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Information on EC 2.7.1.26 - riboflavin kinase and Organism(s) Homo sapiens and UniProt Accession Q969G6
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2.7.1.26 riboflavin kinaseIUBMB Comments
The cofactors FMN and FAD participate in numerous processes in all organisms, including mitochondrial electron transport, photosynthesis, fatty-acid oxidation, and metabolism of vitamin B6, vitamin B12 and folates . While monofunctional riboflavin kinase is found in eukaryotes, some bacteria have a bifunctional enzyme that exhibits both this activity and that of EC 2.7.7.2, FMN adenylyltransferase . A divalent metal cation is required for activity (with different species preferring Mg2+, Mn2+ or Zn2+). In Bacillus subtilis, ATP can be replaced by other phosphate donors but with decreasing enzyme activity in the order ATP > dATP > CTP > UTP .
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Word Map
- 2.7.1.26
- mononucleotide
- ammoniagenes
-
fadss
- isoalloxazine
-
kyphoplasty
-
flavocoenzyme
-
flavinogenic
-
ribityl
- davawensis
- roseoflavin
- famata
-
ctp-dependent
- synthesis
- drug development
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
rfk, flavokinase, riboflavin kinase, fad synthetase, fmnat, cafads, fmn adenylyltransferase, hsrfk, atfmn/fhy, flavokinase/fad synthetase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
FK
-
-
-
-
flavokinase
kinase, riboflavin
-
-
-
-
riboflavine kinase
-
-
-
-
flavokinase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + riboflavin = ADP + FMN
ordered reaction mechanism, FMN binding o the binary enzyme-MgADP complex induces important conformational changes
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
ATP:riboflavin 5'-phosphotransferase
The cofactors FMN and FAD participate in numerous processes in all organisms, including mitochondrial electron transport, photosynthesis, fatty-acid oxidation, and metabolism of vitamin B6, vitamin B12 and folates [5]. While monofunctional riboflavin kinase is found in eukaryotes, some bacteria have a bifunctional enzyme that exhibits both this activity and that of EC 2.7.7.2, FMN adenylyltransferase [5]. A divalent metal cation is required for activity (with different species preferring Mg2+, Mn2+ or Zn2+). In Bacillus subtilis, ATP can be replaced by other phosphate donors but with decreasing enzyme activity in the order ATP > dATP > CTP > UTP [6].
CAS REGISTRY NUMBER
COMMENTARY
9032-82-0
-
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
ATP + riboflavin
ADP + FMN
essential enzyme catalyzing the phosphorylation of riboflavin to form FMN, an obligatory step in vitamin B2 utilization and flavin cofactor synthesis
-
-
?
ATP + riboflavin
ADP + FMN
substrate and product binding structure, overview
-
-
ir
additional information
?
-
substrate binding structure analysis using crystal structures of substrate-bound RFK. Binding of HsRFK substrates is the kinetically preferred process compared to product inhibition, kinetic modeling, overview
-
-
-
additional information
?
-
-
substrate binding structure analysis using crystal structures of substrate-bound RFK. Binding of HsRFK substrates is the kinetically preferred process compared to product inhibition, kinetic modeling, 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
ATP + riboflavin
ADP + FMN
essential enzyme catalyzing the phosphorylation of riboflavin to form FMN, an obligatory step in vitamin B2 utilization and flavin cofactor synthesis
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ADP
product inhibition, fitted to the Lineweaver-Burk equation for competitive inhibition
FMN
product inhibition, fitted to the Lineweaver-Burk equation for competitive inhibition
additional information
the inhibition mechanism of the products of the RFK reaction, FMN and ADP, kinetics, overview
-
additional information
-
the inhibition mechanism of the products of the RFK reaction, FMN and ADP, kinetics, overview
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
Michaelis-Menten kinetics and modeling, cooperativity model, pre-steady-state kinetics/pre-steady-state stopped-flow kinetics and dissociation constants, overview. Isothermal titration calorimetry, and Gibbs free energy flow for the interaction of HsRFK with substrates and products. Thermodynamics modulates the ligand binding landscape of HsRFK. Cooperativity coefficients, ANP and FLV ligands cooperate in their binding to HsRFK
-
additional information
additional information
-
Michaelis-Menten kinetics and modeling, cooperativity model, pre-steady-state kinetics/pre-steady-state stopped-flow kinetics and dissociation constants, overview. Isothermal titration calorimetry, and Gibbs free energy flow for the interaction of HsRFK with substrates and products. Thermodynamics modulates the ligand binding landscape of HsRFK. Cooperativity coefficients, ANP and FLV ligands cooperate in their binding to HsRFK
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
inhibition kinetics, recombinant enzyme, overview
-
additional information
additional information
-
inhibition kinetics, recombinant enzyme, overview
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
different organisms, different regulatory strategies of RFKs, overview
malfunction
enzyme RFK downregulation alters expression profiles of clock-controlled metabolic-genes and destroys flavins protection on stroke treatments, while its activity reduction links to protein-energy malnutrition and thyroid hormones decrease
physiological function
human riboflavin kinase is an essential enzyme that catalyzes the biosynthesis of the flavin mononucleotide (FMN) cofactor using riboflavin (RF, vitamin B2) and ATP as substrates. Human riboflavin kinase (HsRFK) catalyzes vitamin B2 (riboflavin) phosphorylation to flavin mononucleotide (FMN), obligatory step in flavin cofactor synthesis. HsRFK expression is related to protection from oxidative stress, amyloid-beta toxicity, and some malignant cancers progression. HsRFK is also predicted as involved in a protein-protein association network that at the system level affects to different cellular processes
physiological function
additional information
physiological function
-
riboflavin kinase is a TNF-receptor-1 binding protein that couples TNF-receptor-1 to NADPH oxidase
physiological function
-
the enzyme plays a critical role in the KD548-Fc-mediated reactive oxygen species accumulation and downstream signaling. The enzyme is essential in recruiting Nox1 to death receptor4/5
additional information
molecular dynamics simulations, structure-function analysis
additional information
-
molecular dynamics simulations, structure-function analysis
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). RIFK_HUMAN
155
0
17623
Swiss-Prot
Mitochondrion (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
structure-function analysis, apo-HsRFK structural model
additional information
-
structure-function analysis, apo-HsRFK structural model
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of the crystallographic structure of HsRFK in complex with FMN and ADP in either the open (PDB ID 1P4M) or the closed conformation (PDB ID 1Q9S) of the flavin binding site overview
purified recombinant enzyme with bound products FMN and MgADP, hanging drop vapour diffusion method, 34 mg/ml protein in 50 mM Tris, pH 7.4, 0.3 M NaCl, 1 mM DTT, 20°C, mixing with equal volume of reservoir solution containing 0.1 M sodium acetate, pH 4.7, 30% PEG monomethyl ether 5000, and 0.2 M ammonium sulfate, followed by microseeding in reservoir solution containing 0.1 M sodium acetate, pH 4.4, 22.5% PEG monomethyl ether 5000, and 0.2 M ammonium sulfate, cryoprotection in 30% glycerol in reservoir solution, storage in liquid propane, X-ray diffraction structure determination and analysis at 2.4 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E86Q
-
destroying the kinase domain, purified as C-terminal glutathione S-transferase fusionprotein
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme RFK from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, tag cleavage by a protease, followed by ammonium sulfate fractionation, hydrophobic interaction chromatography, and dialysis. HsRFK is purified free of flavin and adenine ligands
recombinant, His-tagged enzyme by nickel affinity chromatography, removal of His-tag by TEV-protease treatment
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene RFK, recombinant expression of His-tagged enzyme from codon-optimzed gene in Escherichia coli strain BL21(DE3)
expressed in Escherichis coli BL-21pLysS (DE3), C-terminal glutathione S-transferase fusionprotein
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
HsRFK parameters differ from those of the so far evaluated bacterial counterparts, suggesting species-specific mechanisms in RFK catalysis. Thus, HsRFK is a potential therapeutic target because of its key functions, while bacterial RFK modules are potential antimicrobial targets
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Karthikeyan, S.; Zhou, Q.; Mseeh, F.; Grishin, N.V.; Osterman, A.L.; Zhang, H.
Crystal structure of human riboflavin kinase reveals a beta barrel fold and a novel active site arch
Structure
11
265-273
2003
Homo sapiens (Q969G6), Homo sapiens
Karthikeyan, S.; Zhou, Q.; Osterman, A.L.; Zhang, H.
Ligand binding-induced conformational changes in riboflavin kinase: structural basis for the ordered mechanism
Biochemistry
42
12532-12538
2003
Homo sapiens (Q969G6), Homo sapiens
Yazdanpanah, B.; Wiegmann, K.; Tchikov, V.; Krut, O.; Pongratz, C.; Schramm, M.; Kleinridders, A.; Wunderlich, T.; Kashkar, H.; Utermoehlen, O.; Bruening, J.C.; Schuetze, S.; Kroenke, M.
Riboflavin kinase couples TNF receptor 1 to NADPH oxidase
Nature
460
1159-1163
2009
Homo sapiens, Mus musculus
Park, K.J.; Lee, C.H.; Kim, A.; Jeong, K.J.; Kim, C.H.; Kim, Y.S.
Death receptors 4 and 5 activate Nox1 NADPH oxidase through riboflavin kinase to induce reactive oxygen species-mediated apoptotic cell death
J. Biol. Chem.
287
3313-3325
2012
Homo sapiens
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