BRENDA - Enzyme Database show

Structural determinants of substrate specificity differences between human multidrug resistance protein (MRP) 1 (ABCC1) and MRP3 (ABCC3)

Grant, C.E.; Gao, M.; DeGorter, M.K.; Cole, S.P.; Deeley, R.G.; Drug Metab. Dispos. 36, 2571-2581 (2008)

Data extracted from this reference:

Cloned(Commentary)
EC Number
Commentary
Organism
7.6.2.2
wild-type MRP1 and mutant hybrid MRP1/MRP3 are expressed in Sf21 insect cells as two half-molecules, comprising amino acids 1 to 932 and 932 to 1531, respectively, using the baculovirus expression vector, expression of wild-type and mutant MRP1 in HEK-293 cell membranes
Homo sapiens
Engineering
EC Number
Amino acid exchange
Commentary
Organism
7.6.2.2
A481G/V482A/M483V/M485V
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
A493K/H494Q/S497L/N500S
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
A493K/H494Q/S497L/N500S/N506S
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
A493K/H494Q/S497L/N506S/T487M/K488R/T489A/Y490F
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
I441L
the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
7.6.2.2
M443L
the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
7.6.2.2
M443L/Y440F/1441L
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
additional information
construction of a series of MRP1/MRP3 hybrids. Substitution of the region encompassing transmembrane helices 8 and 9 and portions of cytoplasmic loops 4 and 5 of MRP1 with the equivalent region of MRP3 eliminates LTC4 transport
Homo sapiens
7.6.2.2
V479L/A481G/V482A/M483V/M485V
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
V479L/A481G/V482A/M483V/N500S
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
Y440F
MRP1 mutant, substitution of Tyr440 with Phe, as found in MRP3, reduces leukotriene C4 and GSH-stimulated estrone-3-sulfate transport without affecting transport of other substrates. The mutation increased the Km for LTC4 5fold and substantially reduces photolabeling of MRP1 by both LTC4 and the GSH derivative, azidophenacyl-GSH; the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
7.6.2.2
Y440F/1441L
the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
Localization
EC Number
Localization
Commentary
Organism
GeneOntology No.
Textmining
7.6.2.2
membrane
-
Homo sapiens
16020
-
Metals/Ions
EC Number
Metals/Ions
Commentary
Organism
Structure
7.6.2.2
Mg2+
-
Homo sapiens
Natural Substrates/ Products (Substrates)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
7.6.2.2
ATP + H2O + 17beta-estradiol 17-(beta-D-glucuronide)/in
Homo sapiens
transported by MRP1 and MRP3
ADP + phosphate + 17beta-estradiol 17-(beta-D-glucuronide)/out
-
-
?
7.6.2.2
ATP + H2O + estrone-3-sulfate/in
Homo sapiens
-
ADP + phosphate + estrone-3-sulfate/out
-
-
?
7.6.2.2
ATP + H2O + leukotriene C4/in
Homo sapiens
-
ADP + phosphate + leukotriene C4/out
-
-
?
7.6.2.2
ATP + H2O + xenobiotic/in
Homo sapiens
MRP1 transports a wide range of natural product drugs and structurally diverse conjugated and unconjugated organic anions. Its closest relative is MRP3. MRP1 transports GSH and GSH conjugates and displays GSH-stimulated transport of a number of unconjugated and conjugated compounds. In contrast, MRP3 does not transport GSH and is a poor transporter of GSH conjugates
ADP + phosphate + xenobiotic/out
-
-
?
Organism
EC Number
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
7.6.2.2
Homo sapiens
-
-
-
Specific Activity [micromol/min/mg]
EC Number
Specific Activity Minimum [µmol/min/mg]
Specific Activity Maximum [µmol/min/mg]
Commentary
Organism
7.6.2.2
additional information
-
relative drug resistance factor of wild-type MRP1and MRP3, and mutants, overview. Transport activities of wild-type MRP1 and of the mutant hybride MRP1/MRP3 prepared from Sf21 cells, overview
Homo sapiens
Substrates and Products (Substrate)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
7.6.2.2
ATP + H2O + 17beta-estradiol 17-(beta-D-glucuronide)/in
transported by MRP1 and MRP3
697583
Homo sapiens
ADP + phosphate + 17beta-estradiol 17-(beta-D-glucuronide)/out
-
-
-
?
7.6.2.2
ATP + H2O + doxorubicin/in
-
697583
Homo sapiens
ADP + phosphate + doxorubicin/out
-
-
-
?
7.6.2.2
ATP + H2O + estrone-3-sulfate/in
-
697583
Homo sapiens
ADP + phosphate + estrone-3-sulfate/out
-
-
-
?
7.6.2.2
ATP + H2O + leukotriene C4/in
-
697583
Homo sapiens
ADP + phosphate + leukotriene C4/out
-
-
-
?
7.6.2.2
ATP + H2O + methotrexate/in
-
697583
Homo sapiens
ADP + phosphate + methotrexate/out
-
-
-
?
7.6.2.2
ATP + H2O + vincristine/in
-
697583
Homo sapiens
ADP + phosphate + vincristine/out
-
-
-
?
7.6.2.2
ATP + H2O + VP-16/in
-
697583
Homo sapiens
ADP + phosphate + VP-16/out
-
-
-
?
7.6.2.2
ATP + H2O + xenobiotic/in
MRP1 transports a wide range of natural product drugs and structurally diverse conjugated and unconjugated organic anions. Its closest relative is MRP3. MRP1 transports GSH and GSH conjugates and displays GSH-stimulated transport of a number of unconjugated and conjugated compounds. In contrast, MRP3 does not transport GSH and is a poor transporter of GSH conjugates
697583
Homo sapiens
ADP + phosphate + xenobiotic/out
-
-
-
?
7.6.2.2
ATP + H2O + xenobiotic/in
ATP-dependent transport into inside-out membrane vesicles by recombinant enzymes, overview
697583
Homo sapiens
ADP + phosphate + xenobiotic/out
-
-
-
?
7.6.2.2
additional information
Tyr440, naturally occuring in wild-type MRP3 and recombinantly in MRP1 mutants, makes a major contribution to recognition of GSH and the GSH moiety of conjugates such as LTC4
697583
Homo sapiens
?
-
-
-
-
Temperature Optimum [°C]
EC Number
Temperature Optimum [°C]
Temperature Optimum Maximum [°C]
Commentary
Organism
7.6.2.2
23
37
assay at 23°C or at 37°C dependent on the substrate
Homo sapiens
Cofactor
EC Number
Cofactor
Commentary
Organism
Structure
7.6.2.2
ATP
dependent on
Homo sapiens
Cloned(Commentary) (protein specific)
EC Number
Commentary
Organism
7.6.2.2
wild-type MRP1 and mutant hybrid MRP1/MRP3 are expressed in Sf21 insect cells as two half-molecules, comprising amino acids 1 to 932 and 932 to 1531, respectively, using the baculovirus expression vector, expression of wild-type and mutant MRP1 in HEK-293 cell membranes
Homo sapiens
Cofactor (protein specific)
EC Number
Cofactor
Commentary
Organism
Structure
7.6.2.2
ATP
dependent on
Homo sapiens
Engineering (protein specific)
EC Number
Amino acid exchange
Commentary
Organism
7.6.2.2
A481G/V482A/M483V/M485V
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
A493K/H494Q/S497L/N500S
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
A493K/H494Q/S497L/N500S/N506S
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
A493K/H494Q/S497L/N506S/T487M/K488R/T489A/Y490F
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
I441L
the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
7.6.2.2
M443L
the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
7.6.2.2
M443L/Y440F/1441L
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
additional information
construction of a series of MRP1/MRP3 hybrids. Substitution of the region encompassing transmembrane helices 8 and 9 and portions of cytoplasmic loops 4 and 5 of MRP1 with the equivalent region of MRP3 eliminates LTC4 transport
Homo sapiens
7.6.2.2
V479L/A481G/V482A/M483V/M485V
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
V479L/A481G/V482A/M483V/N500S
the MRP1 mutant shows altered transport activities compared to the wild-type MRP1
Homo sapiens
7.6.2.2
Y440F
MRP1 mutant, substitution of Tyr440 with Phe, as found in MRP3, reduces leukotriene C4 and GSH-stimulated estrone-3-sulfate transport without affecting transport of other substrates. The mutation increased the Km for LTC4 5fold and substantially reduces photolabeling of MRP1 by both LTC4 and the GSH derivative, azidophenacyl-GSH; the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
7.6.2.2
Y440F/1441L
the mutant shows reduced activity with vincristine, VP-16, and doxorubicin compared to the wild-type enzyme
Homo sapiens
Localization (protein specific)
EC Number
Localization
Commentary
Organism
GeneOntology No.
Textmining
7.6.2.2
membrane
-
Homo sapiens
16020
-
Metals/Ions (protein specific)
EC Number
Metals/Ions
Commentary
Organism
Structure
7.6.2.2
Mg2+
-
Homo sapiens
Natural Substrates/ Products (Substrates) (protein specific)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
7.6.2.2
ATP + H2O + 17beta-estradiol 17-(beta-D-glucuronide)/in
Homo sapiens
transported by MRP1 and MRP3
ADP + phosphate + 17beta-estradiol 17-(beta-D-glucuronide)/out
-
-
?
7.6.2.2
ATP + H2O + estrone-3-sulfate/in
Homo sapiens
-
ADP + phosphate + estrone-3-sulfate/out
-
-
?
7.6.2.2
ATP + H2O + leukotriene C4/in
Homo sapiens
-
ADP + phosphate + leukotriene C4/out
-
-
?
7.6.2.2
ATP + H2O + xenobiotic/in
Homo sapiens
MRP1 transports a wide range of natural product drugs and structurally diverse conjugated and unconjugated organic anions. Its closest relative is MRP3. MRP1 transports GSH and GSH conjugates and displays GSH-stimulated transport of a number of unconjugated and conjugated compounds. In contrast, MRP3 does not transport GSH and is a poor transporter of GSH conjugates
ADP + phosphate + xenobiotic/out
-
-
?
Specific Activity [micromol/min/mg] (protein specific)
EC Number
Specific Activity Minimum [µmol/min/mg]
Specific Activity Maximum [µmol/min/mg]
Commentary
Organism
7.6.2.2
additional information
-
relative drug resistance factor of wild-type MRP1and MRP3, and mutants, overview. Transport activities of wild-type MRP1 and of the mutant hybride MRP1/MRP3 prepared from Sf21 cells, overview
Homo sapiens
Substrates and Products (Substrate) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
7.6.2.2
ATP + H2O + 17beta-estradiol 17-(beta-D-glucuronide)/in
transported by MRP1 and MRP3
697583
Homo sapiens
ADP + phosphate + 17beta-estradiol 17-(beta-D-glucuronide)/out
-
-
-
?
7.6.2.2
ATP + H2O + doxorubicin/in
-
697583
Homo sapiens
ADP + phosphate + doxorubicin/out
-
-
-
?
7.6.2.2
ATP + H2O + estrone-3-sulfate/in
-
697583
Homo sapiens
ADP + phosphate + estrone-3-sulfate/out
-
-
-
?
7.6.2.2
ATP + H2O + leukotriene C4/in
-
697583
Homo sapiens
ADP + phosphate + leukotriene C4/out
-
-
-
?
7.6.2.2
ATP + H2O + methotrexate/in
-
697583
Homo sapiens
ADP + phosphate + methotrexate/out
-
-
-
?
7.6.2.2
ATP + H2O + vincristine/in
-
697583
Homo sapiens
ADP + phosphate + vincristine/out
-
-
-
?
7.6.2.2
ATP + H2O + VP-16/in
-
697583
Homo sapiens
ADP + phosphate + VP-16/out
-
-
-
?
7.6.2.2
ATP + H2O + xenobiotic/in
MRP1 transports a wide range of natural product drugs and structurally diverse conjugated and unconjugated organic anions. Its closest relative is MRP3. MRP1 transports GSH and GSH conjugates and displays GSH-stimulated transport of a number of unconjugated and conjugated compounds. In contrast, MRP3 does not transport GSH and is a poor transporter of GSH conjugates
697583
Homo sapiens
ADP + phosphate + xenobiotic/out
-
-
-
?
7.6.2.2
ATP + H2O + xenobiotic/in
ATP-dependent transport into inside-out membrane vesicles by recombinant enzymes, overview
697583
Homo sapiens
ADP + phosphate + xenobiotic/out
-
-
-
?
7.6.2.2
additional information
Tyr440, naturally occuring in wild-type MRP3 and recombinantly in MRP1 mutants, makes a major contribution to recognition of GSH and the GSH moiety of conjugates such as LTC4
697583
Homo sapiens
?
-
-
-
-
Temperature Optimum [°C] (protein specific)
EC Number
Temperature Optimum [°C]
Temperature Optimum Maximum [°C]
Commentary
Organism
7.6.2.2
23
37
assay at 23°C or at 37°C dependent on the substrate
Homo sapiens