physiological function
intracellular procollagen-lysine, 2-oxoglutarate 5-dioxygenase enzymes induce hydroxylation of Lys residues on collagen prior to formation of triple helical pro-collagen molecules. Following secretion of pro-collagen molecules into the extracellular space, the telopeptidyl Hyl residues undergo LOX-induced oxidative deamination into Hylald, which then forms Hylald-derived aldimine cross-links that spontaneously rearrange into stable ketoamines; these further mature into stable Hylald-derived collagen cross-links (HLCCs). Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. Epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen crosslinks. relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Lysyl hydroxylase 2 (LH2) hydroxylates telopeptidyl lysine residues on collagen, and shifts the tumor stroma toward a high-HLCC, low-LCC state, increasing tumor stiffness, and enhancing tumor cell invasion and metastasis. LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma
physiological function
procollagen-lysine,2-oxoglutarate 5-dioxygenase 2, PLOD2, is involved in the posttranscriptional modification of collagen molecules and considered as a key mediator of collagen cross-linking and thus an important factor for the stability of the extracellular matrix. PLOD2 is known to be associated with several connective tissue diseases, such as Ehlers-Danlos syndrome type VI A, systemic sclerosis, and Bruck syndrome. Isozyme PLOD2 is involved in the pathology of brain arteriovenous malformations (bAVM), severe conditions that can cause severe neurologic deficits and mortality. High levels of PLOD2 expression correlate with bAVM size. Although PLOD2 is not directly associated with bAVM hemorrhage, high PLOD2-expressing bAVM have a lower frequency of hemorrhage compared with low or medium PLOD2-expressing bAVM (25% vs. 63% and 75%, respectively)
physiological function
the enzyme hydroxylates lysine residues in collagen telopeptides and is essential for collagen pyridinoline cross-link formation. PLOD2 expression and subsequent pyridinoline cross-links are increased in fibrotic pathologies by transforming growth factorbeta-1 (TGFbeta1). Binding of the TGFbeta1 pathway related transcription factors SMAD3 and SP1-mediated TGFbeta1 enhanced PLOD2 expression and might be correlated to an increase of acetylated histone H3 and H4 at the PLOD2 promoter
physiological function
lysyl hydroxylase 2 is responsible for the formation of telopeptidyl hydroxylysine, leading to the formation of hydroxy-alpha-aminoadipic acid-delta-semialdehyde cross-links by lysyl oxidases. The enzyme is universally up-regulated in fibrosis
physiological function
PLOD2 promotes tissue invasion of human glioma cells
physiological function
procollagen-lysine,2-oxoglutarate 5-dioxygenase (PLOD) family is involved in processes, such as tumor formation and cancer metastasis. A high expression of the PLOD family relates to poor prognosis and high infiltration of immune cells within the tumor microenvironment (TME)
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). PLOD3_HUMAN
738
0
84785
Swiss-Prot
Secretory Pathway (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
82380
2 * 82380, calculation from amino acid sequence, recombinant enzyme: isoform 3
42000
x * 42000, recombinant His-tagged catalytic domain of JMJD6, residues 1-343
88000
2 * 88000 or 97000 SDS-PAGE, recombinant enzymes: isoform 2, possibly two forms are due to variation in the glycosylation of enzymes
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
two distinct catalytic sites at the N- and C-terminal boundaries of each monomer are separated by an accessory domain. Dimerization is essential for lysyl hydroxylase activity, whereas disruption of physiological dimers does not significantly perturb the N-terminal glycosyltransferase activities of LH3
homodimer
2 * 82380, calculation from amino acid sequence, recombinant enzyme: isoform 3
?
x * 42000, recombinant His-tagged catalytic domain of JMJD6, residues 1-343
dimer
-
localization of the region responsible for the dimerization of lysyl hydroxylase 3, to a sequence of amino acids between the glycosyltransferase activity and the lysyl hydroxylase activity domains. This area is covered by amino acids 541-547 and contains no cysteine residues
homodimer
additional information
structure of the catalytic domain of recombinant His-tagged JMJD6 and active site structure, overview
homodimer
2 * 88000 or 97000 SDS-PAGE, recombinant enzymes: isoform 2, possibly two forms are due to variation in the glycosylation of enzymes
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
side-chain modification
additional information
-
posttranslational hydroxylation in both the cytoplasm and the nucleoplasm is ubiquitous
glycoprotein
identification of LH2 glycosylation by nanoLC MS/MS analysis
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
sitting drop vapor diffusion method, crystal structures of full-length human LH3 in complex with cofactors and donor substrates provide a molecular understanding of the biochemical knowledge underlying the multiple functions of this enzyme
purified recombinant His-tagged SeMet-derivatised and wild-type JMJD61-343, at both 20°C and 4°C by the sitting drop vapour diffusion method, X-ray diffraction structure determination and analysis at 1.75-2.0 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N223S
site-directed mutagenesis, the mutant shows 50% reduced lysylhydroxylase activity, while the glycosyltransferase activity is almost abolished
G597V
-
naturally occuring recessive point mutation, leads to abnormal folding and oligomerization of the mutant enzyme, which shows over 95% reduced activity compared to the wild-type enzyme
K694G
-
site-directed mutagenesis, point mutation is introduced in the LH1 part of the expression construct comprising 40 amino acid residues of the C-terminal end of isozyme LH1, responsible for endoplasmic reticulum localization, fused to human cathepsin D and c-Myc-tagged, the exchange of the charged residue and deletion of 8 amino acids of the last 40 residues at the enzymes' C-terminal end has no effect on retention efficiency of the reporter protein, but deletion of the next 8 amino acid residues, leaving 24 residues, increases the secretion level of enzyme from the cell
R594H
-
naturally occuring recessive point mutation, leads to abnormal folding and oligomerization of the mutant enzyme, which shows over 95% reduced activity compared to the wild-type enzyme
R693Q
-
site-directed mutagenesis, point mutation is introduced in the LH1 part of the expression construct comprising 40 amino acid residues of the C-terminal end of isozyme LH1, responsible for endoplasmic reticulum localization, fused to human cathepsin D and c-Myc-tagged, the exchange of the charged residue and deletion of 8 amino acis of the last 40 residues at the enzymes' C-terminal end has no effect on retention efficiency of the reporter protein, but deletion of the next 8 amino acid residues, leaving 24 residues, increases the secretion level of enzyme from the cell
T604I
-
naturally occuring recessive point mutation, leads 70-92% reduced activity, dependent on the 2-oxoglutarate concentration, compared top the wild-type due to a 10fold increase in the Km for 2-oxoglutarate, the mutant shows unaltered folding and oligomerization. The Km values of the T604I mutant for the peptide substrate, Fe2+, and ascorbate are identical to those of the wild-type
W446G
-
naturally occurring mutation T1360G in a highly conserved region of exon 13 of isozyme LH1 in skin fibroblasts is predicted to lead to the W446G exchange in heterozygous Ehlers-Danlos syndrome type IVA, leads to loss of enzyme activity and causes the pathogenic effect probably due to incorect folding of isozyme LH1, structure-function analysis
additional information
additional information
targeted disruption of isoform LH3 by siRNA causes a marked reduction of both glycosyltransferase activities. Overexpression of LH3 increases hydroxylation of lysyl residues and the subsequent galactosylation and glucosylation of hydroxylysyl residues. Treatment of cells in culture medium with a LH3 N-terminal fragment affects the cell behavior, rapidly leading to arrest of growth in a reversible manner
additional information
-
glucosyltransferase, GGT, deficiency, e.g. in the Finnish epidermolysis bullosa simplex family, due to a transcriptional defect in one LH3 allele affects the extracellular matrix deposition and the arrangement of the cytoskeleton in skin fibroblasts, phenotype, overview
additional information
glucosyltransferase, GGT, deficiency, e.g. in the Finnish epidermolysis bullosa simplex family, due to a transcriptional defect in one LH3 allele affects the extracellular matrix deposition and the arrangement of the cytoskeleton in skin fibroblasts, phenotype, overview
additional information
-
A668G, higher apparent molecular mass, reduced collagen galctosyltransferase, EC 2.4.1.50, and reduced glucosyltransferase activity, EC 2.4.1.66, about 50% decreased lysyl hydroxylase activity
additional information
A668G, higher apparent molecular mass, reduced collagen galctosyltransferase, EC 2.4.1.50, and reduced glucosyltransferase activity, EC 2.4.1.66, about 50% decreased lysyl hydroxylase activity
additional information
-
delT2071, lower apparent molecular mass, reduced collagen galctosyltransferase, EC 2.4.1.50, and reduced glucosyltransferase activity, EC 2.4.1.66, complete loss of lysyl hydroxylase activity
additional information
delT2071, lower apparent molecular mass, reduced collagen galctosyltransferase, EC 2.4.1.50, and reduced glucosyltransferase activity, EC 2.4.1.66, complete loss of lysyl hydroxylase activity
additional information
LH-deficient mutant, deficiency of LH3 glycosyltransferase activity decreases cell growth and increases lethality
additional information
overexpression of LH3, increased hydroxylation of lysyl residues and increased galactosylation and glucosylation of hydroxylysyl residues
additional information
identification of a PLOD2 mutant bearing 2 missense mutations in exon 17 in patients with Buck syndrome caused by a pyrolidine deficiency in bone due to decreased enzyme activity
additional information
-
identification of a PLOD2 mutant bearing 2 missense mutations in exon 17 in patients with Buck syndrome caused by a pyrolidine deficiency in bone due to decreased enzyme activity
additional information
-
glucosyltransferase, GGT, deficiency in heterozygous LH3 knock-out mouse embryonic fibroblasts affects the extracellular matrix deposition and the arrangement of the cytoskeleton, phenotype, overview. LH3 knock-out embryos and embryonic fibroblasts indicate that the loss of hydroxylysine glycosylation prevents the assembly and secretion of type IV and VI collagens, LH mutant mice show ultrastructural alterations in their skin and muscle
additional information
glucosyltransferase, GGT, deficiency in heterozygous LH3 knock-out mouse embryonic fibroblasts affects the extracellular matrix deposition and the arrangement of the cytoskeleton, phenotype, overview. LH3 knock-out embryos and embryonic fibroblasts indicate that the loss of hydroxylysine glycosylation prevents the assembly and secretion of type IV and VI collagens, LH mutant mice show ultrastructural alterations in their skin and muscle
additional information
-
mutations in the LH3 gene cause connective tissue disorder. Genotype-phenotype analysis of PLOD3 mutations, phenotypes, detailed overview
additional information
mutations in the LH3 gene cause connective tissue disorder. Genotype-phenotype analysis of PLOD3 mutations, phenotypes, detailed overview
additional information
-
siRNA knockdowns of TIA-1 and TIAL1 both singly and in combination in HEK293 cells decrease the ratio of LH2 (long) to LH2 (short) splicing variants
additional information
-
monomerization inactivates the LH activity of LH3, distribution of monomers, dimers, and multimers in mutant enzyme structures, overview. Glycosyltransferase activity of the mutant enzymes, overview
additional information
generation of an N-terminally truncated enzyme mutant comprising residues 33-758
additional information
-
generation of an N-terminally truncated enzyme mutant comprising residues 33-758
additional information
overexpression of isozyme LH2 in osteoblasts induces a switch in the predominant type of collagen cross-link from LCC to HLCC, which qualitatively affects fibrillogenesis and matrix organization
additional information
-
overexpression of isozyme LH2 in osteoblasts induces a switch in the predominant type of collagen cross-link from LCC to HLCC, which qualitatively affects fibrillogenesis and matrix organization
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ProBond metal chelate affinity resin chromatography and Chelating Sepharose fast flow column chromatography
-
recombinant His-tagged full-length JMJD6 and JMJD61-343 from Escherichia coli strain Rosetta by nickel affinity chromatography
recombinant His-tagged isozymes LH1-3 from Sf9 insect cells by nickel affinity chromatography
-
recombinant wild-type and mutant enzymes from Sf9 insect cells by chelating affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene PLOD3, DNA and amino acid sequence determination and analysis, quantitative expression analysis
gene PLOD3, expression in COS-7 and HT-1080 cells, the enzyme is secreted into the culture medium, expression of enzyme mutants in COS-7 cells
overexpression in HT-1080 cells, expression of fragments in Escherichia coli
all 3 isozymes LH1-3, LH2 in 2 splicing variants, are expressed in as His-tagged proteins in Spodoptera frugiperda Sf9 cells via baculovirus infection system with the signal peptide at the N-terminus in isozymes LH2a and b and LH3 being exchanged for the signal peptide of isozyme LH1
-
DNA and amino acid sequence determination and analysis of mutant DNA from an Ehlers-Danlos syndrome type IVA patient, expression of mutant enzyme W446G in an insect cell system via baculovirus infection
-
endogenous LH2 alternate splicing pattern and conservation analysis of LH2 genomic sequence., overview. Construction and expression of a functional LH2 minigene in HEK-293 cells, human neonatal skin fibroblasts, and mouse embryonic fibroblasts. The TIA proteins play a role in the regulation of the alternative splicing of LH2, overview
-
expression in insect cells using a baculovirus vector
expression of 40 amino acid residues of the C-terminal end of isozyme LH1 fused to human cathepsin D and c-Myc-tagged and 2 mutant variants thereof in COS-7 cells
-
expression of a synthetic gene encoding LH3, SEQ ID, in Nicotiana tabacum leaves. Co-expression of the human genes encoding recombinant heterotrimeric collagen type I, rhCOL1, the human prolyl-4-hydroxylase, and the lysyl hydroxylase 3, all responsible for key posttranslational modifications of collagen. Plants coexpressing all five vacuole-targeted proteins generate intact procollagen yields ofabout 2% of the extracted total soluble protein, overview
-
expression of GFP-tagged Jmjd6 in HEK-293 cells, GFP pulldown interaction analysis with U2AF65, overview
-
expression of His-tagged full-length JMJD6 and JMJD61-343 in Escherichia coli strain Rosetta
expression of wild-type and mutantenzymes in Spodoptera frugiperda Sf9 cells using the baculovirus transfection method
-
gene PLOD2
gene PLOD2, binding of the TGFbeta1 pathway related transcription factors SMAD3 and SP1-mediated TGFbeta1 enhanced PLOD2 expression and might be correlated to an increase of acetylated histone H3 and H4 at the PLOD2 promoter. Depletion of SMAD3 reduces gene PLOD2 acetylated H3 and H4, histone methylation marks at the PLOD2 promoter depicted an increase of the active histone mark H3K79me2, a decrease of the repressive H4K20me3 mark, but no role for the generally strong transcription-related modifications: H3K4me3, H3K9me3 and H3K27me3. TGFbeta1 induces a SP1- and SMAD3-dependent recruitment of histone modifying enzymes to the PLOD2 promoter other than the currently known TGFbeta1 downstream co-activators and epigenetic modifications. Quantitative real-time PCR enzyme expression analysis
gene PLOD2, encoding for splice variants LH2a and LH2b, quantitative expression analysis of LH2b
-
gene PLOD2, large-scale transfection with N-terminal His8 and human growth hormone (hGH) tags transfection with polyethylenimine and recombinant expression of wild-type enzyme, N-terminally truncated enzyme mutant, and of inactive mutant D689A in engineered CHO cells and secretion to the cell culture medium
genomic structure of isozyme LH2, expression analysis of the 2 splicing variants of isozyme LH2
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
highly expressed in lower-grade glioma tumor tissues compared to normal tissues
highly expressed in lower-grade glioma tumor tissues compared to normal tissues
hypoxia upregulates PLOD2 protein in U87 and U251 human glioma cell lines. siRNA knockdown of endogenous HIF-1alpha or treatment of cells with the HIF-1alpha inhibitor PX-478 largely abolishes the hypoxia-mediated PLOD2 upregulation
hypoxia-inducible factor 1 activates transcription of the PLOD1 and PLOD2 genes in hypoxic breast cancer cells, knockdown of HIF-1a expression blocks PLOD1 and PLOD2 induction under hypoxic conditions
-
in osteoarthritic human synovial fibroblasts, the enzyme expression is induced by TGF-beta via kinase ALK5, not ALK1, and Smad2/3P
-
overexpression of the TIA proteins in HEK-293 cells leads to an increase in levels of the LH2(long) spliced product in the minigene
-
PLOD2 mRNA is significantly overexpressed in glioblastoma compared to low-grade tumors. High PLOD2 expression is associated with poor prognosis
procollagen lysyl hydroxylase 2 expression is regulated by an alternative downstream transforming growth factor beta-1 activation mechanism. TGF-beta1 induces the enzyme, mechanism of TGFbeta1-enhanced PLOD2 expression, detailed overview
reduction of TIA protein levels in mous embryonic fibroblasts and HEK-293 cells leads to a corresponding decrease in the LH2(long) spliced product in both the minigene and the endogenous gene
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
the expression level of the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in lower-grade glioma (LGG)
medicine
deficiency in enzyme activity causes the Ehler-Danlos syndrome type 6
diagnostics
medicine
diagnostics
-
PLOD expression is associated with human breast cancer progression, PLOD2 expression is specifically prognostic in breast cancer
diagnostics
the expression level of the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in lower-grade glioma (LGG)
medicine
-
deficiency in enzyme activity causes the Ehler-Danlos syndrome type 6
medicine
-
LH2b is an interesting target to interfere with osteoarthritis-related persistent fibrosis
medicine
isozyme LH2 is of interest as candidate mediator of a p21-independent transcriptional program that regulates the metastatic propensity of KC cells. LH2 promotes lung cancer metastatic behavior and predicts poor prognosis in patients
REF.
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TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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Homo sapiens
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Homo sapiens (O00469), Homo sapiens
Passoja, K.; Rautavuoma, K.; Ala-Kokko, L.; Kosonen, T.; Kivirikko, K.I.
Cloning and characterization of a third human lysyl hydroxylase isoform
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Homo sapiens (O60568), Homo sapiens
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Gallus gallus, Homo sapiens, Rattus norvegicus (Q63321)
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Homo sapiens
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Homo sapiens (O00469), Homo sapiens
Risteli, M.; Niemitalo, O.; Lankinen, H.; Juffer, A.H.; Myllyla, R.
Characterization of collagenous peptides bound to lysyl hydroxylase isoforms
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279
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2004
Caenorhabditis elegans, Homo sapiens
Walker, L.C.; Overstreet, M.A.; Siddiqui, A.; De Paepe, A.; Ceylaner, G.; Malfait, F.; Symoens, S.; Atsawasuwan, P.; Yamauchi, M.; Ceylaner, S.; Bank, R.A.; Yeowell, H.N.
A novel mutation in the lysyl hydroxylase 1 gene causes decreased lysyl hydroxylase activity in an Ehlers-Danlos VIA patient
J. Invest. Dermatol.
124
914-918
2005
Homo sapiens
Walker, L.C.; Overstreet, M.A.; Yeowell, H.N.
Tissue-specific expression and regulation of the alternatively-spliced forms of lysyl hydroxylase 2 (LH2) in human kidney cells and skin fibroblasts
Matrix Biol.
23
515-523
2005
Homo sapiens (O00469), Homo sapiens
Wu, J.; Reinhardt, D.P.; Batmunkh, C.; Lindenmaier, W.; Far, R.K.; Notbohm, H.; Hunzelmann, N.; Brinckmann, J.
Functional diversity of lysyl hydroxylase 2 in collagen synthesis of human dermal fibroblasts
Exp. Cell Res.
312
3485-3494
2006
Homo sapiens
Zuurmond, A.M.; van der Slot-Verhoeven, A.J.; van Dura, E.A.; De Groot, J.; Bank, R.A.
Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: implications for collagen cross-linking and treatment of fibrosis
Matrix Biol.
24
261-270
2005
Homo sapiens
Takaluoma, K.; Lantto, J.; Myllyharju, J.
Lysyl hydroxylase 2 is a specific telopeptide hydroxylase, while all three isoenzymes hydroxylate collagenous sequences
Matrix Biol.
26
396-403
2007
Homo sapiens
Salo, A.M.; Cox, H.; Farndon, P.; Moss, C.; Grindulis, H.; Risteli, M.; Robins, S.P.; Myllylae, R.
A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene
Am. J. Hum. Genet.
83
495-503
2008
Homo sapiens, Homo sapiens (O60568)
Stein, H.; Wilensky, M.; Tsafrir, Y.; Rosenthal, M.; Amir, R.; Avraham, T.; Ofir, K.; Dgany, O.; Yayon, A.; Shoseyov, O.
Production of bioactive, post-translationally modified, heterotrimeric, human recombinant type-I collagen in transgenic tobacco
Biomacromolecules
10
2640-2645
2009
Homo sapiens
Risteli, M.; Ruotsalainen, H.; Salo, A.M.; Sormunen, R.; Sipilae, L.; Baker, N.L.; Lamande, S.R.; Vimpari-Kauppinen, L.; Myllylae, R.
Reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix
J. Biol. Chem.
284
28204-28211
2009
Homo sapiens, Homo sapiens (O60568)
Hyry, M.; Lantto, J.; Myllyharju, J.
Missense mutations that cause Bruck syndrome affect enzymatic activity, folding, and oligomerization of lysyl hydroxylase 2
J. Biol. Chem.
284
30917-30924
2009
Homo sapiens
Wang, C.; Kovanen, V.; Raudasoja, P.; Eskelinen, S.; Pospiech, H.; Myllylae, R.
The glycosyltransferase activities of lysyl hydroxylase 3 (LH3) in the extracellular space are important for cell growth and viability
J. Cell. Mol. Med.
13
508-521
2009
Homo sapiens (O60568)
Yeowell, H.N.; Walker, L.C.; Mauger, D.M.; Seth, P.; Garcia-Blanco, M.A.
TIA nuclear proteins regulate the alternate splicing of lysyl hydroxylase 2
J. Invest. Dermatol.
129
1402-1411
2009
Homo sapiens
Webby, C.J.; Wolf, A.; Gromak, N.; Dreger, M.; Kramer, H.; Kessler, B.; Nielsen, M.L.; Schmitz, C.; Butler, D.S.; Yates, J.R.; Delahunty, C.M.; Hahn, P.; Lengeling, A.; Mann, M.; Proudfoot, N.J.; Schofield, C.J.; Boettger, A.
Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing
Science
325
90-93
2009
Homo sapiens
Mantri, M.; Krojer, T.; Bagg, E.A.; Webby, C.J.; Butler, D.S.; Kochan, G.; Kavanagh, K.L.; Oppermann, U.; McDonough, M.A.; Schofield, C.J.
Crystal structure of the 2-oxoglutarate- and Fe(II)-dependent lysyl hydroxylase JMJD6
J. Mol. Biol.
401
211-222
2010
Homo sapiens (Q6NYC1)
Wang, C.; Ristiluoma, M.M.; Salo, A.M.; Eskelinen, S.; Myllylae, R.
Lysyl hydroxylase 3 is secreted from cells by two pathways
J. Cell. Physiol.
227
668-675
2012
Canis lupus familiaris, Homo sapiens (O60568), Canis lupus familiaris Madin-Darby
Remst, D.F.; Blaney Davidson, E.N.; Vitters, E.L.; Bank, R.A.; van den Berg, W.B.; van der Kraan, P.M.
TGF-beta induces lysyl hydroxylase 2b in human synovial osteoarthritic fibroblasts through ALK5 signaling
Cell Tissue Res.
355
163-171
2013
Homo sapiens
Heikkinen, J.; Risteli, M.; Lampela, O.; Alavesa, P.; Karppinen, M.; Juffer, A.; Myllylae, R.
Dimerization of human lysyl hydroxylase 3 (LH3) is mediated by the amino acids 541-547
Matrix Biol.
30
27-33
2011
Homo sapiens
Mantri, M.; Webby, C.; Loik, N.; Hamed, R.; Nielsen, M.; McDonough, M.; McCullagh, J.; Boettger, A.; Schofield, C.; Wolf, A.
Self-hydroxylation of the splicing factor lysyl hydroxylase, JMJD6
MedChemComm
3
80-85
2012
Homo sapiens
-
Gilkes, D.M.; Bajpai, S.; Wong, C.C.; Chaturvedi, P.; Hubbi, M.E.; Wirtz, D.; Semenza, G.L.
Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis
Mol. Cancer Res.
11
456-466
2013
Homo sapiens
Guo, H.F.; Cho, E.J.; Devkota, A.K.; Chen, Y.; Russell, W.; Phillips, G.N.; Yamauchi, M.; Dalby, K.N.; Kurie, J.M.
A scalable lysyl hydroxylase 2 expression system and luciferase-based enzymatic activity assay
Arch. Biochem. Biophys.
618
45-51
2017
Homo sapiens (O00469), Homo sapiens
Dayer, C.; Stamenkovic, I.
Recruitment of matrix metalloproteinase-9 (MMP-9) to the fibroblast cell surface by lysyl hydroxylase 3 (LH3) triggers transforming growth factor-beta (TGF-beta) activation and fibroblast differentiation
J. Biol. Chem.
290
13763-13778
2015
Homo sapiens (O60568)
Gjaltema, R.A.; de Rond, S.; Rots, M.G.; Bank, R.A.
Procollagen lysyl hydroxylase 2 expression is regulated by an alternative downstream transforming growth factor beta-1 activation mechanism
J. Biol. Chem.
290
28465-28476
2015
Homo sapiens (O00469)
Chen, Y.; Terajima, M.; Yang, Y.; Sun, L.; Ahn, Y.H.; Pankova, D.; Puperi, D.S.; Watanabe, T.; Kim, M.P.; Blackmon, S.H.; Rodriguez, J.; Liu, H.; Behrens, C.; Wistuba, I.I.; Minelli, R.; Scott, K.L.; Sanchez-Adams, J.; Guilak, F.; Pati, D.; Thilaganathan, N.; Burns, A.R.; Creighton, C.J.; Martinez, E.D.; Zal, T.; Allen, K.; Yamauchi, M.; Kurie, J.M.
Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma
J. Clin. Invest.
125
1147-1162
2015
Homo sapiens (O00469), Homo sapiens, Mus musculus (Q9R0B9), Mus musculus
Neyazi, B.; Tanrikulu, L.; Wilkens, L.; Hartmann, C.; Stein, K.P.; Dumitru, C.A.; Sandalcioglu, I.E.
Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 expression in brain arteriovenous malformations and its association with brain arteriovenous malformation size
World Neurosurg.
102
79-84
2017
Homo sapiens (O00469), Homo sapiens
Scietti, L.; Chiapparino, A.; De Giorgi, F.; Fumagalli, M.; Khoriauli, L.; Nergadze, S.; Basu, S.; Olieric, V.; Cucca, L.; Banushi, B.; Profumo, A.; Giulotto, E.; Gissen, P.; Forneris, F.
Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3
Nat. Commun.
9
3163
2018
Homo sapiens (O60568), Homo sapiens
Piersma, B.; Bank, R.A.
Collagen cross-linking mediated by lysyl hydroxylase 2 an enzymatic battlefield to combat fibrosis
Essays Biochem.
63
377-387
2019
Homo sapiens (O00469)
Gong, S.; Wu, C.; Koehler, F.; Meixensberger, J.; Schopow, N.; Kallendrusch, S.
Procollagen-lysine, 2-oxoglutarate 5-dioxygenase family novel prognostic biomarkers and tumor microenvironment regulators for lower-grade glioma
Front. Cell. Neurosci.
16
838548
2022
Homo sapiens (O00469), Homo sapiens (O60568), Homo sapiens (Q02809)
Xu, Y.; Zhang, L.; Wei, Y.; Zhang, X.; Xu, R.; Han, M.; Huang, B.; Chen, A.; Li, W.; Zhang, Q.; Li, G.; Wang, J.; Zhao, P.; Li, X.
Procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 promotes hypoxia-induced glioma migration and invasion
Oncotarget
8
23401-23413
2017
Homo sapiens (O00469), Homo sapiens
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