- ข้อความ
- ประวัติศาสตร์
CYP2A6 uses a heme cofactor to oxid
CYP2A6 uses a heme cofactor to oxidize the substrates. The
active site of this enzyme is compact and composed by a hydrophobic
Phe-cluster formed by residues Phe107, Phe111, Phe108,Phe209 and Phe480 (Fig. 1). In this region only one hydrogen bond
donor is available and it is provided by Asn297, that directs the
natural substrate (coumarin) towards regioselective oxidation [33].
Analyzing the X-ray structures available on the protein databank
(www.pdb.org/pdb) for CYP2A6 complexed with the natural
substrate (coumarin, PDB entry 1Z10) and with a linear psoralen
inhibitor (xanthotoxin, PDB entry 1Z11), it was found that both
compounds bind in a similar manner, and that the carbonyl group of
the coumarinmoiety interacts very closely with Asn297 [34]. Theonly
observed difference was in the type of interactions nearby the iron
atom from the heme cofactor. In the natural substrate, the position 7
of the coumarin ring is very close to this centre (3.09 Å), thus favoring
the hydroxylation reaction in this position. In the psoralen, it is the
oxygen fromthe furan group that comes closer to this centre (3.25 Å).
This result indicates that the inhibitory power of the psoralen may be
related to the chelation of the oxygen fromthe furanringwiththe iron
from the heme, possibly resulting in the inactivation of the enzyme.
The molecular docking studies performed with compounds 1,
3e6 show that the binding poses of some of the compounds are
very similar to those that are represented on Fig. 1, while others
differ significantly (Fig. 2).
The binding pose of compounds 1 and 6 are the closest ones,
presenting the carbonyl group from the coumarin ring pointing
towards the Asn297 (2.83 Å and 3.26Å, respectively). However,
these compounds interact with the ferryl heme of the CYP2A6 in
different ways: compound 6 uses the position 10 (2.98 Å), while the
compound 1 interacts directly through the oxygen from the furan
ring, similarly to what was observed for the potent xanthotoxin
inhibitor (illustrated on the right side of Fig. 1).
Compounds 4 and 5 were found to bind in the opposite direction
of compounds 1 and 6. In those cases, the oxygen from the furan
ring is located nearby the amino group of Asn297 (3.07 Å and
3.29 Å, respectively), while the oxygen from the coumarin moiety
interact with the ferryl heme of the CYP2A6 (2.86 Å and 3.04 Å, and
3.07 Å and 3.74 Å, respectively). These results show that the active
site region around Asn297 is quite narrow and cannot accommodate
very large molecules. From all the studied psoralens with
bulky groups at position 2, compound 1 is the only exception that
was still able to bind similarly to the potent inhibitor xanthotoxin.
The binding pose of compound 3 is quite different from all the
other studied compounds. The carboxylic group attached to carbon
2 of the psoralen was found to interact directly with the iron of the
heme group (1.43 Å) and to establish two hydrogen bonds with
Gly301 and Thr275 (2.43 Å and 2.39 Å). The remaining part of the
psoralen structure is pointing towards the Asn297, but is too far to
interact with it (4.79 Å), contrasting to what was observed for the
other compounds.
active site of this enzyme is compact and composed by a hydrophobic
Phe-cluster formed by residues Phe107, Phe111, Phe108,Phe209 and Phe480 (Fig. 1). In this region only one hydrogen bond
donor is available and it is provided by Asn297, that directs the
natural substrate (coumarin) towards regioselective oxidation [33].
Analyzing the X-ray structures available on the protein databank
(www.pdb.org/pdb) for CYP2A6 complexed with the natural
substrate (coumarin, PDB entry 1Z10) and with a linear psoralen
inhibitor (xanthotoxin, PDB entry 1Z11), it was found that both
compounds bind in a similar manner, and that the carbonyl group of
the coumarinmoiety interacts very closely with Asn297 [34]. Theonly
observed difference was in the type of interactions nearby the iron
atom from the heme cofactor. In the natural substrate, the position 7
of the coumarin ring is very close to this centre (3.09 Å), thus favoring
the hydroxylation reaction in this position. In the psoralen, it is the
oxygen fromthe furan group that comes closer to this centre (3.25 Å).
This result indicates that the inhibitory power of the psoralen may be
related to the chelation of the oxygen fromthe furanringwiththe iron
from the heme, possibly resulting in the inactivation of the enzyme.
The molecular docking studies performed with compounds 1,
3e6 show that the binding poses of some of the compounds are
very similar to those that are represented on Fig. 1, while others
differ significantly (Fig. 2).
The binding pose of compounds 1 and 6 are the closest ones,
presenting the carbonyl group from the coumarin ring pointing
towards the Asn297 (2.83 Å and 3.26Å, respectively). However,
these compounds interact with the ferryl heme of the CYP2A6 in
different ways: compound 6 uses the position 10 (2.98 Å), while the
compound 1 interacts directly through the oxygen from the furan
ring, similarly to what was observed for the potent xanthotoxin
inhibitor (illustrated on the right side of Fig. 1).
Compounds 4 and 5 were found to bind in the opposite direction
of compounds 1 and 6. In those cases, the oxygen from the furan
ring is located nearby the amino group of Asn297 (3.07 Å and
3.29 Å, respectively), while the oxygen from the coumarin moiety
interact with the ferryl heme of the CYP2A6 (2.86 Å and 3.04 Å, and
3.07 Å and 3.74 Å, respectively). These results show that the active
site region around Asn297 is quite narrow and cannot accommodate
very large molecules. From all the studied psoralens with
bulky groups at position 2, compound 1 is the only exception that
was still able to bind similarly to the potent inhibitor xanthotoxin.
The binding pose of compound 3 is quite different from all the
other studied compounds. The carboxylic group attached to carbon
2 of the psoralen was found to interact directly with the iron of the
heme group (1.43 Å) and to establish two hydrogen bonds with
Gly301 and Thr275 (2.43 Å and 2.39 Å). The remaining part of the
psoralen structure is pointing towards the Asn297, but is too far to
interact with it (4.79 Å), contrasting to what was observed for the
other compounds.
0/5000
CYP2A6 uses a heme cofactor to oxidize the substrates. Theactive site of this enzyme is compact and composed by a hydrophobicPhe-cluster formed by residues Phe107, Phe111, Phe108,Phe209 and Phe480 (Fig. 1). In this region only one hydrogen bonddonor is available and it is provided by Asn297, that directs thenatural substrate (coumarin) towards regioselective oxidation [33].Analyzing the X-ray structures available on the protein databank(www.pdb.org/pdb) for CYP2A6 complexed with the naturalsubstrate (coumarin, PDB entry 1Z10) and with a linear psoraleninhibitor (xanthotoxin, PDB entry 1Z11), it was found that bothcompounds bind in a similar manner, and that the carbonyl group ofthe coumarinmoiety interacts very closely with Asn297 [34]. Theonlyobserved difference was in the type of interactions nearby the ironatom from the heme cofactor. In the natural substrate, the position 7of the coumarin ring is very close to this centre (3.09 Å), thus favoringthe hydroxylation reaction in this position. In the psoralen, it is theoxygen fromthe furan group that comes closer to this centre (3.25 Å).This result indicates that the inhibitory power of the psoralen may berelated to the chelation of the oxygen fromthe furanringwiththe ironfrom the heme, possibly resulting in the inactivation of the enzyme.The molecular docking studies performed with compounds 1,3e6 show that the binding poses of some of the compounds arevery similar to those that are represented on Fig. 1, while othersdiffer significantly (Fig. 2).The binding pose of compounds 1 and 6 are the closest ones,presenting the carbonyl group from the coumarin ring pointingtowards the Asn297 (2.83 Å and 3.26Å, respectively). However,these compounds interact with the ferryl heme of the CYP2A6 indifferent ways: compound 6 uses the position 10 (2.98 Å), while thecompound 1 interacts directly through the oxygen from the furanring, similarly to what was observed for the potent xanthotoxininhibitor (illustrated on the right side of Fig. 1).Compounds 4 and 5 were found to bind in the opposite directionof compounds 1 and 6. In those cases, the oxygen from the furanring is located nearby the amino group of Asn297 (3.07 Å and3.29 Å, respectively), while the oxygen from the coumarin moietyinteract with the ferryl heme of the CYP2A6 (2.86 Å and 3.04 Å, and3.07 Å and 3.74 Å, respectively). These results show that the activesite region around Asn297 is quite narrow and cannot accommodatevery large molecules. From all the studied psoralens withbulky groups at position 2, compound 1 is the only exception thatwas still able to bind similarly to the potent inhibitor xanthotoxin.The binding pose of compound 3 is quite different from all theother studied compounds. The carboxylic group attached to carbon2 of the psoralen was found to interact directly with the iron of theheme group (1.43 Å) and to establish two hydrogen bonds withGly301 and Thr275 (2.43 Å and 2.39 Å). The remaining part of thepsoralen structure is pointing towards the Asn297, but is too far tointeract with it (4.79 Å), contrasting to what was observed for theother compounds.
การแปล กรุณารอสักครู่..
CYP2A6 uses a heme cofactor to oxidize the substrates. The
active site of this enzyme is compact and composed by a hydrophobic
Phe-cluster formed by residues Phe107, Phe111, Phe108,Phe209 and Phe480 (Fig. 1). In this region only one hydrogen bond
donor is available and it is provided by Asn297, that directs the
natural substrate (coumarin) towards regioselective oxidation [33].
Analyzing the X-ray structures available on the protein databank
(www.pdb.org/pdb) for CYP2A6 complexed with the natural
substrate (coumarin, PDB entry 1Z10) and with a linear psoralen
inhibitor (xanthotoxin, PDB entry 1Z11), it was found that both
compounds bind in a similar manner, and that the carbonyl group of
the coumarinmoiety interacts very closely with Asn297 [34]. Theonly
observed difference was in the type of interactions nearby the iron
atom from the heme cofactor. In the natural substrate, the position 7
of the coumarin ring is very close to this centre (3.09 Å), thus favoring
the hydroxylation reaction in this position. In the psoralen, it is the
oxygen fromthe furan group that comes closer to this centre (3.25 Å).
This result indicates that the inhibitory power of the psoralen may be
related to the chelation of the oxygen fromthe furanringwiththe iron
from the heme, possibly resulting in the inactivation of the enzyme.
The molecular docking studies performed with compounds 1,
3e6 show that the binding poses of some of the compounds are
very similar to those that are represented on Fig. 1, while others
differ significantly (Fig. 2).
The binding pose of compounds 1 and 6 are the closest ones,
presenting the carbonyl group from the coumarin ring pointing
towards the Asn297 (2.83 Å and 3.26Å, respectively). However,
these compounds interact with the ferryl heme of the CYP2A6 in
different ways: compound 6 uses the position 10 (2.98 Å), while the
compound 1 interacts directly through the oxygen from the furan
ring, similarly to what was observed for the potent xanthotoxin
inhibitor (illustrated on the right side of Fig. 1).
Compounds 4 and 5 were found to bind in the opposite direction
of compounds 1 and 6. In those cases, the oxygen from the furan
ring is located nearby the amino group of Asn297 (3.07 Å and
3.29 Å, respectively), while the oxygen from the coumarin moiety
interact with the ferryl heme of the CYP2A6 (2.86 Å and 3.04 Å, and
3.07 Å and 3.74 Å, respectively). These results show that the active
site region around Asn297 is quite narrow and cannot accommodate
very large molecules. From all the studied psoralens with
bulky groups at position 2, compound 1 is the only exception that
was still able to bind similarly to the potent inhibitor xanthotoxin.
The binding pose of compound 3 is quite different from all the
other studied compounds. The carboxylic group attached to carbon
2 of the psoralen was found to interact directly with the iron of the
heme group (1.43 Å) and to establish two hydrogen bonds with
Gly301 and Thr275 (2.43 Å and 2.39 Å). The remaining part of the
psoralen structure is pointing towards the Asn297, but is too far to
interact with it (4.79 Å), contrasting to what was observed for the
other compounds.
active site of this enzyme is compact and composed by a hydrophobic
Phe-cluster formed by residues Phe107, Phe111, Phe108,Phe209 and Phe480 (Fig. 1). In this region only one hydrogen bond
donor is available and it is provided by Asn297, that directs the
natural substrate (coumarin) towards regioselective oxidation [33].
Analyzing the X-ray structures available on the protein databank
(www.pdb.org/pdb) for CYP2A6 complexed with the natural
substrate (coumarin, PDB entry 1Z10) and with a linear psoralen
inhibitor (xanthotoxin, PDB entry 1Z11), it was found that both
compounds bind in a similar manner, and that the carbonyl group of
the coumarinmoiety interacts very closely with Asn297 [34]. Theonly
observed difference was in the type of interactions nearby the iron
atom from the heme cofactor. In the natural substrate, the position 7
of the coumarin ring is very close to this centre (3.09 Å), thus favoring
the hydroxylation reaction in this position. In the psoralen, it is the
oxygen fromthe furan group that comes closer to this centre (3.25 Å).
This result indicates that the inhibitory power of the psoralen may be
related to the chelation of the oxygen fromthe furanringwiththe iron
from the heme, possibly resulting in the inactivation of the enzyme.
The molecular docking studies performed with compounds 1,
3e6 show that the binding poses of some of the compounds are
very similar to those that are represented on Fig. 1, while others
differ significantly (Fig. 2).
The binding pose of compounds 1 and 6 are the closest ones,
presenting the carbonyl group from the coumarin ring pointing
towards the Asn297 (2.83 Å and 3.26Å, respectively). However,
these compounds interact with the ferryl heme of the CYP2A6 in
different ways: compound 6 uses the position 10 (2.98 Å), while the
compound 1 interacts directly through the oxygen from the furan
ring, similarly to what was observed for the potent xanthotoxin
inhibitor (illustrated on the right side of Fig. 1).
Compounds 4 and 5 were found to bind in the opposite direction
of compounds 1 and 6. In those cases, the oxygen from the furan
ring is located nearby the amino group of Asn297 (3.07 Å and
3.29 Å, respectively), while the oxygen from the coumarin moiety
interact with the ferryl heme of the CYP2A6 (2.86 Å and 3.04 Å, and
3.07 Å and 3.74 Å, respectively). These results show that the active
site region around Asn297 is quite narrow and cannot accommodate
very large molecules. From all the studied psoralens with
bulky groups at position 2, compound 1 is the only exception that
was still able to bind similarly to the potent inhibitor xanthotoxin.
The binding pose of compound 3 is quite different from all the
other studied compounds. The carboxylic group attached to carbon
2 of the psoralen was found to interact directly with the iron of the
heme group (1.43 Å) and to establish two hydrogen bonds with
Gly301 and Thr275 (2.43 Å and 2.39 Å). The remaining part of the
psoralen structure is pointing towards the Asn297, but is too far to
interact with it (4.79 Å), contrasting to what was observed for the
other compounds.
การแปล กรุณารอสักครู่..
1.14% ใช้ท่านโคแฟคเตอร์ในการออกซิไดซ์สารอาหาร .
active site ของเอนไซม์นี้มีขนาดกะทัดรัด และแต่งโดยกลุ่มเกิดจากสารตกค้าง )
เพ phe107 phe111 phe108 , , , และ phe209 phe480 ( รูปที่ 1 ) ในภูมิภาคนี้เพียงหนึ่งพันธะไฮโดรเจน
ผู้บริจาคสามารถใช้ได้และมันมีให้โดย asn297 ที่ชี้ทาง
พื้นผิวธรรมชาติ ( coumarin ) ต่อปฏิกิริยาออกซิเดชัน regioselective [ 33 ] .
การวิเคราะห์ X-ray โครงสร้างที่มีอยู่ในโปรตีน databank
( www.pdb . org / PDB ) 1.14% complexed กับธรรมชาติ
พื้นผิว ( coumarin , PDB รายการ 1z10 ) และยับยั้ง psoralen
เส้น ( xanthotoxin PDB , รายการ 1z11 ) พบว่าสารทั้ง
ไว้ในลักษณะที่คล้ายกัน และคาร์บอนิลกลุ่ม
coumarinmoiety ติดต่ออย่างใกล้ชิดกับ asn297 [ 34 ] เพียง
สังเกตความแตกต่างในชนิดของปฏิกิริยาที่อะตอมจาก heme เหล็ก
โคแฟกเตอร์ . ในพื้นผิวธรรมชาติ ตำแหน่ง 7
ของแหวนคูมารินอยู่ใกล้กับศูนย์นี้ ( 3.09 Å ) จึงนิยม
การเตรียมแบบปฏิกิริยาในตำแหน่งนี้ ใน psoralen เป็น
ออกซิเจนจาก furan กลุ่มนั้นมาใกล้ศูนย์นี้ ( 3.25
กริพเพน )
active site ของเอนไซม์นี้มีขนาดกะทัดรัด และแต่งโดยกลุ่มเกิดจากสารตกค้าง )
เพ phe107 phe111 phe108 , , , และ phe209 phe480 ( รูปที่ 1 ) ในภูมิภาคนี้เพียงหนึ่งพันธะไฮโดรเจน
ผู้บริจาคสามารถใช้ได้และมันมีให้โดย asn297 ที่ชี้ทาง
พื้นผิวธรรมชาติ ( coumarin ) ต่อปฏิกิริยาออกซิเดชัน regioselective [ 33 ] .
การวิเคราะห์ X-ray โครงสร้างที่มีอยู่ในโปรตีน databank
( www.pdb . org / PDB ) 1.14% complexed กับธรรมชาติ
พื้นผิว ( coumarin , PDB รายการ 1z10 ) และยับยั้ง psoralen
เส้น ( xanthotoxin PDB , รายการ 1z11 ) พบว่าสารทั้ง
ไว้ในลักษณะที่คล้ายกัน และคาร์บอนิลกลุ่ม
coumarinmoiety ติดต่ออย่างใกล้ชิดกับ asn297 [ 34 ] เพียง
สังเกตความแตกต่างในชนิดของปฏิกิริยาที่อะตอมจาก heme เหล็ก
โคแฟกเตอร์ . ในพื้นผิวธรรมชาติ ตำแหน่ง 7
ของแหวนคูมารินอยู่ใกล้กับศูนย์นี้ ( 3.09 Å ) จึงนิยม
การเตรียมแบบปฏิกิริยาในตำแหน่งนี้ ใน psoralen เป็น
ออกซิเจนจาก furan กลุ่มนั้นมาใกล้ศูนย์นี้ ( 3.25
กริพเพน )
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