Summary: Flavin-binding monooxygenase-like
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Flavin-containing monooxygenase Edit Wikipedia article
Ribbon diagram of yeast FMO (PDB: 1VQW).
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
|Flavin-containing monooxygenase FMO|
The flavin-containing monooxygenase (FMO) protein family specializes in the oxidation of xeno-substrates in order to facilitate the excretion of these compounds from living organisms. These enzymes can oxidize a wide array of heteroatoms, particularly soft nucleophiles, such as amines, sulfides, and phosphites. This reaction requires an oxygen, an NADPH cofactor, and an FAD prosthetic group. FMOs share several structural features, such as a NADPH binding domain, FAD binding domain, and a conserved arginine residue present in the active site. Recently, FMO enzymes have received a great deal of attention from the pharmaceutical industry both as a drug target for various diseases and as a means to metabolize pro-drug compounds into active pharmaceuticals. These monooxygenases are often misclassified because they share activity profiles similar to those of cytochrome P450 (CYP450), which is the major contributor to oxidative xenobiotic metabolism. However, a key difference between the two enzymes lies in how they proceed to oxidize their respective substrates; CYP enzymes make use of an oxygenated heme prosthetic group, while the FMO family utilizes FAD to oxidize its substrates.
- 1 History
- 2 Evolution of FMO gene family
- 3 Classification and characterization
- 4 Structure
- 5 Function
- 6 Mechanism
- 7 Cellular expression in humans
- 8 Clinical significance
- 9 References
- 10 External links
Prior to the 1960s, the oxidation of xenotoxic materials was thought to be completely accomplished by CYP450. However, in the early 1970s, Dr. Daniel Ziegler from the University of Texas at Austin discovered a hepatic flavoprotein isolated from pig liver that was found to oxidize a vast array of various amines to their corresponding nitro state. This flavoprotein named "Ziegler's enzyme" exhibited unusual chemical and spectrometric properties. Upon further spectroscopic characterization and investigation of the substrate pool of this enzyme, Dr. Ziegler discovered that this enzyme solely bound FAD molecule that could form a C4a-hydroxyperoxyflavin intermediate, and that this enzyme could oxidize a wide variety of substrates with no common structural features, including phosphines, sulfides, selenium compounds, amongst others. Once this was noticed, Dr. Ziegler's enzyme was reclassified as a broadband flavin monooxygenase.
In 1984, the first evidence for multiple forms of FMOs was elucidated by two different laboratories when two distinct FMOs were isolated from rabbit lungs. Since then, over 150 different FMO enzymes have been successfully isolated from a wide variety of organisms. Up until 2002, only 5 FMO enzymes were successfully isolated from mammals. However, a group of researchers found a sixth FMO gene located on human chromosome 1. In addition to the sixth FMO discovered as of 2002, the laboratories of Dr. Ian Philips and Elizabeth Sheppard discovered a second gene cluster in humans that consists of 5 additional pseudogenes for FMO on human chromosome 1.
Evolution of FMO gene family
The FMO family of genes is conserved across all phyla that have been studied so far, therefore some form of the FMO gene family can be found in all studied eukaryotes. FMO genes are characterized by specific structural and functional constraints, which led to the evolution of different types of FMO's in order to perform a variety of functions. Divergence between the functional types of FMO's (FMO 1â€“5) occurred before the amphibians and mammals diverged into separate classes. FMO5 found in vertebrates appears to be evolutionarily older than other types of FMO's, making FMO5 the first functionally distinct member of the FMO family. Phylogenetic studies suggest that FMO1 and FMO3 are the most recent FMO's to evolve into enzymes with distinct functions. Although FMO5 was the first distinct FMO, it is not clear what function it serves since it does not oxygenate the typical FMO substrates involved in first-pass metabolism.
Analyses of FMO genes across several species have shown extensive silent DNA mutations, which indicate that the current FMO gene family exists because of selective pressure at the protein level rather than the nucleotide level. FMO's found in invertebrates are found to have originated polyphyletically; meaning that a phenotypically similar gene evolved in invertebrates which was not inherited from a common ancestor.
Classification and characterization
FMOs are one subfamily of class B external flavoprotein monooxygenases (EC 1.14.13), which belong to the family of monooxygenase oxidoreductases, along with the other subfamilies Baeyer-Villiger monooxygenases and microbial N-hydroxylating monooxygenases. FMO's are found in fungi, yeast, plants, mammals, and bacteria.
Developmental and tissue specific expression has been studied in several mammalian species, including humans, mice, rats, and rabbits. However, because FMO expression is unique to each animal species, it is difficult to make conclusions about human FMO regulation and activity based on other mammalian studies. It is likely that species-specific expression of FMO's contributes to differences in susceptibility to toxins and xenobiotics as well as the efficiency with excreting among different mammals.
Six functional forms of human FMO genes have been reported. However, FMO6 is considered to be a pseudogene. FMOs 1â€“5 share between 50â€“58% amino acid identity across the different species. Recently, five more human FMO genes were discovered, although they fall in the category of pseudogenes.
Unlike mammals, yeast (Saccharomyces cerevisiae) do not have several isoforms of FMO, but instead only have one called yFMO. This enzyme does not accept xenobiotic compounds. Instead, yFMO helps to fold proteins that contain disulfide bonds by catalyzing O2 and NADPH-dependent oxidations of biological thiols, just like mammalian FMO's. An example is the oxidation of glutathione to glutathione disulfide, both of which form a redox buffering system in the cell between the endoplasmic reticulum and the cytoplasm. yFMO is localized in the cytoplasm in order to maintain the optimum redox buffer ratio necessary for proteins containing disulfide bonds to fold properly. This non-xenobiotic role of yFMO may represent the original role of the FMO's before the rise of the modern FMO family of enzymes found in mammals.
Plant FMO's play a role in defending against pathogens and catalyze specific steps in the biosynthesis of auxin, a plant hormone. Plant FMO's also play a role in the metabolism of glucosinolates. These non-xenobiotic roles of plant FMO's suggest that other FMO functions could be identified in non-plant organisms.
Crystal structures have been determined for yeast (Schizosaccharomyces pombe) FMO (PDB: 1VQW) and bacterial (Methylophaga aminisulfidivorans) FMO (PDB: 2XVH). The crystal structures are similar to each other and they share 27% sequence identity. These enzymes share 22% and 31% sequence identity with human FMOs, respectively.
FMOs have a tightly bound FAD prosthetic group and a binding NADPH cofactor. Both dinucleotide binding motifs form Rossmann folds. The yeast FMO and bacterial FMO are dimers, with each monomer consisting of two structural domains: the smaller NADPH binding domain and the larger FAD-binding domain. The two domains are connected by a double linker. A channel between the two domains leads to the active site where NADPH binds both domains and occupies a cleft that blocks access to the flavin group of FAD, which is bound to the large domain along the channel together with a water molecule. The nicotinamide group of NADPH interacts with the flavin group of FAD, and the NADPH binding site overlaps with the substrate binding site on the flavin group.
- FAD-binding motif (GXGXXG)
- FMO identifying motif (FXGXXXHXXXF/Y)
- NADPH-binding motif (GXSXXA)
- F/LATGY motif
- arginine residue in the active site
The FMO identifying motif interacts with the flavin of FAD. The F/LATGY motif is a sequence motif common in N-hydroxylating enzymes. The arginine residue interacts with the phosphate group of NADPH.
The general function of these enzymes is to metabolise xenobiotics. Hence, they are considered to be xenobiotic detoxication catalysts. These proteins catalyze the oxygenation of multiple heteroatom-containing compounds that are present in our diet, such as amine-, sulfide-, phosphorus-, and other nucleophilic heteroatom-containing compounds. FMOs have been implicated in the metabolism of a number of pharmaceuticals, pesticides and toxicants, by converting the lipophilic xenobiotics into polar, oxygenated, and readily excreted metabolites.
FMO substrates are structurally diverse compounds. However, they all share similar characteristics:
- Soft nucleophiles (basic amines, sulfides, Se- or P-containing compounds)
- Neutral or single-positively charged
The majority of drugs function as alternate substrate competitive inhibitors to FMOs (i.e. good nucleophiles that compete with the drug for FMO oxygenation), since they are not likely to serve as FMO substrates. Only a few true FMO competitive inhibitors have been reported. Those include indole-3-carbinol and N,N-dimethylamino stilbene carboxylates. A well-known FMO inhibitor is methimazole (MMI).
The FMO catalytic cycle proceeds as follows:
- The cofactor NADPH binds to the oxidized state of the FAD prosthetic group, reducing it to FADH2.
- Molecular oxygen binds to the formed NADP+-FADH2-enzyme complex and is reduced, resulting in 4a-hydroperoxyflavin (4a-HPF or FADH-OOH). This species is stabilized by NADP+ in the catalytic site of the enzyme. These first two steps in the cycle are fast.
- In the presence of a substrate (S), a nucleophilic attack occurs on the distal O-atom of the prosthetic group. The substrate is oxygenated to SO, forming the 4a-hydroxyflavin (FADH-OH). Only when the flavin is in the hydroperoxy form is when the xenobiotic substrate will react.
- The flavin product then breaks down with release of water to reform FAD.
- Due to the low dissociation constant of the NADP+-enzyme complex, NADP+ is released by the end of the cycle and the enzyme returns to its original state.The rate-limiting step involves either the breakdown of FADH-OH to water or the release of NADP+.
- Quantum mechanics simulations showed the N-hydroxylation catalyzed by flavin-containing monooxygenases initiated by homolysis of the O-O bond in the C4a-hydroperoxyflavin intermediate resulting in the formation of an internal hydrogen bonded hydroxyl radical.
Cellular expression in humans
Expression of each type of FMO relies on several factors including, cofactor supply, physiological & environmental factors, as well as diet. Because of these factors, each type of FMO is expressed differently depending on the species and tissue. In humans, expression of FMO's is mainly concentrated to the human liver, lungs, and kidneys, where most of the metabolism of xenobiotics occur. However, FMO's can also be found in the human brain and small intestine. While FMO1-5 can be found in the brain, liver, kidneys, lungs, and small intestine, the distribution of each type of FMO differs depending on the tissue and the developmental stage of the person.
Expression in adult tissues
In an adult, FMO1 is predominately expressed in the kidneys and to a lesser extent in the lungs and small intestine. FMO2 is the most abundant of the FMO's and is mostly expressed in the lungs and kidneys, with lower expression in the liver and small intestine. FMO3 is highly concentrated in the liver, but is also expressed in the lungs. FMO4 is expressed mostly in the liver and kidneys. FMO5 is highly expressed in the liver, but also has substantial expression in the lungs and small intestine. Though FMO2 is the most expressed FMO in the brain, it only constitutes about 1% of that found in the lungs, making FMO expression in the brain fairly low.
Expression in fetal Tissues
The distribution of FMO's in various types of tissues changes as a person continues to develop, making the fetal distribution of FMO's quite different than adult distribution of FMO's. While the adult liver is dominated by the expression of FMO3 and FMO5, the fetal liver is dominated by the expression of FMO1 and FMO5. Another difference is in the brain, where adults mostly express FMO2 and fetuses mostly express FMO1.
Further information: Drug development
Drug metabolism is one of the most important factors to consider when developing new drugs for therapeutic applications. The degradation rate of these new drugs in an organism's system determines the duration and intensity of their pharmacological action. During the past few years, FMOs have gained a lot of attention in drug development since these enzymes are not readily induced or inhibited by the chemicals or drugs surrounding their environment. CYPs are the primary enzymes involved in drug metabolism. However, recent efforts have been directed towards the development of drug candidates that incorporate functional groups that can be metabolized by FMOs. By doing this, the number of potential adverse drug-drug interactions is minimized and the reliance on CYP450 metabolism is decreased. Several approaches have been made to screen potential drug interactions. One of them includes human FMO3 (hFMO3), which is described as the most vital FMO regarding drug interactions. In order to successfully screen hFMO3 in a high throughput fashion hFMO3 was successfully fixed to graphene oxide chips in order to measure the change in electrical potential generated as a result of the drug being oxidized when it interacts with the enzyme.
There is evidence that FMOs are associated to the regulation of blood pressure. FMO3 is involved in the formation of TMA N-oxides (TMAO). Some studies indicate that hypertension can develop when there are no organic osmolytes (i.e. TMAO) that can counteract an increase in osmotic pressure and peripheral resistance. Individuals with deficient FMO3 activity have a higher prevalence of hypertension and other cardiovascular diseases, since there is a decrease in formation of TMA N-oxides to counterbalance the effects of a higher osmotic pressure and peripheral resistance.
Fish odor syndrome
Further information: Trimethylaminuria disorder
The trimethylaminuria disorder, also known as fish odor syndrome, causes abnormal FMO3-mediated metabolism or a deficiency of this enzyme in an individual. A person with this disorder has a low capacity to oxidize the trimethylamine (TMA) that comes from their diet to its odourless metabolite TMAO. When this happens, large amounts of TMA are excreted through the individual's urine, sweat, and breath, with a strong fish-like odor. As of today, there is no known cure or treatment for this disorder. However, doctors recommend patients to avoid foods containing choline, carnitine, nitrogen, sulfur and lecithin.
FMOs have also been associated with other diseases, such as cancer and diabetes. Yet, additional studies are imperative to elucidate what is the relationship between FMO function and these diseases, as well as to define these enzymesâ€™ clinical relevance.
- Eswaramoorthy S, Bonanno JB, Burley SK, Swaminathan S (June 2006). "Mechanism of action of a flavin-containing monooxygenase". Proceedings of the National Academy of Sciences of the United States of America. 103 (26): 9832â€“9837. doi:10.1073/pnas.0602398103. PMC 1502539. PMID 16777962.
- Cashman JR (March 1995). "Structural and catalytic properties of the mammalian flavin-containing monooxygenase". Chemical Research in Toxicology. 8 (2): 166â€“81. doi:10.1021/tx00044a001. PMID 7766799.
- Poulsen LL, Ziegler DM (April 1995). "Multisubstrate flavin-containing monooxygenases: applications of mechanism to specificity". Chemico-Biological Interactions. 96 (1): 57â€“73. doi:10.1016/0009-2797(94)03583-T. PMID 7720105.
- Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacology & Therapeutics. 106 (3): 357â€“387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602. PMID 15922018.
- Hernandez D, Addou S, Lee D, Orengo C, Shephard EA, Phillips IR (September 2003). "Trimethylaminuria and a human FMO3 mutation database". Human Mutation. 22 (3): 209â€“13. doi:10.1002/humu.10252. PMID 12938085.
- Ziegler, D (2002). "An overview of the mechanism, substrate specificities, and structure of FMOs". Drug Metabolism Reviews. 34 (3): 503â€“511. doi:10.1081/DMR-120005650. PMID 12214662.
- van Berkel, W.J.H.; Kamerbeek, N.M.; Fraaije, M.W. (August 2006). "Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts". Journal of Biotechnology. 124 (4): 670â€“689. doi:10.1016/j.jbiotec.2006.03.044. PMID 16712999.
- Hines, RN; Hopp, KA; Franco, J; Saeian, K; Begun, FP (August 2002). "Alternative processing of the human FMO6 gene renders transcripts incapable of encoding a functional flavin-containing monooxygenase". Molecular Pharmacology. 62 (2): 320â€“5. doi:10.1124/mol.62.2.320. PMID 12130684.
- Hernandez, D; Janmohamed, A; Chandan, P; Phillips, IR; Shephard, EA (February 2004). "Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters". Pharmacogenetics. 14 (2): 117â€“30. doi:10.1097/00008571-200402000-00006. PMID 15077013.
- Hao da C, Chen SL, Mu J, Xiao PG (November 2009). "Molecular phylogeny, long-term evolution, and functional divergence of flavin-containing monooxygenases". Genetica. 137 (2): 173â€“187. doi:10.1007/s10709-009-9382-y. PMID 19579011.
- van Berkel WJ, Kamerbeek NM, Fraaije MW (August 2006). "Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts". Journal of Biotechnology. 124 (4): 670â€“89. doi:10.1016/j.jbiotec.2006.03.044. PMID 16712999.
- Chen Y, Patel NA, Crombie A, Scrivens JH, Murrell JC (October 2011). "Bacterial flavin-containing monooxygenase is trimethylamine monooxygenase". Proceedings of the National Academy of Sciences of the United States of America. 108 (43): 17791â€“17796. doi:10.1073/pnas.1112928108. PMC 3203794. PMID 22006322.
- Hines RN, Cashman JR, Philpot RM, Williams DE, Ziegler DM (1994). "The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression". Toxicol. Appl. Pharmacol. 125 (1): 1â€“6. doi:10.1006/taap.1994.1042. PMID 8128486.
- Cashman JR, Zhang J (2006). "Human flavin-containing monooxygenases". Annual Review of Pharmacology and Toxicology. 46: 65â€“100. doi:10.1146/annurev.pharmtox.46.120604.141043. PMID 16402899.
- Hines RN, Hopp KA, Franco J, Saeian K, Begun FP (2002). "Alternative processing of the human FMO6 gene renders transcripts incapable of encoding a functional flavin-containing monooxygenase". Mol. Pharmacol. 62 (2): 320â€“5. doi:10.1124/mol.62.2.320. PMID 12130684.
- Lawton MP, Cashman JR, Cresteil T, Dolphin CT, Elfarra AA, Hines RN, Hodgson E, Kimura T, Ozols J, Phillips IR (January 1994). "A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities". Archives of Biochemistry and Biophysics. 308 (1): 254â€“257. doi:10.1006/abbi.1994.1035. PMID 8311461.
- Hernandez D, Janmohamed A, Chandan P, Phillips IR, Shephard EA (February 2004). "Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters". Pharmacogenetics. 14 (2): 117â€“130. doi:10.1097/00008571-200402000-00006. PMID 15077013.
- Suh JK, Poulsen LL, Ziegler DM, Robertus JD (March 1999). "Yeast flavin-containing monooxygenase generates oxidizing equivalents that control protein folding in the endoplasmic reticulum". Proceedings of the National Academy of Sciences of the United States of America. 96 (6): 2687â€“91. doi:10.1073/pnas.96.6.2687. PMC 15830. PMID 10077572.
- Suh JK, Poulsen LL, Ziegler DM, Robertus JD (1996). "Molecular cloning and kinetic characterization of a flavin-containing monooxygenase from Saccharomyces cerevisiae". Arch. Biochem. Biophys. 336 (2): 268â€“74. doi:10.1006/abbi.1996.0557. PMID 8954574.
- Schlaich NL (September 2007). "Flavin-containing monooxygenases in plants: looking beyond detox". Trends in Plant Science. 12 (9): 412â€“418. doi:10.1016/j.tplants.2007.08.009. PMID 17765596.
- Cho HJ, Cho HY, Kim KJ, Kim MH, Kim SW, Kang BS (July 2011). "Structural and functional analysis of bacterial flavin-containing monooxygenase reveals its ping-pong-type reaction mechanism". Journal of Structural Biology. 175 (1): 39â€“48. doi:10.1016/j.jsb.2011.04.007. PMID 21527346.
- Alfieri A, Malito E, Orru R, Fraaije MW, Mattevi A (May 2008). "Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase". Proceedings of the National Academy of Sciences of the United States of America. 105 (18): 6572â€“6577. doi:10.1073/pnas.0800859105. PMC 2373336. PMID 18443301.
- Cashman, JR; Xiong, Y; Lin, J; Verhagen, H; et al. (September 1999). "In vitro and in vivo inhibition of human flavin-containing monooxygenase form 3 in the presence of dietary indoles". Biochem. Pharmacol. 58 (6): 1047â€“1055. doi:10.1016/S0006-2952(99)00166-5. PMID 10509757.
- Clement, B; Weide, M; Ziegler, DM (1996). "Inhibition of Purified and Membrane-Bound Flavin-Containing Monooxygenase 1 by (N,N-Dimethylamino)stilbene Carboxylates". Chem. Res. Toxicol. 9 (3): 599â€“604. doi:10.1021/tx950145x. PMID 8728504.
- Ziegler, DM (1980). "Microsomal flavin-containing monooxygenase: oxygenation of nucleophilic nitrogen and sulfur compounds". Enzymatic Basis of Detoxication. 1. New York: Academic Press. pp. 201â€“227.
- Ziegler, DM (1990). "Flavin-containing monooxygenases: enzymes adapted for multisubstrate specificity". Trends Pharmacol. Sci. 11 (8): 321â€“324. doi:10.1016/0165-6147(90)90235-Z.
- Ziegler DM (August 2002). "An overview of the mechanism, substrate specificities, and structure of FMOs". Drug Metabolism Reviews. 34 (3): 503â€“511. doi:10.1081/DMR-120005650. PMID 12214662.
- Testa B, KrÃ¤mer SD (March 2007). "The biochemistry of drug metabolismâ€”an introduction: Part 2. Redox reactions and their enzymes". Chemistry & Biodiversity. 4 (3): 257â€“405. doi:10.1002/cbdv.200790032. PMID 17372942.
- Badieyan S, Bach RD, Sobrado P (February 2015). "Mechanism of N-hydroxylation catalyzed by flavin-dependent monooxygenases". Journal of Organic Chemistry. 80 (4): 2139â€“2147. doi:10.1021/jo502651v. PMID 25633869.
- Ziegler, DM; Poulsen, LL (1998). "Catalytic Mechanism of FMO-Catalyzed N- and S- Oxidations". Drug Metabolism. Towards the Next Millennium. Amsterdam: IOS Press. pp. 30â€“38.
- CastrignanÃ² S, Gilardi G, Sadeghi SJ (February 2015). "Human Flavin-Containing Monooxygenase 3 on Graphene Oxide for Drug Metabolism Screening". Analytical Chemistry. 87 (5): 2974â€“80. doi:10.1021/ac504535y. PMID 25630629.
- Lifton RP (May 1996). "Molecular genetics of human blood pressure variation". Science. 272 (5262): 676â€“680. doi:10.1126/science.272.5262.676. PMID 8614826.
- Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, Bruce AG, Knight M, Danks DM, Cashman JR, Forrest SM (May 1998). "Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication". Human Molecular Genetics. 7 (5): 839â€“845. doi:10.1093/hmg/7.5.839. PMID 9536088.
- "Abstracts of papers presented at the 38th European Organization for Caries Research (ORCA) Congress. Corfu, Greece, July 10â€“13, 1991". Caries Research. 25 (3): 655â€“657. 1993. doi:10.1159/000261370. PMID 1678986.
- Hamman MA, Haehner-Daniels BD, Wrighton SA, Rettie AE, Hall SD (July 2000). "Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes". Biochemical Pharmacology. 60 (1): 7â€“17. doi:10.1016/S0006-2952(00)00301-4. PMID 10807940.
- Wang T, Shankar K, Ronis MJ, Mehendale HM (August 2000). "Potentiation of thioacetamide liver injury in diabetic rats is due to induced CYP2E1". The Journal of Pharmacology and Experimental Therapeutics. 294 (2): 473â€“479. PMID 10900221.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Flavin-binding monooxygenase-like Provide feedback
This family includes FMO proteins, cyclohexanone mono-oxygenase and a number of different mono-oxygenases.
Internal database links
|SCOOP:||2-Hacid_dh_C AlaDh_PNT_C Amino_oxidase DAO FAD_binding_2 FAD_binding_3 FAD_oxidored GIDA HI0933_like IlvN K_oxygenase Lycopene_cycl NAD_binding_8 NAD_binding_9 Pyr_redox Pyr_redox_2 Pyr_redox_3 Shikimate_DH Thi4|
|Similarity to PfamA using HHSearch:||DAO Pyr_redox_2 K_oxygenase NAD_binding_8 NAD_binding_9 Pyr_redox_3|
This tab holds annotation information from the InterPro database.
InterPro entry IPR020946
Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic-metabolising enzymes [PUBMED:8311461]. Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorus and selenium atoms in a range of structurally diverse compounds. FMOs have been implicated in the metabolism of a number of pharmaceuticals, pesticides and toxicants. In man, lack of hepatic FMO-catalysed trimethylamine metabolism results in trimethylaminuria (fish odour syndrome). Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 [PUBMED:1712018, PUBMED:2318837, PUBMED:1542660, PUBMED:1417778, PUBMED:8486656]. This is a recent nomenclature based on comparison of amino acid sequences, and has been introduced in an attempt to eliminate confusion inherent in multiple, laboratory-specific designations and tissue-based classifications [PUBMED:8311461]. Following the determination of the complete nucleotide sequence of Saccharomyces cerevisiae (Baker's yeast) [PUBMED:8091229], a novel gene was found to encode a protein with similarity to mammalian monooygenases. In Aspergillus, flavin-containing monooxygenases ustF1 and ustF2 are components in the biosynthesis of the antimitotic tetrapeptide ustiloxin B, a secondary metabolite. The monooxygenases modify the side chain of the intermediate S-deoxyustiloxin H [PUBMED:27166860].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||NADP binding (GO:0050661)|
|flavin adenine dinucleotide binding (GO:0050660)|
|N,N-dimethylaniline monooxygenase activity (GO:0004499)|
|Biological process||oxidation-reduction process (GO:0055114)|
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Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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A class of redox enzymes are two domain proteins. One domain, termed the catalytic domain, confers substrate specificity and the precise reaction of the enzyme. The other domain, which is common to this class of redox enzymes, is a Rossmann-fold domain. The Rossmann domain binds nicotinamide adenine dinucleotide (NAD+) and it is this cofactor that reversibly accepts a hydride ion, which is lost or gained by the substrate in the redox reaction. Rossmann domains have an alpha/beta fold, which has a central beta sheet, with approximately five alpha helices found surrounding the beta sheet.The strands forming the beta sheet are found in the following characteristic order 654123. The inter sheet crossover of the stands in the sheet form the NAD+ binding site . In some more distantly relate Rossmann domains the NAD+ cofactor is replaced by the functionally similar cofactor FAD.
The clan contains the following 204 members:2-Hacid_dh_C 3Beta_HSD 3HCDH_N 3HCDH_RFF adh_short adh_short_C2 ADH_zinc_N ADH_zinc_N_2 AdoHcyase_NAD AdoMet_MTase AlaDh_PNT_C Amino_oxidase ApbA AviRa B12-binding Bac_GDH Bin3 Bmt2 CbiJ CheR CMAS CmcI CoA_binding CoA_binding_2 CoA_binding_3 Cons_hypoth95 DAO DapB_N DFP DNA_methylase DOT1 DRE2_N DREV DUF1188 DUF1442 DUF1611_N DUF166 DUF1776 DUF2431 DUF268 DUF2855 DUF3410 DUF364 DUF43 DUF5129 DUF5130 DUF938 DXP_reductoisom DXPR_C Eco57I ELFV_dehydrog Eno-Rase_FAD_bd Eno-Rase_NADH_b Enoyl_reductase Epimerase F420_oxidored FAD_binding_2 FAD_binding_3 FAD_oxidored Fibrillarin FMO-like FmrO FtsJ G6PD_N GCD14 GDI GDP_Man_Dehyd GFO_IDH_MocA GIDA GidB GLF Glu_dehyd_C Glyco_hydro_4 Glyco_tran_WecB GMC_oxred_N Gp_dh_N GRAS GRDA HI0933_like HIM1 IlvN ISPD_C K_oxygenase KR LCM Ldh_1_N LpxI_N Lycopene_cycl Malic_M Mannitol_dh MCRA Met_10 Methyltr_RsmB-F Methyltr_RsmF_N Methyltrans_Mon Methyltrans_SAM Methyltransf_10 Methyltransf_11 Methyltransf_12 Methyltransf_14 Methyltransf_15 Methyltransf_16 Methyltransf_17 Methyltransf_18 Methyltransf_19 Methyltransf_2 Methyltransf_20 Methyltransf_21 Methyltransf_22 Methyltransf_23 Methyltransf_24 Methyltransf_25 Methyltransf_28 Methyltransf_29 Methyltransf_3 Methyltransf_30 Methyltransf_31 Methyltransf_32 Methyltransf_33 Methyltransf_34 Methyltransf_4 Methyltransf_5 Methyltransf_7 Methyltransf_8 Methyltransf_9 Methyltransf_PK MethyltransfD12 MetW Mg-por_mtran_C MOLO1 Mqo MT-A70 MTS Mur_ligase N2227 N6-adenineMlase N6_Mtase N6_N4_Mtase NAD_binding_10 NAD_binding_2 NAD_binding_3 NAD_binding_4 NAD_binding_5 NAD_binding_7 NAD_binding_8 NAD_binding_9 NAD_Gly3P_dh_N NAS NmrA NNMT_PNMT_TEMT NodS NSP11 NSP16 OCD_Mu_crystall Orbi_VP4 PALP PARP_regulatory PCMT PDH PglD_N Polysacc_syn_2C Polysacc_synt_2 Pox_MCEL Pox_mRNA-cap Prenylcys_lyase PrmA PRMT5 Pyr_redox Pyr_redox_2 Pyr_redox_3 Reovirus_L2 RmlD_sub_bind Rossmann-like rRNA_methylase RrnaAD Rsm22 RsmJ Sacchrp_dh_NADP SAM_MT SE Semialdhyde_dh Shikimate_DH Spermine_synth TehB THF_DHG_CYH_C Thi4 ThiF TPM_phosphatase TPMT TrkA_N TRM TRM13 TrmK tRNA_U5-meth_tr Trp_halogenase TylF Ubie_methyltran UDPG_MGDP_dh_N UPF0020 UPF0146 Urocanase V_cholerae_RfbT XdhC_C YjeF_N
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_437 (release 2.1)|
|Number in seed:||5|
|Number in full:||18650|
|Average length of the domain:||258.80 aa|
|Average identity of full alignment:||17 %|
|Average coverage of the sequence by the domain:||57.68 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FMO-like domain has been found. There are 148 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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