cytochrome P450 (CYP) superfamily; Cytochrome P450 (P450, CYP) is a large superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs with > 40% sequence identity are members of the same family. There are approximately 2250 CYP families: mammals, insects, plants, fungi, bacteria, and archaea have around 18, 208, 277, 805, 591, and 14 families, respectively. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop. Their monooxygenase activity relies on the reductive scission of molecular oxygen bound to the P450 heme iron, and the delivery of two electrons to the heme iron during the catalytic cycle. CYPs use a variety of redox partners, such as the eukaryotic diflavin enzyme NADPH-cytochrome P450 oxidoreductase and the bacterial/mitochondrial NAD(P)H-ferredoxin reductase and ferredoxin partners. Some CYPs are naturally linked to their redox partners and others have evolved to bypass requirements for redox partners, and instead react directly with hydrogen peroxide or NAD(P)H to facilitate oxidative or reductive catalysis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS 140
Cdd:cd20665    1 YGPVFTLYLGMKPTVVLHGYEAVKEALIDLGEEFSGRGRFPIFEKVNKGLGIVFSNGERWKETRRFSLMTLRNFGMGKRS 80

                         90       100
                 ....*....|....*....|.
gi 119570404 141 IEDRVQEEARCLVEELRKTKG 161
Cdd:cd20665   81 IEDRVQEEARCLVEELRKTNG 101

cytochrome P450 family 2, subfamily C, and similar cytochrome P450s; This CYP2C-like group includes CYP2C, and similar CYPs including mammalian CYP2E1, also called 4-nitrophenol 2-hydroxylase, as well as chicken CYP2H1 and CYP2H2. The CYP2C subfamily is composed of four human members (CYP2C8, CYP2C9, CYP2C18, CYP2C19) that metabolize approximately 20% of clinically used drugs, and all four exhibit genetic polymorphisms that results in toxicity or altered efficacy of some drugs in affected individuals. CYP2E1 participates in the metabolism of endogenous substrates, including acetone and fatty acids, and exogenous compounds such as anesthetics, ethanol, nicotine, acetaminophen, aspartame, and chlorzoxazone, among others. The CYP2C-like subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS 140
Cdd:cd20665    1 YGPVFTLYLGMKPTVVLHGYEAVKEALIDLGEEFSGRGRFPIFEKVNKGLGIVFSNGERWKETRRFSLMTLRNFGMGKRS 80

                         90       100
                 ....*....|....*....|.
gi 119570404 141 IEDRVQEEARCLVEELRKTKG 161
Cdd:cd20665   81 IEDRVQEEARCLVEELRKTNG 101

trans-cinnamate 4-monooxygenase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  28 KLPPGPTPLPVIGNILQIGIKDISKSLTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGR------GIFp 101
Cdd:PLN02394  30 KLPPGPAAVPIFGNWLQVGDDLNHRNLAEMAKKYGDVFLLRMGQRNLVVVSSPELAKEVLHTQGVEFGSRtrnvvfDIF- 108

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404 102 laerANRGFGIVFSN-GKKWKEIRRfsLMTLrNFGMGKRSIEDRV--QEEARCLVEELRK 158
Cdd:PLN02394 109 ----TGKGQDMVFTVyGDHWRKMRR--IMTV-PFFTNKVVQQYRYgwEEEADLVVEDVRA 161

Cytochrome P450 [Secondary metabolites biosynthesis, transport and catabolism, Defense mechanisms]; Cytochrome P450 is part of the Pathway/BioSystem: Biotin biosynthesis

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDlGEEFSGRGIFPLAERANRGFG--IVFSNGKKWKEIRRfslMTLRNFGMGK 138
Cdd:COG2124   31 YGPVFRVRLPGGGAWLVTRYEDVREVLRD-PRTFSSDGGLPEVLRPLPLLGdsLLTLDGPEHTRLRR---LVQPAFTPRR 106

                         90       100
                 ....*....|....*....|
gi 119570404 139 -RSIEDRVQEEARCLVEELR 157
Cdd:COG2124  107 vAALRPRIREIADELLDRLA 126

cytochrome P450 family 2, subfamily C, and similar cytochrome P450s; This CYP2C-like group includes CYP2C, and similar CYPs including mammalian CYP2E1, also called 4-nitrophenol 2-hydroxylase, as well as chicken CYP2H1 and CYP2H2. The CYP2C subfamily is composed of four human members (CYP2C8, CYP2C9, CYP2C18, CYP2C19) that metabolize approximately 20% of clinically used drugs, and all four exhibit genetic polymorphisms that results in toxicity or altered efficacy of some drugs in affected individuals. CYP2E1 participates in the metabolism of endogenous substrates, including acetone and fatty acids, and exogenous compounds such as anesthetics, ethanol, nicotine, acetaminophen, aspartame, and chlorzoxazone, among others. The CYP2C-like subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS 140
Cdd:cd20665    1 YGPVFTLYLGMKPTVVLHGYEAVKEALIDLGEEFSGRGRFPIFEKVNKGLGIVFSNGERWKETRRFSLMTLRNFGMGKRS 80

                         90       100
                 ....*....|....*....|.
gi 119570404 141 IEDRVQEEARCLVEELRKTKG 161
Cdd:cd20665   81 IEDRVQEEARCLVEELRKTNG 101

cytochrome P450 family 2, subfamily F; Cytochrome P450 family 2, subfamily F (CYP2F) members are selectively expressed in lung tissues. They are responsible for the bioactivation of several pneumotoxic and carcinogenic chemicals such as benzene, styrene, naphthalene, and 1,1-dichloroethylene. CYP2F1 and CYP2F3 selectively catalyzes the 3-methyl dehydrogenation of 3-methylindole, forming toxic reactive intermediates that can form adducts with proteins and DNA. The CYP2F subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS 140
Cdd:cd20669    1 YGSVYTVYLGPRPVVVLCGYQAVKEALVDQAEEFSGRGDYPVFFNFTKGNGIAFSNGERWKILRRFALQTLRNFGMGKRS 80

                         90       100
                 ....*....|....*....|.
gi 119570404 141 IEDRVQEEARCLVEELRKTKG 161
Cdd:cd20669   81 IEERILEEAQFLLEELRKTKG 101

Cytochrome P450; Cytochrome P450s are haem-thiolate proteins involved in the oxidative degradation of various compounds. They are particularly well known for their role in the degradation of environmental toxins and mutagens. They can be divided into 4 classes, according to the method by which electrons from NAD(P)H are delivered to the catalytic site. Sequence conservation is relatively low within the family - there are only 3 absolutely conserved residues - but their general topography and structural fold are highly conserved. The conserved core is composed of a coil termed the 'meander', a four-helix bundle, helices J and K, and two sets of beta-sheets. These constitute the haem-binding loop (with an absolutely conserved cysteine that serves as the 5th ligand for the haem iron), the proton-transfer groove and the absolutely conserved EXXR motif in helix K. While prokaryotic P450s are soluble proteins, most eukaryotic P450s are associated with microsomal membranes. their general enzymatic function is to catalyze regiospecific and stereospecific oxidation of non-activated hydrocarbons at physiological temperatures.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404   30 PPGPTPLPVIGNILQIGIKDISKS-LTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPL---AER 105
Cdd:pfam00067   1 PPGPPPLPLFGNLLQLGRKGNLHSvFTKLQKKYGPIFRLYLGPKPVVVLSGPEAVKEVLIKKGEEFSGRPDEPWfatSRG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 119570404  106 ANRGFGIVFSNGKKWKEIRRFSLMTLRNFgmGKRSIEDRVQEEARCLVEELRKTKG 161
Cdd:pfam00067  81 PFLGKGIVFANGPRWRQLRRFLTPTFTSF--GKLSFEPRVEEEARDLVEKLRKTAG 134

cytochrome P450 family 2, subfamily K; Members of CYP2K are present in fish, birds, and amphibians. CYP2K6 from zebrafish has been shown to catalyze the conversion of aflatoxin B1 (AFB1) to its cytotoxic derivative AFB1 exo-8,9-epoxide, while its ortholog in rainbow trout CYP2K1 is also capable of oxidizing lauric acid. In birds, CYP2K is one of the largest CYP2 subfamilies. The CYP2K subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS 140
Cdd:cd20664    1 YGSIFTVQMGTKKVVVLAGYKTVKEALVNHAEAFGGRPIIPIFEDFNKGYGILFSNGENWKEMRRFTLTTLRDFGMGKKT 80

                         90       100
                 ....*....|....*....|.
gi 119570404 141 IEDRVQEEARCLVEELRKTKG 161
Cdd:cd20664   81 SEDKILEEIPYLIEVFEKHKG 101

cytochrome P450 family 2, subfamily J; Members of CYP2J are expressed in multiple tissues in mice and humans. They function as catalysts of arachidonic acid metabolism and are active in the metabolism of fatty acids to generate bioactive compounds. Human CYP2J2, also called arachidonic acid epoxygenase or albendazole monooxygenase (hydroxylating), is a membrane-bound cytochrome P450 primarily expressed in the heart and plays a significant role in cardiovascular diseases. The CYP2J subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS 140
Cdd:cd20662    1 YGNIFSLQLGSISSVIVTGLPLIKEALVTQEQNFMNRPETPLRERIFNKNGLIFSSGQTWKEQRRFALMTLRNFGLGKKS 80

                         90       100
                 ....*....|....*....|.
gi 119570404 141 IEDRVQEEARCLVEELRKTKG 161
Cdd:cd20662   81 LEERIQEECRHLVEAIREEKG 101

cytochrome P450 family 2, subfamily W, polypeptide 1; Cytochrome P450 2W1 (CYP2W1) is expressed during development of the gastrointestinal tract, is silenced after birth in the intestine and colon by epigenetic modifications, but is activated following demethylation in colorectal cancer (CRC). Its expression levels in CRC correlate with the degree of malignancy, are higher in metastases and are predictive of survival. Thus, it is an attractive tumor-specific diagnostic and therapeutic target. CYP2W1 belongs to family 2 of the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS 140
Cdd:cd20671    1 YGPVFTIHLGMQKTVVLTGYEAVKEALVGTGDEFADRPPIPIFQAIQHGNGVFFSSGERWRTTRRFTVRSMKSLGMGKRT 80

                         90       100
                 ....*....|....*....|..
gi 119570404 141 IEDRVQEEARCLVEELRKTKGG 162
Cdd:cd20671   81 IEDKILEELQFLNGQIDSFNGK 102

cytochrome P450 family 2, subfamily D; Members of CYP2D are present in mammals, birds, reptiles, and amphibians. The hominin CYP2D subfamily consists of a functional CYP2D6 and two paralogs, CYP2D7 and CYP2D8, that are often not functional in some species. Human CYP2D6 has a high affinity for alkaloids and can detoxify them. It is also responsible for metabolizing about 25% of commonly used drugs, such as antidepressants, beta-blockers, and antiarrhythmics. The CYP2D subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAER---ANRGFGIVFSN-GKKWKEIRRFSLMTLRNFGM 136
Cdd:cd20663    1 FGDVFSLQMAWKPVVVLNGLKAVREALVTCGEDTADRPPVPIFEHlgfGPKSQGVVLARyGPAWREQRRFSVSTLRNFGL 80

                         90
                 ....*....|....*.
gi 119570404 137 GKRSIEDRVQEEARCL 152
Cdd:cd20663   81 GKKSLEQWVTEEAGHL 96

cytochrome P450 family 2, subfamily U, polypeptide 1; CYP2U1 is a thymus- and brain-specific cytochrome P450 that catalyzes omega- and (omega-1)-hydroxylation of fatty acids such as arachidonic acid, docosahexaenoic acid, and other long chain fatty acids. Mutations in CYP2U1 are associated with hereditary spastic paraplegia (HSP), a neurological disorder, and pigmentary degenerative maculopathy associated with progressive spastic paraplegia. CYP2U1 belongs to family 2 of the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSN-GKKWKEIRRFSLMTLRNFGMGKR 139
Cdd:cd20666    1 YGNIFSLFIGSQLVVVLNDFESVREALVQKAEVFSDRPSVPLVTILTKGKGIVFAPyGPVWRQQRKFSHSTLRHFGLGKL 80

                         90
                 ....*....|....*....
gi 119570404 140 SIEDRVQEEARCLVEELRK 158
Cdd:cd20666   81 SLEPKIIEEFRYVKAEMLK 99

cytochrome P450 family 1; The cytochrome P450 family 1 (CYP1 or Cyp1) is composed of three functional human members: CYP1A1, CYP1A2 and CYP1B1, which are regulated by the aryl hydrocarbon receptor (AhR), ligand-activated transcriptional factor that dimerizes with AhR nuclear translocator (ARNT). CYP1 enzymes are involved in the metabolism of endogenous hormones, xenobiotics, and drugs. Included in the CYP1 family is CYP1D1 (cytochrome P450 family 1, subfamily D, polypeptide 1), which is not expressed in humans as its gene is pseudogenized due to five nonsense mutations in the putative coding region, but is functional in in other organisms including cynomolgus monkey. Zebrafish CYP1D1 expression is not regulated by AhR. The CYP1 family belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFS-NGKKWKEIRRFSLMTLRNFGMGKR 139
Cdd:cd11028    1 YGDVFQIRMGSRPVVVLNGLETIKQALVRQGEDFAGRPDFYSFQFISNGKSMAFSdYGPRWKLHRKLAQNALRTFSNART 80

                         90       100
                 ....*....|....*....|....*
gi 119570404 140 S--IEDRVQEEARCLVEELRKTKGG 162
Cdd:cd11028   81 HnpLEEHVTEEAEELVTELTENNGK 105

cytochrome P450 family 1, subfamily B, polypeptide 1 and similar cytochrome P450s; Cytochrome P450 1B1 (CYP1B1) is expressed in liver and extrahepatic tissues where it carries out the metabolism of numerous xenobiotics, including metabolic activation of polycyclic aromatic hydrocarbons. It is also important in regulating endogenous metabolic pathways, including the metabolism of steroid hormones, fatty acids, melatonin, and vitamins. CYP1B1 is overexpressed in a wide variety of tumors and is associated with angiogenesis. It is also associated with adipogenesis, obesity, hypertension, and atherosclerosis. It is therefore a target for the treatment of metabolic diseases and cancer. Also included in this subfamily are CYP1C proteins from fish, birds and amphibians. The CYP1B1-like subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPlaeranrGFGIVfSNGK---------KWKEIRRFSLMTL 131
Cdd:cd20675    1 YGDVFQIRLGSRPVVVLNGERAIRQALVQQGTDFAGRPDFA-------SFRVV-SGGRslafggyseRWKAHRRVAHSTV 72

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 119570404 132 RNFGMG----KRSIEDRVQEEARCLVEE-LRKTKGG 162
Cdd:cd20675   73 RAFSTRnprtRKAFERHVLGEARELVALfLRKSAGG 108

cytochrome P450 306A1 and similar cytochrome P450s; This subfamily is composed of insect and crustacean cytochrome P450s including insect cytochrome P450 306A1 (CYP306A1 or Cyp306a1) and CYP18A1. CYP306A1 functions as a carbon 25-hydroxylase and has an essential role in ecdysteroid biosynthesis during insect development. CYP18A1 is a 26-hydroxylase and plays a key role in steroid hormone inactivation. The CYP306A1-like subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  62 GPVFTLYFGLKPIVVLHGYEAVKEALIDlgEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRS- 140
Cdd:cd20652    1 GSIFSLKMGSVYTVVLSDPKLIRDTFRR--DEFTGRAPLYLTHGIMGGNGIICAEGDLWRDQRRFVHDWLRQFGMTKFGn 78

                         90       100
                 ....*....|....*....|....*
gi 119570404 141 ----IEDRVQEEARCLVEELRKTKG 161
Cdd:cd20652   79 grakMEKRIATGVHELIKHLKAESG 103

cytochrome P450 family 1, subfamily A; Cytochrome P450 family 1, subfamily A (CYP1A) consists of two human members, CYP1A1 and CYP1A2, which overlap in their activities. CYP1A2 is the highly expressed cytochrome enzyme in the human liver, while CYP1A1 is mostly found in extrahepatic tissues. Known common substrates include aromatic compounds such as polycyclic aromatic hydrocarbons, arachidonic acid and eicosapentoic acid, as well as melatonin and 6-hydroxylate melatonin. In addition, CYP1A1 activates procarcinogens into carcinogens via epoxides, and metabolizes heterocyclic aromatic amines of industrial origin. CYP1A2 metabolizes numerous natural products that result in toxic products, such as the transformation of methyleugenol to 1'-hydroxymethyleugenol, estragole to reactive metabolites, and oxidation of nephrotoxins. It also plays an important role in the metabolism of several clinical drugs including analgesics, antipyretics, antipsychotics, antidepressants, anti-inflammatory, and cardiovascular drugs. The CYP1A subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSN--GKKWKEIRRFSLMTLRNFGM-- 136
Cdd:cd20676    1 YGDVLQIQIGSRPVVVLSGLDTIRQALVKQGDDFKGRPDLYSFRFISDGQSLTFSTdsGPVWRARRKLAQNALKTFSIas 80

                         90       100
                 ....*....|....*....|....*..
gi 119570404 137 GKRS-----IEDRVQEEARCLVEELRK 158
Cdd:cd20676   81 SPTSsssclLEEHVSKEAEYLVSKLQE 107

flavonoid 3'-monooxygenase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  21 RQSSGRGK--LPPGPTPLPVIGNILQIGIKDiSKSLTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRG 98
Cdd:PLN02687  25 RGGSGKHKrpLPPGPRGWPVLGNLPQLGPKP-HHTMAALAKTYGPLFRLRFGFVDVVVAASASVAAQFLRTHDANFSNRP 103

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 119570404  99 IFPLAER-ANRGFGIVFSN-GKKWKEIRR------FSLMTLRNFgmgkRSIEdrvQEEARCLVEELRKTKG 161
Cdd:PLN02687 104 PNSGAEHmAYNYQDLVFAPyGPRWRALRKicavhlFSAKALDDF----RHVR---EEEVALLVRELARQHG 167

ent-kaurene oxidase

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 119570404  31 PGptpLPVIGNILQIGIKDISKSLTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALID 89
Cdd:PLN02655   5 PG---LPVIGNLLQLKEKKPHRTFTKWSEIYGPIYTIRTGASSVVVLNSTEVAKEAMVT 60

cytochrome P450 83B1; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  28 KLPPGPTPLPVIGNILQIGIKDISKSLTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGR 97
Cdd:PLN03234  28 RLPPGPKGLPIIGNLHQMEKFNPQHFLFRLSKLYGPIFTMKIGGRRLAVISSAELAKELLKTQDLNFTAR 97

cytochrome P450 21, also called steroid 21-hydroxylase; Cytochrome P450 21 (CYP21 or Cyp21), also called steroid 21-hydroxylase (EC 1.14.14.16) or cytochrome P-450c21 or CYP21A2 (in humans), catalyzes the 21-hydroxylation of steroids such as progesterone and 17-alpha-hydroxyprogesterone (17-alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively. It is required for the adrenal synthesis of mineralocorticoids and glucocorticoids. Deficiency of this CYP is involved in ~95% of cases of human congenital adrenal hyperplasia, a disorder of adrenal steroidogenesis. There are two CYP21 genes in the human genome, CYP21A1 (a pseudogene) and CYP21A2 (the functional gene). Deficiencies in steroid 21-hydroxylase activity lead to a type of congenital adrenal hyperplasia, which has three clinical forms: a severe form with concurrent defects in both cortisol and aldosterone biosynthesis; a form with adequate aldosterone biosynthesis; and a mild, non-classic form that can be asymptomatic or associated with signs of postpubertal androgen excess without cortisol deficiency. CYP21A2 is also the major autoantigen in autoimmune Addison disease. Cyp21 belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGfGIVFSNGK---KWKEIRRFSLMTLRNfGMg 137
Cdd:cd20674    1 YGPIYRLRLGLQDVVVLNSKRTIREALVRKWADFAGRPHSYTGKLVSQG-GQDLSLGDyslLWKAHRKLTRSALQL-GI- 77

                         90       100
                 ....*....|....*....|....
gi 119570404 138 KRSIEDRVQEEARCLVEELRKTKG 161
Cdd:cd20674   78 RNSLEPVVEQLTQELCERMRAQAG 101

cytochrome P450 family 64-like fungal cytochrome P450s; This group includes Aspergillus flavus cytochrome P450 64 (CYP64), also called O-methylsterigmatocystin (OMST) oxidoreductase or aflatoxin B synthase or aflatoxin biosynthesis protein Q, and similar fungal cytochrome P450s. CYP64 converts OMST to aflatoxin B1 and converts dihydro-O-methylsterigmatocystin (DHOMST) to aflatoxin B2 in the aflatoxin biosynthesis pathway. The CYP64-like subfamily belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAER-ANRGFGIVFSN-GKKWKEIRRF--SLMTLRN 133
Cdd:cd11065    1 YGPIISLKVGGQTIIVLNSPKAAKDLLEKRSAIYSSRPRMPMAGElMGWGMRLLLMPyGPRWRLHRRLfhQLLNPSA 77

flavonoid 3',5'-hydroxylase (F3'5'H); Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  28 KLPPGPTPLPVIGNILQIGIKDiSKSLTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGR----GIFPLA 103
Cdd:PLN00110  31 KLPPGPRGWPLLGALPLLGNMP-HVALAKMAKRYGPVMFLKMGTNSMVVASTPEAARAFLKTLDINFSNRppnaGATHLA 109

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 119570404 104 ERANrgfGIVFSN-GKKWKEIRRFSLMTLrnfgMGKRSIED 143
Cdd:PLN00110 110 YGAQ---DMVFADyGPRWKLLRKLSNLHM----LGGKALED 143

cytochrome P450 families 77 and 89, and similar cytochrome P450s; This group includes cytochrome P450 families 73 (CYP77) and 89 (CYP89), which are sister families that share a common ancestor. CYP89, present only in angiosperms, is younger than CYP77, which is already found in lycopods; thus, CYP89 may have evolved from CYP77 after duplication and divergence. Also included in this group is ent-kaurene oxidase, called CYP701A3 in Arabidopsis thaliana and CYP701B1 in Physcomitrella patens, that catalyzes the oxidation of ent-kaurene to form ent-kaurenoic acid. CYP701A3 is sensitive to inhibitor uniconazole-P while CYP701B1 is not. This CYP77/89 group belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIF-PLAERANRG-FGIVFSN-GKKWKEIRR 125
Cdd:cd11075    2 YGPIFTLRMGSRPLIVVASRELAHEALVQKGSSFASRPPAnPLRVLFSSNkHMVNSSPyGPLWRTLRR 69

Plant cytochrome P450s, clan CYP71; The number of cytochrome P450s (P450s, CYPs) in plants is considerably larger than in other taxa. In individual plant genomes, CYPs form the third largest family of plant genes; the two largest gene families code for F-box proteins and receptor-like kinases. CYPs have been classified into families and subfamilies based on homology and phylogenetic criteria; family membership is defined as 40% amino acid sequence identity or higher. However, there is a phenomenon called family creep, where a sequence (below 40% identity) is absorbed into a large family; this is seen in the plant CYP71 and CYP89 families. The plant CYPs have also been classified according to clans; land plants have 11 clans that form two groups: single-family clans (CYP51, CYP74, CYP97, CYP710, CYP711, CYP727, CYP746) and multi-family clans (CYP71, CYP72, CYP85, CYP86). The CYP71 clan has expanded dramatically and represents 50% of all plant CYPs; it includes several families including CYP71, CYP73, CYP76, CYP81, CYP82, CYP89, and CYP93, among others. It belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  62 GPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAER-ANRGFGIVFS-NGKKWKEIRRFSLMTLRNfgmGKR 139
Cdd:cd20618    1 GPLMYLRLGSVPTVVVSSPEMAKEVLKTQDAVFASRPRTAAGKIfSYNGQDIVFApYGPHWRHLRKICTLELFS---AKR 77

                         90       100
                 ....*....|....*....|.
gi 119570404 140 --SIEDRVQEEARCLVEELRK 158
Cdd:cd20618   78 leSFQGVRKEELSHLVKSLLE 98

cytochrome P450 family 4; Cytochrome P450 family 4 (CYP4) proteins catalyze the omega-hydroxylation of the terminal carbon of fatty acids, including essential signaling molecules such as eicosanoids, prostaglandins and leukotrienes, and they are important for chemical defense. There are seven vertebrate family 4 subfamilies: CYP4A, CYP4B, CYP4F, CYP4T, CYP4V, CYP4X, and CYP4Z; three (CYP4X, CYP4A, CYP4Z) are specific to mammals. CYP4 enzymes metabolize fatty acids off various length, level of saturation, and branching. Specific subfamilies show preferences for the length of fatty acids; CYP4B, CYP4A and CYP4V, and CYP4F preferentially metabolize short (C7-C10), medium (C10-C16), and long to very long (C18-C26) fatty acid chains, respectively. CYP4 belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  62 GPVFTLYFGLKPIVVLHGYEAVKE-----ALIDLGEEFsgRGIFPLAeranrGFGIVFSNGKKWKEIRR-----FSLMTL 131
Cdd:cd20628    1 GGVFRLWIGPKPYVVVTNPEDIEVilsssKLITKSFLY--DFLKPWL-----GDGLLTSTGEKWRKRRKlltpaFHFKIL 73

                         90       100       110
                 ....*....|....*....|....*....|.
gi 119570404 132 RNFgmgkrsiEDRVQEEARCLVEELRKTKGG 162
Cdd:cd20628   74 ESF-------VEVFNENSKILVEKLKKKAGG 97

cytochrome P450 family 3, subfamily A and similar cytochrome P450s; This family includes vertebrate CYP3A subfamily enzymes and CYP5a1, and similar proteins. CYP5A1, also called thromboxane-A synthase, converts prostaglandin H2 into thromboxane A2, a biologically active metabolite of arachidonic acid. CYP3A enzymes are drug-metabolizing enzymes embedded in the endoplasmic reticulum, where they can catalyze a wide variety of biochemical reactions including hydroxylation, N-demethylation, O-dealkylation, S-oxidation, deamination, or epoxidation of substrates. The CYP3A-like family belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  61 YGPVFTLYFGLKPIVVLHGYEAVKEALIdlgEEFS---GRGIFPLA-ERANRgfGIVFSNGKKWKEIRR-----FSLMTL 131
Cdd:cd11055    2 YGKVFGLYFGTIPVIVVSDPEMIKEILV---KEFSnftNRPLFILLdEPFDS--SLLFLKGERWKRLRTtlsptFSSGKL 76

                         90       100
                 ....*....|....*....|....*..
gi 119570404 132 RnfGMgKRSIEDRVQEearcLVEELRK 158
Cdd:cd11055   77 K--LM-VPIINDCCDE----LVEKLEK 96

cytochrome P450 family 82; Cytochrome P450 family 82 (CYP82 or Cyp82) genes specifically reside in dicots and are usually induced by distinct environmental stresses. Characterized members include: Glycine max CYP82A3 that is induced by infection, salinity and drought stresses, and is involved in the jasmonic acid and ethylene signaling pathway, enhancing plant resistance; Arabidopsis thaliana CYP82G1 that catalyzes the breakdown of the C(20)-precursor (E,E)-geranyllinalool to the insect-induced C(16)-homoterpene (E,E)-4,8,12-trimethyltrideca-1,3,7,11-tetraene (TMTT); and Papaver somniferum CYP82N4, also called methyltetrahydroprotoberberine 14-monooxygenase, and CYP82Y1, also called N-methylcanadine 1-hydroxylase. CYP82N4 catalyzes the conversion of N-methylated protoberberine alkaloids N-methylstylopine and N-methylcanadine into protopine and allocryptopine, respectively, in the biosynthesis of isoquinoline alkaloid sanguinarine. CYP82Y1 catalyzes the 1-hydroxylation of N-methylcanadine to 1-hydroxy-N-methylcanadine, the first committed step in the formation of noscapine. CYP82 belongs to the large cytochrome P450 (P450, CYP) superfamily of heme-containing proteins that catalyze a variety of oxidative reactions of a large number of structurally different endogenous and exogenous compounds in organisms from all major domains of life. CYPs bind their diverse ligands in a buried, hydrophobic active site, which is accessed through a substrate access channel formed by two flexible helices and their connecting loop.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 119570404  62 GPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAE---RANRGFGivFSN-GKKWKEIRRFSLMTL 131
Cdd:cd20654    1 GPIFTLRLGSHPTLVVSSWEMAKECFTTNDKAFSSRPKTAAAKlmgYNYAMFG--FAPyGPYWRELRKIATLEL 72

cytokinin trans-hydroxylase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119570404  32 GPTPLPVIGNILQIGiKDISKSLTN-------------------LSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGE 92
Cdd:PLN02290  46 GPKPRPLTGNILDVS-ALVSQSTSKdmdsihhdivgrllphyvaWSKQYGKRFIYWNGTEPRLCLTETELIKELLTKYNT 124

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 119570404  93 EfSGRGIfpLAERANRGF---GIVFSNGKKWKEIR 124
Cdd:PLN02290 125 V-TGKSW--LQQQGTKHFigrGLLMANGADWYHQR 156