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• W2015134782 abstract "X-ray crystal structures are available for 29 eukaryotic microsomal, chloroplast, or mitochondrial cytochrome P450s, including two non-monooxygenase P450s. These structures provide a basis for understanding structure-function relations that underlie their distinct catalytic activities. Moreover, structural plasticity has been characterized for individual P450s that aids in understanding substrate binding in P450s that mediate drug clearance. X-ray crystal structures are available for 29 eukaryotic microsomal, chloroplast, or mitochondrial cytochrome P450s, including two non-monooxygenase P450s. These structures provide a basis for understanding structure-function relations that underlie their distinct catalytic activities. Moreover, structural plasticity has been characterized for individual P450s that aids in understanding substrate binding in P450s that mediate drug clearance. Structural characterization of eukaryotic membrane cytochrome P450s has focused largely on human cytochrome P450s because of their importance in human health. Human P450s are either specialists that exhibit highly conserved functions in vertebrate species or generalists that facilitate metabolic clearance of structurally diverse compounds to reduce toxic exposures, although in some cases, mutagenic or more toxic metabolites are produced. Genes encoding generalist P450s vary between closely related species, leading to functionally distinct enzymes (1Nelson D.R. Zeldin D.C. Hoffman S.M. Maltais L.J. Wain H.M. Nebert D.W. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants.Pharmacogenetics. 2004; 14: 1-18Crossref PubMed Scopus (746) Google Scholar, 2Thomas J.H. Rapid birth-death evolution specific to xenobiotic cytochrome P450 genes in vertebrates.PLoS Genet. 2007; 3: e67Crossref PubMed Scopus (146) Google Scholar). P450s are identified by a family number, subfamily letter, and either a shared number for orthologs in different species or a unique number for paralogs. Family and subfamily designations reflect >35% and >70% amino acid sequence identity, respectively. Orthologs typically exhibit 70% or greater sequence identity. There are 57 genes encoding human P450s comprising 18 families, including 35 genes for predominantly generalist P450s in families 1–4. The catalytic domain of ∼460 amino acids folds into a triangular prism shape (Fig. 1A) that is similar to that of soluble prokaryotic P450s (3Williams P.A. Cosme J. Sridhar V. Johnson E.F. McRee D.E. The crystallographic structure of a mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity.Mol. Cell. 2000; 5: 121-131Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar). Twelve α-helices first identified for the structure of soluble prokaryotic 101A1 (4Poulos T.L. Finzel B.C. Gunsalus I.C. Wagner G.C. Kraut J. The 2.6-Å crystal structure of the Pseudomonas putida cytochrome P-450.J. Biol. Chem. 1985; 260: 16122-16130Abstract Full Text PDF PubMed Google Scholar) are designated by letters A–L. Additionally, there is a highly conserved β-sheet domain near the N terminus of the protein. The number of helices is typically larger, but these helices are less conserved (Fig. 1). Spatial conservation is highest for the structural core of the protein and diverges most for the substrate-binding site (5Poulos T.L. Johnson E.F. Structures of cytochrome P450 enzymes.in: Ortiz de Montellano P.R. Cytochrome P450: Structure, Mechanism, and Biochemistry. 3rd Ed. Kluwer Academic/Plenum Publishers, New York2005: 87-114Crossref Scopus (111) Google Scholar, 6Sirim D. Widmann M. Wagner F. Pleiss J. Prediction and analysis of the modular structure of cytochrome P450 monooxygenases.BMC Struct. Biol. 2010; 10: 34Crossref PubMed Scopus (90) Google Scholar). The heme prosthetic group is the catalytic center of the enzyme, where a reactive hypervalent oxo-iron protoporphyrin IX radical cation intermediate is formed for subsequent insertion of the iron-bound oxygen atom into a substrate bond (7Rittle J. Green M.T. Cytochrome P450 compound I: capture, characterization, and C-H bond activation kinetics.Science. 2010; 330: 933-937Crossref PubMed Scopus (970) Google Scholar). Substrates bind in a cavity or cleft above the surface of the heme in proximity to the reactive intermediate (Fig. 1). The thiolate side chain of a conserved cysteine binds to the axial coordination site of the iron opposite to the bound oxygen, giving rise to the unique spectral and functional properties of P450 enzymes. Most P450s are monooxygenases, and electrons for reduction of the heme and subsequently the oxygen substrate are provided by protein partners that bind to the face of the protein proximal to the heme (8Bridges A. Gruenke L. Chang Y.T. Vakser I.A. Loew G. Waskell L. Identification of the binding site on cytochrome P450 2B4 for cytochrome b5 and cytochrome P450 reductase.J. Biol. Chem. 1998; 273: 17036-17049Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar9Sevrioukova I.F. Li H. Zhang H. Peterson J.A. Poulos T.L. Structure of a cytochrome P450-redox partner electron-transfer complex.Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 1863-1868Crossref PubMed Scopus (458) Google Scholar, 10Strushkevich N. MacKenzie F. Cherkesova T. Grabovec I. Usanov S. Park H.W. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 10139-10143Crossref PubMed Scopus (218) Google Scholar11Zhang W. Pochapsky S.S. Pochapsky T.C. Jain N.U. Solution NMR structure of putidaredoxin-cytochrome P450cam complex via a combined residual dipolar coupling-spin labeling approach suggests a role for Trp106 of putidaredoxin in complex formation.J. Mol. Biol. 2008; 384: 349-363Crossref PubMed Scopus (38) Google Scholar). Reduced adrenodoxin (12Ewen K.M. Kleser M. Bernhardt R. Adrenodoxin: the archetype of vertebrate-type [2Fe-2S] cluster ferredoxins.Biochim. Biophys. Acta. 2011; 1814: 111-125Crossref PubMed Scopus (74) Google Scholar), a soluble Fe-S protein, serves as the reductant for vertebrate mitochondrial P450s, and in turn, it is reduced by the flavoprotein NADPH-adrenodoxin oxidoreductase. A structure of mitochondrial 11A1 crystallized with a tethered adrenodoxin bound to its proximal surface reveals the binding interaction between the proteins (10Strushkevich N. MacKenzie F. Cherkesova T. Grabovec I. Usanov S. Park H.W. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 10139-10143Crossref PubMed Scopus (218) Google Scholar). Microsomal NADPH-cytochrome P450 oxidoreductase, which has an FMN and an FAD domain, provides two electrons for reduction of oxygen by microsomal P450s. The microsomal reductase has been crystallized in a closed form in which the flavodoxin-like FMN domain is positioned for reduction by the FAD domain (13Wang M. Roberts D.L. Paschke R. Shea T.M. Masters B.S.S. Kim J.J.P. Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes.Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 8411-8416Crossref PubMed Scopus (665) Google Scholar) and in a more open form in which the FMN domain is more accessible for interaction with the proximal face of the P450 (8Bridges A. Gruenke L. Chang Y.T. Vakser I.A. Loew G. Waskell L. Identification of the binding site on cytochrome P450 2B4 for cytochrome b5 and cytochrome P450 reductase.J. Biol. Chem. 1998; 273: 17036-17049Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 14Xia C. Hamdane D. Shen A.L. Choi V. Kasper C.B. Pearl N.M. Zhang H. Im S.C. Waskell L. Kim J.J. Conformational changes of NADPH-cytochrome P450 oxidoreductase are essential for catalysis and cofactor binding.J. Biol. Chem. 2011; 286: 16246-16260Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 15Hamdane D. Xia C. Im S.C. Zhang H. Kim J.J. Waskell L. Structure and function of an NADPH-cytochrome P450 oxidoreductase in an open conformation capable of reducing cytochrome P450.J. Biol. Chem. 2009; 284: 11374-11384Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). Microsomal cytochrome b5 can also serve as a donor of the second electron, and interactions between cytochrome b5 and P450s can modulate rates and product profiles (16Im S.C. Waskell L. The interaction of microsomal cytochrome P450 2B4 with its redox partners, cytochrome P450 reductase and cytochrome b5.Arch. Biochem. Biophys. 2011; 507: 144-153Crossref PubMed Scopus (111) Google Scholar). Helices C, D, and I–L, together with β-sheets 1 and 2, comprise the structural core that forms portions of the heme-binding site and the proximal surface where protein partners bind. Helix F-G, helix B-C, and the N- and C-terminal regions, which form the outer boundaries of the substrate-binding cavity, are more dynamic and exhibit more varied secondary and tertiary structures (Fig. 1). The flexibility of this architecture was first demonstrated for P450 102A1, which exhibited an open channel to the active site when crystallized without a substrate (17Ravichandran K.G. Boddupalli S.S. Hasermann C.A. Peterson J.A. Deisenhofer J. Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450s.Science. 1993; 261: 731-736Crossref PubMed Scopus (907) Google Scholar) and a closed form when a substrate was bound (18Li H. Poulos T.L. The structure of the cytochrome P450BM-3 haem domain complexed with the fatty acid substrate, palmitoleic acid.Nat. Struct. Biol. 1997; 4: 140-146Crossref PubMed Scopus (464) Google Scholar). Several solvent access channels (Fig. 2) that can expand, contract, and merge for substrate access and product exit have been defined from structures and molecular dynamics studies (19Cojocaru V. Winn P.J. Wade R.C. The ins and outs of cytochrome P450s.Biochim. Biophys. Acta. 2007; 1770: 390-401Crossref PubMed Scopus (288) Google Scholar). Microsomal P450s are targeted to the endoplasmic reticulum by an N-terminal leader that includes a transmembrane helix (Fig. 2) that is linked by a polar connector to the catalytic domain, which is sequestered to the cytoplasmic side of the membrane (20Black S.D. Membrane topology of the mammalian P450 cytochromes.FASEB J. 1992; 6: 680-685Crossref PubMed Scopus (122) Google Scholar). With the exception of 19A1 (21Ghosh D. Griswold J. Erman M. Pangborn W. X-ray structure of human aromatase reveals an androgen-specific active site.J. Steroid Biochem. Mol. Biol. 2010; 118: 197-202Crossref PubMed Scopus (75) Google Scholar), microsomal P450s have been expressed for structure determinations without their N-terminal leader sequences, as described initially for rabbit microsomal 2C5 (3Williams P.A. Cosme J. Sridhar V. Johnson E.F. McRee D.E. The crystallographic structure of a mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity.Mol. Cell. 2000; 5: 121-131Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar, 22Cosme J. Johnson E.F. Engineering microsomal cytochrome P450 2C5 to be a soluble, monomeric enzyme. Mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding.J. Biol. Chem. 2000; 275: 2545-2553Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). The hydrophobic surfaces of helices A′, F′, and G′ of microsomal P450s provide additional interactions with the membrane surface (3Williams P.A. Cosme J. Sridhar V. Johnson E.F. McRee D.E. The crystallographic structure of a mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity.Mol. Cell. 2000; 5: 121-131Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar, 22Cosme J. Johnson E.F. Engineering microsomal cytochrome P450 2C5 to be a soluble, monomeric enzyme. Mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding.J. Biol. Chem. 2000; 275: 2545-2553Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar23Von Wachenfeldt C. Johnson E.F. Structures of eukaryotic cytochrome P450 enzymes.in: Ortiz de Montellano P.R. Cytochrome P450: Structure, Mechanism, and Biochemistry. 2nd Ed. Plenum Press, New York1995: 183-223Crossref Google Scholar, 24Ozalp C. Szczesna-Skorupa E. Kemper B. Identification of membrane-contacting loops of the catalytic domain of cytochrome P450 2C2 by tryptophan fluorescence scanning.Biochemistry. 2006; 45: 4629-4637Crossref PubMed Scopus (28) Google Scholar25Mast N. Liao W.L. Pikuleva I.A. Turko I.V. Combined use of mass spectrometry and heterologous expression for identification of membrane-interacting peptides in cytochrome P450 46A1 and NADPH-cytochrome P450 oxidoreductase.Arch. Biochem. Biophys. 2009; 483: 81-89Crossref PubMed Scopus (20) Google Scholar). Helices F′ and G′ are not typically seen in prokaryotic P450s, and they are formed by a longer polypeptide chain connecting helices F and G in eukaryotic membrane P450s. Helix F′ resides between β-sheet 1 and the helix B-C loop and above a heme propionate. In membrane P450s, this heme propionate is usually positioned below the plane of the heme, which increases space below helix F′, whereas in soluble prokaryotic P450s, this propionate typically resides above the plane (26Denisov I.G. Shih A.Y. Sligar S.G. Structural differences between soluble and membrane bound cytochrome P450s.J. Inorg. Biochem. 2012; 108: 150-158Crossref PubMed Scopus (72) Google Scholar). The leader sequences targeting family 11, 24, and 27 P450s to mitochondria are cleaved upon import (27DuBois R.N. Simpson E.R. Tuckey J. Lambeth J.D. Waterman M.R. Evidence for a higher molecular weight precursor of cholesterol side chain cleavage cytochrome P-450 and induction of mitochondrial and cytosolic proteins by corticotropin in adult bovine adrenal cells.Proc. Natl. Acad. Sci. U.S.A. 1981; 78: 1028-1032Crossref PubMed Scopus (68) Google Scholar, 28Nabi N. Kominami S. Takemori S. Omura T. In vitro synthesis of mitochondrial cytochromes P-450(scc) and P-450 (11-β) and microsomal cytochrome P-450(C-21) by both free and bound polysomes isolated from bovine adrenal cortex.Biochem. Biophys. Res. Commun. 1980; 97: 687-693Crossref PubMed Scopus (27) Google Scholar), and membrane binding to the matrix side of the inner membrane is likely to reflect interactions of the hydrophobic external surfaces of helices A′ and G′ with the membrane (Fig. 2) (29Headlam M.J. Wilce M.C. Tuckey R.C. The F-G loop region of cytochrome P450scc (CYP11A1) interacts with the phospholipid membrane.Biochim. Biophys. Acta. 2003; 1617: 96-108Crossref PubMed Scopus (60) Google Scholar, 30Annalora A.J. Goodin D.B. Hong W.X. Zhang Q. Johnson E.F. Stout C.D. The crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism.J. Mol. Biol. 2010; 396: 441-451Crossref PubMed Scopus (143) Google Scholar). Interactions of helices A′, F′, and G′ with the membrane suggest that some substrate access channels are likely to open into the membrane, whereas those that open on sides of the active site and under the helix F-G region will open to the cytosol (Fig. 2). Molecular dynamics studies of microsomal 2C9 (31Berka K. Hendrychová T. Anzenbacher P. Otyepka M. Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site.J. Phys. Chem. A. 2011; 115: 11248-11255Crossref PubMed Scopus (118) Google Scholar, 32Cojocaru V. Balali-Mood K. Sansom M.S. Wade R.C. Structure and dynamics of the membrane-bound cytochrome P450 2C9.PLoS Comput. Biol. 2011; 7: e1002152Crossref PubMed Scopus (123) Google Scholar) and 3A4 (26Denisov I.G. Shih A.Y. Sligar S.G. Structural differences between soluble and membrane bound cytochrome P450s.J. Inorg. Biochem. 2012; 108: 150-158Crossref PubMed Scopus (72) Google Scholar) in solution and bound to phospholipid bilayers indicate that the opening and closing of solvent channels can be modulated by such interactions compared with simulations in a homogeneous aqueous medium. Mitochondrial enzymes are specialists that generate specific products that fulfill their physiologic functions. Mitochondrial 11A1 catalyzes the first step in steroid hormone synthesis by successive oxygenations that result in scission of the C21–C22 bond of cholesterol to form pregnenolone and isocaproaldehyde. Structures of 11A1 co-crystallized with cholesterol and with the two intermediate products, (22R)-hydroxycholesterol (Fig. 2B) and (22R,20R)-dihydroxycholesterol, bound in the active site (10Strushkevich N. MacKenzie F. Cherkesova T. Grabovec I. Usanov S. Park H.W. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 10139-10143Crossref PubMed Scopus (218) Google Scholar) indicate that the sterol ring system is positioned under helix F′, with the side chain positioned with C22 and C20 in close proximity to the heme iron for each substrate. A structure determined for the bovine 11A1 (22R)-hydroxycholesterol complex (33Mast N. Annalora A.J. Lodowski D.T. Palczewski K. Stout C.D. Pikuleva I.A. Structural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1.J. Biol. Chem. 2011; 286: 5607-5613Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar) indicates that this substrate-binding site is highly conserved. Mitochondrial 24A1 catalyzes a similar reaction that cleaves the side chain of calcitriol to inactivate the hormone. A structure of rat mitochondrial 24A1 crystallized in the absence of its substrate exhibits an open substrate-binding cleft between helices A′ and F′, and when calcitriol binds, the cleft is likely to close and resemble structures of 11A1 (Fig. 2B) (30Annalora A.J. Goodin D.B. Hong W.X. Zhang Q. Johnson E.F. Stout C.D. The crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism.J. Mol. Biol. 2010; 396: 441-451Crossref PubMed Scopus (143) Google Scholar). Cholesterol 3-sulfate binds in a similar way in a structure of microsomal 46A1, with the side chain positioned for hydroxylation of C24. This is an important reaction for the clearance of excess cholesterol from the brain. Interestingly, the substrate-free structure of 46A1 exhibits a much different cavity shape (34Mast N. White M.A. Bjorkhem I. Johnson E.F. Stout C.D. Pikuleva I.A. Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain.Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 9546-9551Crossref PubMed Scopus (105) Google Scholar), and the 46A1 active site adapts to bind several structurally unrelated inhibitors (35Mast N. Linger M. Clark M. Wiseman J. Stout C.D. Pikuleva I.A. In silico and intuitive predictions of CYP46A1 inhibition by marketed drugs with subsequent enzyme crystallization in complex with fluvoxamine.Mol. Pharmacol. 2012; 82: 824-834Crossref PubMed Scopus (29) Google Scholar, 36Mast N. Charvet C. Pikuleva I.A. Stout C.D. Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain.J. Biol. Chem. 2010; 285: 31783-31795Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). In contrast, structures of microsomal 2R1 (37Strushkevich N. Usanov S.A. Plotnikov A.N. Jones G. Park H.W. Structural analysis of CYP2R1 in complex with vitamin D3.J. Mol. Biol. 2008; 380: 95-106Crossref PubMed Scopus (143) Google Scholar) indicate that the secosterol moiety of vitamin D3 and related compounds is bound between helices I and G and the helix B-C loop. This positions the side chain for 25-hydroxylation, which is the first step in the conversion of vitamin D3 to calcitriol. The sterol ring system is positioned much differently in a structure of microsomal 7A1 (Protein Data Bank code 3SN5), where cholest-4-en-3-one resides above the heme propionate side chains, with the plane of the sterol rings parallel to the heme plane. The site of metabolism, C7, is positioned closest to the heme iron. Hydroxylation at C7 is the rate-limiting step in bile acid formation from cholesterol. Similarly, a structure of the human aromatase, microsomal 19A1, crystallized with androstenedione (21Ghosh D. Griswold J. Erman M. Pangborn W. X-ray structure of human aromatase reveals an androgen-specific active site.J. Steroid Biochem. Mol. Biol. 2010; 118: 197-202Crossref PubMed Scopus (75) Google Scholar) indicates that the long axis of the steroid is almost parallel to the heme plane, with the 19-methyl group positioned for reaction with the reactive intermediate. Estrogens are formed by three successive oxygenations at C19, which leads to elimination of formic acid and to aromatization of ring A (38Akhtar M. Wright J.N. Lee-Robichaud P. A review of mechanistic studies on aromatase (CYP19) and 17α-hydroxylase-17,20-lyase (CYP17).J. Steroid Biochem. Mol. Biol. 2011; 125: 2-12Crossref PubMed Scopus (94) Google Scholar). A structure of 19A1 complexed with exemestane, an inhibitor used clinically to reduce estrogen formation in breast cancer patients, led to the synthesis of new inhibitors with increased potency (39Ghosh D. Lo J. Morton D. Valette D. Xi J. Griswold J. Hubbell S. Egbuta C. Jiang W. An J. Davies H.M. Novel aromatase inhibitors by structure-guided design.J. Med. Chem. 2012; 55: 8464-8476Crossref PubMed Scopus (137) Google Scholar). Similarly, inhibitors of microsomal 17A1 are used to inhibit androgen formation to treat prostate cancer. The first step of androgen biosynthesis is 17α-hydroxylation of pregnenolone, which is followed by a second oxygenation that results in scission of the C17–C20 bond to produce androstenedione and acetic acid. Structures of 17A1 were determined with a Food and Drug Administration-approved first-in-class inhibitor (abiraterone) and with another inhibitor (TOK-001) that is in clinical trials (40DeVore N.M. Scott E.E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001.Nature. 2012; 482: 116-119Crossref PubMed Scopus (251) Google Scholar). In this case, the long axis of the inhibitors is almost perpendicular to the plane of the heme (40DeVore N.M. Scott E.E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001.Nature. 2012; 482: 116-119Crossref PubMed Scopus (251) Google Scholar). A similar orientation was observed for 17α-hydroxyprogesterone in a structure of 21A2 (41Zhao B. Lei L. Kagawa N. Sundaramoorthy M. Banerjee S. Nagy L.D. Guengerich F.P. Waterman M.R. Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants.J. Biol. Chem. 2012; 287: 10613-10622Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Microsomal 21A2 catalyzes the 21-hydroxylation of 17α-progesterone and progesterone to form precursors for the synthesis of cortisol by 11B1 and aldosterone by 11B2, respectively. The binding of deoxycorticosterone to mitochondrial 11B2 is similar to that of androstenedione in 19A1, but with C11 and the 18-methyl group placed near the heme iron (42Strushkevich N. Gilep A.A. Shen L. Arrowsmith C.H. Edwards A.M. Usanov S.A. Park H.W. Structural insights into aldosterone synthase substrate specificity and targeted inhibition.Mol. Endocrinol. 2013; 27: 315-324Crossref PubMed Scopus (103) Google Scholar). Interestingly, human microsomal 51A1 is an anti-target for development of therapeutic inhibitors that target 51A1 in fungal pathogens. Human 51A catalyzes the 14α-demethylation of lanosterol, another carbon–carbon bond scission reaction, in the pathway for de novo synthesis of cholesterol. It is anticipated that the availability of structures for human 51A1 (43Strushkevich N. Usanov S.A. Park H.W. Structural basis of human CYP51 inhibition by antifungal azoles.J. Mol. Biol. 2010; 397: 1067-1078Crossref PubMed Scopus (208) Google Scholar) and 51A1 orthologs in fungal pathogens (44Lepesheva G.I. Park H.W. Hargrove T.Y. Vanhollebeke B. Wawrzak Z. Harp J.M. Sundaramoorthy M. Nes W.D. Pays E. Chaudhuri M. Villalta F. Waterman M.R. Crystal structures of Trypanosoma brucei sterol 14α-demethylase and implications for selective treatment of human infections.J. Biol. Chem. 2010; 285: 1773-1780Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 45Hargrove T.Y. Wawrzak Z. Liu J. Waterman M.R. Nes W.D. Lepesheva G.I. Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Δ7–24,25-dihydrolanosterol.J. Lipid Res. 2012; 53: 311-320Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar46Lepesheva G.I. Hargrove T.Y. Anderson S. Kleshchenko Y. Furtak V. Wawrzak Z. Villalta F. Waterman M.R. Structural insights into inhibition of sterol 14α-demethylase in the human pathogen Trypanosoma cruzi.J. Biol. Chem. 2010; 285: 25582-25590Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar) will aid in the design of drugs that are more selective for fungal 51A relative to the human enzyme. Humans express two specialist microsomal P450s (8A1 and 5A1) that catalyze the isomerization of prostaglandin H1 to produce prostacyclin and thromboxane, respectively. Structures of human (47Chiang C.W. Yeh H.C. Wang L.H. Chan N.L. Crystal structure of the human prostacyclin synthase.J. Mol. Biol. 2006; 364: 266-274Crossref PubMed Scopus (56) Google Scholar) and zebrafish (48Li Y.C. Chiang C.W. Yeh H.C. Hsu P.Y. Whitby F.G. Wang L.H. Chan N.L. Structures of prostacyclin synthase and its complexes with substrate-analog and inhibitor reveal a ligand-specific heme conformation change.J. Biol. Chem. 2008; 283: 2917-2926Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) 8A1 in the ligand-free state have been determined, and conserved characteristics of the active site architectures were noted (48Li Y.C. Chiang C.W. Yeh H.C. Hsu P.Y. Whitby F.G. Wang L.H. Chan N.L. Structures of prostacyclin synthase and its complexes with substrate-analog and inhibitor reveal a ligand-specific heme conformation change.J. Biol. Chem. 2008; 283: 2917-2926Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). U51605, a substrate analog with nitrogens substituted for the endoperoxide oxygens, binds with the C11 nitrogen coordinated to the heme iron (48Li Y.C. Chiang C.W. Yeh H.C. Hsu P.Y. Whitby F.G. Wang L.H. Chan N.L. Structures of prostacyclin synthase and its complexes with substrate-analog and inhibitor reveal a ligand-specific heme conformation change.J. Biol. Chem. 2008; 283: 2917-2926Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). This is consistent with the proposed initial binding of the C11 oxygen of the endoperoxide moiety to the heme iron to initiate the isomerase reaction (49Hecker M. Ullrich V. On the mechanism of prostacyclin and thromboxane A2 biosynthesis.J. Biol. Chem. 1989; 264: 141-150Abstract Full Text PDF PubMed Google Scholar). The C9 nitrogen exhibits a hydrogen bond with the side chain of Asn-277 on helix I of 8A1 (48Li Y.C. Chiang C.W. Yeh H.C. Hsu P.Y. Whitby F.G. Wang L.H. Chan N.L. Structures of prostacyclin synthase and its complexes with substrate-analog and inhibitor reveal a ligand-specific heme conformation change.J. Biol. Chem. 2008; 283: 2917-2926Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). This asparagine is conserved in plant non-monooxygenases of the CYP74 family, such as chloroplast allene oxide synthase, in which the corresponding asparagine is thought to facilitate conversion of lipid peroxides to allene oxides (50Lee D.S. Nioche P. Hamberg M. Raman C.S. Structural insights into the evolutionary paths of oxylipin biosynthetic enzymes.Nature. 2008; 455: 363-368Crossref PubMed Scopus (224) Google Scholar). These studies also noted that alterations in the proximal surface would likely prevent interactions with electron donors for P450 monooxygenases (48Li Y.C. Chiang C.W. Yeh H.C. Hsu P.Y. Whitby F.G. Wang L.H. Chan N.L. Structures of prostacyclin synthase and its complexes with substrate-analog and inhibitor reveal a ligand-specific heme conformation change.J. Biol. Chem. 2008; 283: 2917-2926Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 50Lee D.S. Nioche P. Hamberg M. Raman C.S. Structural insights into the evolutionary paths of oxylipin biosynthetic enzymes.Nature. 2008; 455: 363-368Crossref PubMed Scopus (224) Google Scholar). Each generalist P450 transforms a wide range of lipophilic substrates to more polar compounds to enhance elimination. Unfortunately, P450s can also transform procarcinogens to direct acting mutagens. Six microsomal P450s (1A1, 1A2, 1B1, 2E1, 3A4, and 2A6) account for >90% of known carcinogen activation pathways (51Rendic S. Guengerich F.P. Contributions of human enzymes in carcinogen metabolism.Chem. Res. Toxicol. 2012; 25: 1316-1383Crossref PubMed Scopus (198) Google Scholar). Structures of 1A1 (Protein Data Bank code 4I8V), 1A2 (52Sansen S. Yano J.K. Reynald R.L. Schoch G.A. Griffin K.J. Stout C.D. Johnson E.F. Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2.J. Biol. Chem. 2007; 282: 14348-14355Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar), and 1B1 (53Wang A. Savas U. Stout C.D. Johnson E.F. Structural characterization of the complex between α-naphthoflavone and human cytochrome P450 1B1.J. Biol. Chem. 2011; 286: 5736-5743Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar) co-crystallized with the inhibitor α-naphthoflavone (272 Da) indicate that their active sites are narrow, with large hydrophobic surfaces suita" @default.
• W2015134782 created "2016-06-24" @default.
• W2015134782 creator A5071803873 @default.
• W2015134782 creator A5090868883 @default.
• W2015134782 date "2013-06-01" @default.
• W2015134782 modified "2023-10-18" @default.
• W2015134782 title "Structural Diversity of Eukaryotic Membrane Cytochrome P450s" @default.
• W2015134782 cites W1498652161 @default.
• W2015134782 cites W1547482025 @default.
• W2015134782 cites W1745529008 @default.
• W2015134782 cites W1764799499 @default.
• W2015134782 cites W1963968986 @default.
• W2015134782 cites W1967094363 @default.
• W2015134782 cites W1968400590 @default.
• W2015134782 cites W1968973920 @default.
• W2015134782 cites W1970009415 @default.
• W2015134782 cites W1971223189 @default.
• W2015134782 cites W1972490547 @default.
• W2015134782 cites W1973276283 @default.
• W2015134782 cites W1974302220 @default.
• W2015134782 cites W1974543768 @default.
• W2015134782 cites W1975206909 @default.
• W2015134782 cites W1975264032 @default.
• W2015134782 cites W1975786509 @default.
• W2015134782 cites W1977087092 @default.
• W2015134782 cites W1979556755 @default.
• W2015134782 cites W1980255186 @default.
• W2015134782 cites W1982320452 @default.
• W2015134782 cites W1986080936 @default.
• W2015134782 cites W1993209079 @default.
• W2015134782 cites W1995307921 @default.
• W2015134782 cites W1997075839 @default.
• W2015134782 cites W1998118464 @default.
• W2015134782 cites W2000051743 @default.
• W2015134782 cites W2000153504 @default.
• W2015134782 cites W2000966246 @default.
• W2015134782 cites W2006358281 @default.
• W2015134782 cites W2014301837 @default.
• W2015134782 cites W2014919794 @default.
• W2015134782 cites W2015219850 @default.
• W2015134782 cites W2015780823 @default.
• W2015134782 cites W2017434392 @default.
• W2015134782 cites W2018873107 @default.
• W2015134782 cites W2021232512 @default.
• W2015134782 cites W2026863951 @default.
• W2015134782 cites W2027757388 @default.
• W2015134782 cites W2031584287 @default.
• W2015134782 cites W2033479383 @default.
• W2015134782 cites W2037448827 @default.
• W2015134782 cites W2041774824 @default.
• W2015134782 cites W2043998269 @default.
• W2015134782 cites W2044793333 @default.
• W2015134782 cites W2051639214 @default.
• W2015134782 cites W2053490888 @default.
• W2015134782 cites W2055409139 @default.
• W2015134782 cites W2055678902 @default.
• W2015134782 cites W2055944089 @default.
• W2015134782 cites W2060907949 @default.
• W2015134782 cites W2061370608 @default.
• W2015134782 cites W2061508473 @default.
• W2015134782 cites W2061869842 @default.
• W2015134782 cites W2062882834 @default.
• W2015134782 cites W2066157547 @default.
• W2015134782 cites W2066840001 @default.
• W2015134782 cites W2068252164 @default.
• W2015134782 cites W2068780263 @default.
• W2015134782 cites W2069447114 @default.
• W2015134782 cites W2069518737 @default.
• W2015134782 cites W2070098436 @default.
• W2015134782 cites W2083219665 @default.
• W2015134782 cites W2084546279 @default.
• W2015134782 cites W2085717234 @default.
• W2015134782 cites W2086564513 @default.
• W2015134782 cites W2086746579 @default.
• W2015134782 cites W2090505208 @default.
• W2015134782 cites W2092612050 @default.
• W2015134782 cites W2104180764 @default.
• W2015134782 cites W2105587896 @default.
• W2015134782 cites W2110809638 @default.
• W2015134782 cites W2111329465 @default.
• W2015134782 cites W2112575348 @default.
• W2015134782 cites W2118792521 @default.
• W2015134782 cites W2122062071 @default.
• W2015134782 cites W2122368088 @default.
• W2015134782 cites W2124388227 @default.
• W2015134782 cites W2125187374 @default.
• W2015134782 cites W2126592776 @default.
• W2015134782 cites W2130434638 @default.
• W2015134782 cites W2130983257 @default.
• W2015134782 cites W2132618768 @default.
• W2015134782 cites W2137589721 @default.
• W2015134782 cites W2138101271 @default.
• W2015134782 cites W2140211058 @default.
• W2015134782 cites W2141825656 @default.
• W2015134782 cites W2142034214 @default.
• W2015134782 cites W2143836494 @default.
• W2015134782 cites W2147472643 @default.
• W2015134782 cites W2151690949 @default.

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