Conformational plasticity and structure/function relationships in cytochromes P450.
The cytochrome P450s are a superfamily of enzymes that are found in all kingdoms of living organisms, and typically catalyze the oxidative addition of atomic oxygen to an unactivated C-C or C-H bond. Over 8000 nonredundant sequences of putative and confirmed P450 enzymes have been identified, but three-dimensional structures have been determined for only a small fraction of these. While all P450 enzymes for which structures have been determined share a common global fold, the flexibility and modularity of structure around the active site account for the ability of P450 enzymes to accommodate a vast number of structurally dissimilar substrates and support a wide range of selective oxidations. In this review, known P450 structures are compared, and some structural criteria for prediction of substrate selectivity and reaction type are suggested. The importance of dynamic processes such as redox-dependent and effector-induced conformational changes in determining catalytic competence and regio- and stereoselectivity is discussed, and noncrystallographic methods for characterizing P450 structures and dynamics, in particular, mass spectrometry and nuclear magnetic resonance spectroscopy are reviewed.
Pochapsky
Thomas C
TC
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110, USA. pochapsk@brandeis.edu
Kazanis
Sophia
S
Dang
Marina
M
D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000201:enzymology* / Q000378:metabolism; D013058:Mass Spectrometry; D019906:Nuclear Magnetic Resonance, Biomolecular; D011387:Prokaryotic Cells / Q000201:enzymology* / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D003577:Cytochrome P-450 Enzyme System
J Biol Chem. 2006 Dec 22;281(51):39437-43
17028183
Mol Cell. 2000 Jan;5(1):121-31
10678174
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18463-8
19833867
J Mol Biol. 1994 Mar 4;236(4):1169-85
8120894
Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9546-51
18621681
Biochim Biophys Acta. 2007 Mar;1770(3):330-44
16978787
Biochemistry. 1989 Sep 19;28(19):7586-92
2611203
J Biol Chem. 2008 Feb 1;283(5):2917-26
18032380
Nat Struct Biol. 1995 Feb;2(2):144-53
7749919
J Biol Chem. 2009 Oct 16;284(42):29170-9
19625248
Biochemistry. 1998 Jun 30;37(26):9211-9
9649301
J Biol Chem. 2003 Feb 14;278(7):5141-7
12435731
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7426-31
19416919
J Biol Chem. 2009 Dec 18;284(51):35524-33
19846552
Curr Drug Metab. 2007 Jan;8(1):59-77
17266524
Biochemistry. 2003 May 20;42(19):5649-56
12741821
J Biol Chem. 2002 Dec 6;277(49):47476-85
12207020
Drug Metab Rev. 2007;39(2-3):557-66
17786638
Biochemistry. 2009 Jun 9;48(22):4762-71
19397311
J Biol Chem. 2009 Oct 9;284(41):28467-28475
19692330
J Biomol NMR. 2009 Mar;43(3):171-8
19199046
Acta Crystallogr D Biol Crystallogr. 2002 Jan;58(Pt 1):81-9
11752781
Biochemistry. 2003 Aug 12;42(31):9335-45
12899620
J Biol Chem. 2005 Jun 10;280(23):22102-7
15824115
J Am Chem Soc. 2005 Oct 12;127(40):13816-21
16201802
Nature. 2008 Sep 18;455(7211):363-8
18716621
J Biol Chem. 1992 Jan 5;267(1):83-90
1730627
Curr Med Chem. 2009;16(27):3480-675
19515014
J Biol Chem. 2009 Dec 25;284(52):36711-36719
19858213
Biochemistry. 2003 Jun 3;42(21):6370-9
12767218
Curr Drug Metab. 2008 May;9(4):310-22
18473749
Biochemistry. 2008 Nov 18;47(46):11964-72
18937506
J Biol Chem. 1976 Feb 25;251(4):1116-24
2601
J Biol Chem. 2005 Dec 23;280(51):42188-97
16239228
J Inorg Biochem. 2000 Aug 31;81(3):183-90
11051563
J Biol Chem. 2008 Nov 28;283(48):33406-16
18818197
Biochemistry. 1991 Dec 3;30(48):11420-9
1742281
Biochemistry. 2005 Nov 1;44(43):14143-51
16245930
J Mol Biol. 2008 Nov 14;383(3):561-74
18762195
PLoS Negl Trop Dis. 2009;3(2):e372
19190730
Biochemistry. 2001 Nov 13;40(45):13456-65
11695892
Nature. 2003 Jul 24;424(6947):464-8
12861225
Protein Eng. 1991 Feb;4(3):271-82
1857713
J Am Chem Soc. 2003 Dec 10;125(49):15010-20
14653735
J Med Chem. 2006 Nov 30;49(24):6987-7001
17125252
Drug Metab Pharmacokinet. 2010;25(1):62-71
20208389
J Biol Chem. 2006 Mar 17;281(11):7614-22
16352597
Biochim Biophys Acta. 2006 Apr;1764(4):645-70
16503427
J Am Chem Soc. 2002 May 22;124(20):5684-91
12010041
J Biol Chem. 1992 Nov 5;267(31):22587-94
1429608
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12420-5
11606730
Biochemistry. 2009 May 26;48(20):4254-61
19366254
J Mol Biol. 2004 Sep 3;342(1):207-17
15313618
Nat Struct Biol. 1997 Oct;4(10):827-32
9334748
Science. 2000 Mar 3;287(5458):1615-22
10698731
J Am Chem Soc. 2009 May 20;131(19):6748-62
19385626
Protein Sci. 2004 Jan;13(1):255-68
14691240
Biochemistry. 2003 Aug 5;42(30):9091-101
12885242
J Bacteriol. 2009 Feb;191(4):1211-9
19074393
J Mol Biol. 1987 Jun 5;195(3):687-700
3656428
J Mol Biol. 2008 Dec 12;384(2):349-63
18835276
J Biol Chem. 2000 Feb 18;275(7):4816-26
10671516
J Inorg Biochem. 2004 Jul;98(7):1194-9
15219985
Curr Top Med Chem. 2006;6(15):1609-18
16918472
J Inorg Biochem. 2002 Sep 20;91(4):491-501
12237217
Biochim Biophys Acta. 2007 Dec;1768(12):3061-70
18005930
J Biol Chem. 2007 May 11;282(19):14348-55
17311915
J Mol Biol. 2000 Nov 10;303(5):813-30
11061977
J Biol Chem. 2004 Aug 20;279(34):35630-7
15181000
J Mol Biol. 2010 Apr 9;397(4):1067-78
20149798
Biochemistry. 2008 Feb 19;47(7):2071-9
18197710
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5481-6
19293375
Protein Sci. 1996 Apr;5(4):627-39
8845752
Biochemistry. 1990 Sep 4;29(35):8119-26
2261467
Drug Metab Dispos. 2008 Dec;36(12):2582-90
18779312
Biochemistry. 2008 Mar 25;47(12):3662-70
18298086
J Biol Chem. 2008 Feb 22;283(8):5069-80
18089574
Nat Struct Biol. 1996 May;3(5):414-7
8612070
Structure. 2008 Jun;16(6):916-23
18513977
J Biol Chem. 2003 Nov 21;278(47):46727-33
12888556
Biochemistry. 1993 Mar 2;32(8):1905-13
8448148
Biochemistry. 2005 Feb 15;44(6):1833-45
15697209
Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15696-701
18838690
Protein Eng Des Sel. 2006 Nov;19(11):491-6
16943206
J Inorg Biochem. 2006 Apr;100(4):507-18
16510191
J Biol Chem. 2000 Oct 6;275(40):31086-92
10859321
Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11591-6
17606921
J Biol Chem. 2010 Jan 15;285(3):1773-80
19923211
Biochemistry. 2008 Apr 1;47(13):4017-27
18314962
J Med Chem. 1994 Mar 18;37(6):860-7
8145237
J Biol Chem. 2001 Feb 16;276(7):5020-6
11076941
Proteins. 2007 Oct 1;69(1):125-38
17598143
Biochemistry. 2007 Oct 16;46(41):11559-67
17887776
Chembiochem. 2009 Jul 6;10(10):1654-6
19492389
Biochemistry. 2008 Jun 24;47(25):6552-9
18512957
J Biol Chem. 2003 Mar 14;278(11):9761-7
12519760
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):12987-90
10557259
J Biol Chem. 2003 Apr 4;278(14):12214-21
12519772
J Biol Chem. 1993 Apr 5;268(10):6939-44
8463225
J Biol Chem. 2004 Oct 8;279(41):42844-9
15269210
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3068-73
11248033
J Biol Chem. 1993 Jan 15;268(2):759-62
8419350
J Biol Chem. 2009 Feb 27;284(9):5723-30
19124459
Nature. 2009 Jan 8;457(7226):219-23
19129847
Biochemistry. 1987 Dec 15;26(25):8165-74
3442650
J Mol Biol. 2000 Nov 10;303(5):797-811
11061976
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13883-8
18787124
J Biol Chem. 2008 May 30;283(22):15152-9
18367444
J Mol Biol. 2001 Aug 3;311(1):101-10
11469860
Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13682-7
16954191
J Biol Chem. 2006 Sep 8;281(36):26289-97
16825192
J Mol Biol. 2007 Oct 26;373(3):633-51
17868686
Biochemistry. 1993 May 4;32(17):4571-8
8485133
Arch Biochem Biophys. 1995 Nov 10;323(2):303-12
7487092
J Biol Chem. 2007 Jun 8;282(23):17306-13
17428784
J Am Chem Soc. 2005 May 18;127(19):6974-6
15884940
Biochemistry. 2007 Jul 31;46(30):8725-33
17614370
Biochem Biophys Res Commun. 2005 Dec 9;338(1):499-506
16182240
Nat Struct Mol Biol. 2005 Sep;12(9):822-3
16086027
Biochem J. 2009 Jan 1;417(1):65-76
18721129
J Mol Biol. 2009 May 15;388(4):801-14
19327368
J Biol Chem. 2004 Sep 10;279(37):38091-4
15258162
Xenobiotica. 2009 Aug;39(8):625-35
19514836
Nature. 1958 Mar 8;181(4610):662-6
13517261
J Biol Chem. 2004 Oct 8;279(41):42836-43
15269211
J Biol Chem. 2003 Nov 7;278(45):44886-93
12933799
Biochemistry. 1991 Mar 12;30(10):2674-84
2001355
J Biol Chem. 2004 Jun 25;279(26):27294-301
15100217
Arch Biochem Biophys. 2008 Jul 15;475(2):175-83
18485885
Biochimie. 1996;78(8-9):723-33
9010601
J Inorg Biochem. 2008 Feb;102(2):364-70
18023482
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
J Biol Chem. 2008 Nov 28;283(48):33698-707
18818195
J Biol Chem. 2006 Mar 3;281(9):5973-81
16373351
Biochemistry. 2009 May 19;48(19):4150-8
19317426
Biochemistry. 1989 Jan 24;28(2):917-22
2713354
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13196-201
14563924
Curr Med Chem. 2009;16(31):4066-218
19754423
Biochemistry. 2006 Feb 14;45(6):1673-84
16460014
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3050-5
10716705
Endocr Res. 2002 Nov;28(4):435-41
12530646
Biochemistry. 2007 Dec 11;46(49):14129-40
18001135
Biochem Biophys Res Commun. 2007 Oct 5;361(4):876-82
17679139
J Mol Biol. 2008 Jun 27;380(1):95-106
18511070
Biochemistry. 1986 Sep 9;25(18):5314-22
3768350
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1863-8
10051560
J Inorg Biochem. 2006 May;100(5-6):1075-90
16403573
J Biol Chem. 2003 Oct 10;278(41):39809-21
12842870
Arch Biochem Biophys. 2009 Mar 1;483(1):81-9
19161969
Arch Biochem Biophys. 1997 Mar 1;339(1):107-14
9056240
J Biol Chem. 2007 Jan 5;282(1):564-72
17077084
Biochemistry. 2007 Dec 11;46(49):14010-7
18004886
Nature. 1965 May 22;206(4986):757-61
5891407
Science. 1993 Aug 6;261(5122):731-6
8342039
Biochemistry. 1995 Nov 14;34(45):14733-40
7578081
Biochemistry. 2001 Nov 13;40(45):13430-8
11695889
J Biol Chem. 2005 Mar 25;280(12):11599-607
15659395
Arch Biochem Biophys. 2003 Jan 1;409(1):25-31
12464241
FEBS Lett. 1997 Oct 6;415(3):253-7
9357977
Antimicrob Agents Chemother. 2007 Nov;51(11):3915-23
17846131
J Biol Chem. 1994 Nov 18;269(46):28815-21
7961838
Curr Med Chem. 2009;16(2):189-202
19149571
J Bacteriol. 2005 Jul;187(14):4992-9
15995215
Biochemistry. 1996 Apr 9;35(14):4540-50
8605204
J Biol Chem. 2005 Sep 9;280(36):31659-63
15994329
Methods Enzymol. 1991;206:11-30
1784202
Biochemistry. 2007 Dec 4;46(48):13696-703
17985934
J Biol Chem. 2008 Jun 20;283(25):17227-37
18413310
J Biol Chem. 2003 Jan 3;278(1):608-16
12401810
Nat Struct Biol. 1997 Feb;4(2):140-6
9033595
Curr Drug Metab. 2006 Aug;7(6):589-98
16918314
Acta Crystallogr D Biol Crystallogr. 1995 Jan 1;51(Pt 1):21-32
15299332
Curr Med Chem. 2006;13(22):2645-52
17017916