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Information on EC 1.13.11.63 - beta-carotene 15,15'-dioxygenase and Organism(s) Mus musculus and UniProt Accession Q9JJS6
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1.13.11.63 beta-carotene 15,15'-dioxygenaseIUBMB Comments
Requires Fe2+. The enzyme cleaves beta-carotene symmetrically, producing two molecules of all-trans-retinal. Both atoms of the oxygen molecule are incorporated into the products . The enzyme can also process beta-cryptoxanthin, 8'-apo-beta-carotenal, 4'-apo-beta-carotenal, alpha-carotene and gamma-carotene in decreasing order. The presence of at least one unsubstituted beta-ionone ring in a substrate greater than C(30) is mandatory . A prokaryotic enzyme has been reported from the uncultured marine bacterium 66A03, where it is involved in the proteorhodopsin system, which uses retinal as its chromophore [6,7].
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The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
beta-cd, bcmo1, ninab, beta-carotene 15,15'-monooxygenase, beta-carotene oxygenase 2, beta-carotene-15,15'-dioxygenase, betaco, beta-carotene 15,15'-monooxygenase 1, beta,beta-carotene 15,15'-monooxygenase, bcmo2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
BLH
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SYSTEMATIC NAME
IUBMB Comments
beta-carotene:oxygen 15,15'-dioxygenase (bond-cleaving)
Requires Fe2+. The enzyme cleaves beta-carotene symmetrically, producing two molecules of all-trans-retinal. Both atoms of the oxygen molecule are incorporated into the products [8]. The enzyme can also process beta-cryptoxanthin, 8'-apo-beta-carotenal, 4'-apo-beta-carotenal, alpha-carotene and gamma-carotene in decreasing order. The presence of at least one unsubstituted beta-ionone ring in a substrate greater than C(30) is mandatory [5]. A prokaryotic enzyme has been reported from the uncultured marine bacterium 66A03, where it is involved in the proteorhodopsin system, which uses retinal as its chromophore [6,7].
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
beta-apo-10'-carotenol + O2
?
beta-apo-10'-carotenol is the major long-chain beta-apocarotenoid in mouse liver
-
-
?
beta-carotene + O2
2 all-trans-retinal
-
-
-
?
beta-carotene + O2
2 all-trans-retinal
BCMO1 cleaves at the central 15,15' position of the polyene chain producing two molecules of retinal
-
-
?
beta-carotene + O2
retinal
crucial enzyme in development and metabolism that governs the de novo entry of vitamin A from plant-derived precursors, enzyme may play a critical role in gastrulation
-
-
?
beta-carotene + O2
retinal
enzyme may play a critical role in gastrulation
-
-
?
beta-carotene + O2
2 retinal
-
tyrosine Y235 and Y326 in mouse BCMO1 fix the position of the substrate on the two sides of the 15,15'-double bond most likely due to a mechanism implicating cation pi-stabilization
-
-
?
beta-carotene + O2
all-trans-retinal
-
BCMO1 is a key enzyme in the pathway of retinoid synthesis from carotenoids, and is responsible for metabolically limiting the amount of intact beta-carotene that can be absorbed by mice from their diet, regulation of BCMO1 activity, overview
-
-
?
additional information
?
-
25-hydroxycholesterol is a secondary autoxidation product derived from 3beta-hydroxy-cholest-5-ene-25-hydroperoxide, a hydroperoxide identified in air-aged cholesterol
-
-
?
additional information
?
-
substrate specificity for BCMO1, overview. BCMO1 requires at least one unsubstituted beta-ionone ring for the cleavage of carotenoid substrates, but also the presence and position of methyl groups on the polyene chain are important. Therefore, activity is limited mainly to alpha- and beta-carotene, beta-apo-carotenals and beta-cryptoxanthin
-
-
?
additional information
?
-
symmetric cleavage by BCO1 yields retinoids, i.e. beta-15'-apocarotenoids, C20
-
-
?
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
beta-apo-10'-carotenol + O2
?
beta-apo-10'-carotenol is the major long-chain beta-apocarotenoid in mouse liver
-
-
?
beta-carotene + O2
all-trans-retinal
-
BCMO1 is a key enzyme in the pathway of retinoid synthesis from carotenoids, and is responsible for metabolically limiting the amount of intact beta-carotene that can be absorbed by mice from their diet, regulation of BCMO1 activity, overview
-
-
?
additional information
?
-
25-hydroxycholesterol is a secondary autoxidation product derived from 3beta-hydroxy-cholest-5-ene-25-hydroperoxide, a hydroperoxide identified in air-aged cholesterol
-
-
?
beta-carotene + O2
2 all-trans-retinal
-
-
-
?
beta-carotene + O2
retinal
crucial enzyme in development and metabolism that governs the de novo entry of vitamin A from plant-derived precursors, enzyme may play a critical role in gastrulation
-
-
?
beta-carotene + O2
retinal
enzyme may play a critical role in gastrulation
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
Fe2+
the enzyme requires Fe2+ as an essential cofactor that binds to four conserved histidine residues in the active centre. Fe2+ is coordinated by the four histidines, water and molecular oxygen forming an octahedral arrangement with cation-pi stabilisation by Y235 and Y326 in the BCMO1 active site
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
type I cellular retinol-binding protein
-
i.e. RBP1, RBP1, but not RBP2, is required for the transport of water-insoluble substrates of retinoid pathway enzymes, e.g. of BCMO1, into the cell, and acts as an intracellular sensor of retinoid status that, when present as apo-RBP1, stimulates BCMO1 activity and the conversion of carotenoids to retinoids
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
mRNA is abundant at embryonic day 7, with lower expression at embryonic days 11, 13 and 15
beta-carotene-15,15'-dioxygenase (BCO1) protein is not expressed in adult hearts of male wild-type mice
additional information
retinoid levels in the developing liver and brain at mid-gestation, overview. BCO1-/- and wild-type female mice reveal a statistically significant decrease in retinol content in the heart, pancreas, spleen, eye and adipose tissue of the knockout females. Retinol concentrations are greater in the lungs of the BCO1-/- females compared to wild-type
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
additional information
determination of BCMO1 subcellular localization in mouse liver, overview
-
additional information
-
determination of BCMO1 subcellular localization in mouse liver, overview
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
cardiac dysfunction in beta-carotene-15,15-dioxygenase-deficient mice is associated with altered retinoid and lipid metabolism. Bco1-/- mice show an increase in heart levels of retinol, nonesterified fatty acids, and ceramides and a decrease in heart triglycerides. These lipid changes are accompanied by elevations in levels of genes important to retinoid metabolism, specifically retinol dehydrogenase 10 and retinol-binding protein 4, as well as genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-gamma, lipoprotein lipase, Cd36, stearoyl-CoA desaturase 1, and fatty acid synthase. The mutant mice show compromised heart function. But the total absence of Bco1 does not substantially affect beta-apo-carotenoid concentrations in the heart. Phenotype, overview
malfunction
deficiency of BCO1 in the liver does not significantly affect retinol or retinyl ester concentrations compared to the wild-type group, even though retinyl ester levels tend to be lower in the absence of BCO1. BCO1-/- and wild-type female mice reveal a statistically significant decrease in retinol content in the heart, pancreas, spleen, eye and adipose tissue of the knockout females. Retinol concentrations are greater in the lungs of the BCO1-/- females compared to wild-type
malfunction
mice lacking beta-carotene-15,15'-dioxygenase exhibit reduced serum testosterone, prostatic androgen receptor signaling, and prostatic cellular proliferation. Bco1 disruption also impacts diverse physiological end points independent of dietary carotenoid feeding, including expression of genes controlling androgen metabolism. co1 disruption significantly reduced Leydig cell number and decreased testicular mRNA expression of Hsd17b3, suggesting inhibition of testicular testosterone synthesis. Decreased androgen receptor nuclear localization in the dorsolateral prostate lobes of Bco1-/- mice. Analysis of prostatic morphology suggests a decreases in gland size and secretion, supported by reduced expression of the proliferation marker Ki-67 in Bco1-/- prostates. Genes differentially regulated in prostates of Bco1?/? mice, overview. Bco1 disruption alters prostatic morphology, reduces prostatic androgen receptor localization, and alters prostatic androgen signaling, but does not impact androgen receptor expression
physiological function
crucial enzyme in development and metabolism that governs the de novo entry of vitamin A from plant-derived precursors
physiological function
beta-carotene-15,15'-dioxygenase (BCO1) cleaves dietary carotenoids at the central 15,15' double bond, most notably acting on beta-carotene to yield retinal
physiological function
dietary carotenoids like beta-carotene are converted within the body either to retinoid, via beta-carotene-15,15'-dioxygenase (BCO1), or to beta-apo-carotenoids, via beta-carotene-9',10'-oxygenase 2. Some beta-apo-carotenoids are potent antagonists of retinoic acid receptor (RAR)-mediated transcriptional regulation, which is required to ensure normal heart development and functions. BCO1 modulates heart metabolism and function, possibly by altering levels of cofactors required for the actions of nuclear hormone receptors
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). BCDO1_MOUSE
566
0
63864
Swiss-Prot
other Location (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
63859
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E469A
about 50% decrease in activity, cells are bleached when left growing overnight
additional information
additional information
mutations in any of the four conserved histidine residues His172, His237, His308 and His514 or Glu405 result in the total loss of BCMO1 activity
additional information
subjection of wild type, Bco1-/-, Bco2-/-, and Bco1-/-/Bco2-/- double knock-out mice to a controlled diet providing beta-carotene as the sole source for apocarotenoid production
additional information
-
phenotype of enzyme-deficient mice, beta-carotene conversion is blocked in BCMO1-deficient mice, comparison of plasma retinol and liver retinyl esters of wild-type, heterozygous and homozygous BCMO1-deficient mice, overview
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 40% glycerol and presence of protease inhibitors, enzyme purified by metal affinity chromatography is stable for several weeks
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
for expression in Escherichia coli cells, genetically engineered to produce beta-carotene
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
mRNA is abundant at embryonic day 7, with lower expression at embryonic days 11, 13, and 15
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
synthesis
synthesis
production of retinal from beta-carotene using recombinant enzyme. The optimum pH, temperature, substrate and detergent concentrations, and enzyme amount for effective retinal production are 9.0, 37°C, 200 mg per ml beta-carotene, 5% w/v Tween 40, and 0.2 U per ml enzyme, respectively. Under optimum conditions, the recombinant enzyme produces 72 mg per ml retinal in a 15 h reaction time, with a conversion yield of 36% w/w
synthesis
stepwise cleavage by BCO2, i.e. beta-carotene-9',10'-oxygenase, and BCO1 with beta-apo-10'-carotenol as an intermediate can provide a mechanism to tailor asymmetric carotenoids such as beta-cryptoxanthin for vitamin A production
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Redmond, T.M.; Gentleman, S.; Duncan, T.; Yu, S.; Wiggert, B.; Gantt, E.; Cunningham, F.X.
Identification, expression, and substrate specificity of a mammalian beta-carotene 15,15'-dioxygenase
J. Biol. Chem.
276
6560-6565
2001
Mus musculus (Q9JJS6), Mus musculus
Poliakov, E.; Gentleman, S.; Cunningham, F.X.; Miller-Ihli, N.J.; Redmond, T.M.
Key role of conserved histidines in recombinant mouse beta-carotene 15,15-monooxygenase-1 activity
J. Biol. Chem.
280
29217-29223
2005
Mus musculus (Q9JJS6), Mus musculus
Fierce, Y.; de Morais Vieira, M.; Piantedosi, R.; Wyss, A.; Blaner, W.S.; Paik, J.
In vitro and in vivo characterization of retinoid synthesis from beta-carotene
Arch. Biochem. Biophys.
472
126-138
2008
Homo sapiens, Mus musculus
Seino, Y.; Miki, T.; Kiyonari, H.; Abe, T.; Fujimoto, W.; Kimura, K.; Takeuchi, A.; Takahashi, Y.; Oiso, Y.; Iwanaga, T.; Seino, S.
Isx participates in the maintenance of vitamin A metabolism by regulation of beta-carotene 15,15'-monooxygenase (Bcmo1) expression
J. Biol. Chem.
283
4905-4911
2008
Mus musculus (Q9JJS6)
Oberhauser, V.; Voolstra, O.; Bangert, A.; von Lintig, J.; Vogt, K.
NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide
Proc. Natl. Acad. Sci. USA
105
19000-19005
2008
Drosophila melanogaster (Q9VFS2), Galleria mellonella, Mus musculus
Kim, Y.-S.; Kim, N.-H.; Kim, H.-J.; Lee, J.-K.; Kim, S.-W.; Oh, D.-K.
Effective production of retinal from beta-carotene using recombinant mouse beta-carotene 15,15'-monooxygenase
Appl. Microbiol. Biotechnol.
76
1339-1345
2007
Mus musculus (Q9JJS6), Mus musculus
Lietz, G.; Lange, J.; Rimbach, G.
Molecular and dietary regulation of beta,beta-carotene 15,15-monooxygenase 1 (BCMO1)
Arch. Biochem. Biophys.
502
8-16
2010
Cavia porcellus, Gallus gallus, Oryctolagus cuniculus, Homo sapiens, Mus musculus, Rattus norvegicus, Sus scrofa
Pham, D.N.; Leclerc, D.; Levesque, N.; Deng, L.; Rozen, R.
beta,beta-carotene 15,15'-monooxygenase and its substrate beta-carotene modulate migration and invasion in colorectal carcinoma cells
Am. J. Clin. Nutr.
98
413-422
2013
Homo sapiens (Q9HAY6), Mus musculus (Q9JJS6), Mus musculus
Kowatz, T.; Babino, D.; Kiser, P.; Palczewski, K.; von Lintig, J.
Characterization of human beta,beta-carotene-15,15'-monooxygenase (BCMO1) as a soluble monomeric enzyme
Arch. Biochem. Biophys.
539
214-222
2013
Homo sapiens (Q9HAY6), Homo sapiens, Mus musculus (Q9JJS6), Mus musculus, Mus musculus C57/BL6 / 129 Sv (Q9JJS6)
Amengual, J.; Widjaja-Adhi, M.A.; Rodriguez-Santiago, S.; Hessel, S.; Golczak, M.; Palczewski, K.; von Lintig, J.
Two carotenoid-oxygenases contribute to mammalian pro-vitamin A metabolism
J. Biol. Chem.
288
34081-34096
2013
Mus musculus (Q9JJS6)
Lietz, G.; Oxley, A.; Boesch-Saadatmandi, C.; Kobayashi, D.
Importance of beta,beta-carotene 15,15-monooxygenase 1 (BCMO1) and beta,beta-carotene 9,10-dioxygenase 2 (BCDO2) in nutrition and health
Mol. Nutr. Food Res.
56
241-250
2012
Cavia porcellus (H0VRY9), Danio rerio, Drosophila melanogaster, Gallus gallus (Q9I993), Homo sapiens (Q9HAY6), Homo sapiens, Mus musculus (Q9JJS6), Mustela putorius furo, no activity in Arabidopsis thaliana, no activity in Zea mays, Oryctolagus cuniculus (G1SEP0), Rattus norvegicus (Q91XT5)
Amengual, J.; Gouranton, E.; van Helden, Y.G.; Hessel, S.; Ribot, J.; Kramer, E.; Kiec-Wilk, B.; Razny, U.; Lietz, G.; Wyss, A.; Dembinska-Kiec, A.; Palou, A.; Keijer, J.; Landrier, J.F.; Bonet, M.L.; von Lintig, J.
Beta-carotene reduces body adiposity of mice via BCMO1
PLoS ONE
6
e20644
2011
Mus musculus (Q9JJS6)
Lee, S.A.; Jiang, H.; Trent, C.M.; Yuen, J.J.; Narayanasamy, S.; Curley, R.W.; Harrison, E.H.; Goldberg, I.J.; Maurer, M.S.; Blaner, W.S.
Cardiac dysfunction in beta-carotene-15,15-dioxygenase-deficient mice is associated with altered retinoid and lipid metabolism
Am. J. Physiol. Heart Circ. Physiol.
307
H1675-H1684
2014
Mus musculus (Q9JJS6)
Smith, J.W.; Ford, N.A.; Thomas-Ahner, J.M.; Moran, N.E.; Bolton, E.C.; Wallig, M.A.; Clinton, S.K.; Erdman, J.W.
Mice lacking beta-carotene-15,15'-dioxygenase exhibit reduced serum testosterone, prostatic androgen receptor signaling, and prostatic cellular proliferation
Am. J. Physiol. Regul. Integr. Comp. Physiol.
311
R1135-R1148
2016
Mus musculus (Q9JJS6), Mus musculus C57BL/6J (Q9JJS6)
Kim, Y.K.; Zuccaro, M.V.; Costabile, B.K.; Rodas, R.; Quadro, L.
Tissue- and sex-specific effects of beta-carotene 15,15' oxygenase (BCO1) on retinoid and lipid metabolism in adult and developing mice
Arch. Biochem. Biophys.
572
11-18
2015
Mus musculus (Q9JJS6), Mus musculus C57BL/6 (Q9JJS6)
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