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PR01123

Identifier
FMOXYGENASE3  [View Relations]  [View Alignment]  
Accession
PR01123
No. of Motifs
7
Creation Date
29-APR-1999
Title
Flavin-containing monooxygenase (FMO) 3 signature
Database References
PRINTS; PR00370 FMOXYGENASE
PFAM; PF00743 FMO-like
INTERPRO; IPR002255
Literature References
1. LAWTON, M.P., CASHMAN, J.R., CRESTEIL, T., DOLPHIN, C.T., ELFARRA, A.A.,
HINES, R.N., HODGSON, E., KIMURA, T., OZOLS, J., PHILLIPS, I.R.,
PHILPOT, R.M., POULSEN, L.L., RETTIE, A.E., SHEPHARD, E.A., WILLIAMS, D.E.
AND ZIEGLER, D.M.
A nomenclature for the mammalian flavin-containing monooxygenase gene
family based on amino acid sequence identities.
ARCH.BIOCHEM.BIOPHYS. 308(19) 254-257 (1994).
 
2. DOLPHIN, C.T., SHEPHARD, E.A., POVEY, S., PALMER, C.N.A., ZIEGLER, D.M.,
AYESH, R., SMITH, R.L. AND PHILLIPS, I.R.
Cloning, primary sequence and chromosome mapping of a human flavin-
containing monooxygenase (FMO1).
J.BIOL.CHEM. 266 12379-12385 (1991).
 
3. LAWTON, M.P., GASSER, R., TYNES, R.E., HODGSON, E. AND PHILPOT, R.M.
The flavin-containing monooxygenase enzymes expressed in rabbit liver and
lung are products of related but distinctly different genes.
J.BIOL.CHEM. 265 5855-5861 (1990).
 
4. LOMRI, N., GU, Q. AND CASHMAN, J.R.
Molecular cloning of the flavin-containing monooxygenase (FORM-II) cDNA
from adult human liver.
PROC.NATL.ACAD.SCI.U.S.A. 89 1685-1689 (1992). 
 
5. DOLPHIN, C.T., SHEPHARD, E.A., POVEY, S., SMITH, R.L. AND PHILLIPS, I. R.
Cloning, primary sequence and chromosomal localisation of human FMO2, a new
member of the flavin-containing monooxygenase family.
BIOCHEM.J. 287 261-267 (1992).
 
6. ATTA-ASAFO-ADJEI, E., LAWTON, M.P. AND PHILPOT, R.M.
Cloning, sequencing, distribution and expression in E.coli of flavin-
containing monooxygenase 1C1 - evidence for a third gene family in rabbits.
J.BIOL.CHEM. 268 9681-9689 (1993).
 
7. JOHNSTON, M., ANDREWS, S., BRINKMAN, R., COOPER, J., DING, H.,
DOVER, J., DU, Z., FAVELLO, A., FULTON, L., GATTUNG, S., GEISEL, C.,
KIRSTEN, J., KUCABA, T., HILLIER, L., JIER, M., JOHNSTON, L., LANGSTON, Y.,
LATREILLE, P., LOUIS, E.J., MACRI, C., MARDIS, E., MENEZES, S., MOUSER, L.,
NHAN, M., RIFKIN, L., RILES, L., ST.PETER, H., TREVASKIS, E., VAUGHAN, K.,
VIGNATI, D., WILCOX, L., WOHLDMAN, P., WATERSTON, R., WILSON R. AND
VAUDIN M.
Complete nucleotide sequence of Saccharomyces cerevisiae chromosome VIII.
SCIENCE 265 2077-2082 (1994). 
 
8. DOLPHIN, C.T., CULLINGFORD, T.E., SHEPHARD, E.A., SMITH, R.L. AND
PHILLIPS, I.R.
Differential developmental and tissue-specific regulation of expression of 
the genes encoding three members of the flavin-containing monooxygenase
family of man, FMO1, FMO3 and FM04.
EUR.J.BIOCHEMISTRY 235 683-689(1996). 
 
9. FALLS, J.G., CHERRINGTON, N.J., CLEMENTS, K.M., PHILPOT, R.M.,
LEVI, P.E., ROSE, R.L. AND HODGSON, E.
Molecular cloning, sequencing, and expression in Escherichia coli of mouse
flavin-containing monooxygenase 3 (FMO3): comparison with the human isoform.
ARCH.BIOCHEM.BIOPHYS. 347 9-18 (1997).
 
10. STEHR, M., DIEKMANN, H., SMAU, L, SETH, O., GHISLA, S., SINGH, M. AND
MACHEROUX, P.
A hydrophobic sequence motif common to N-hydroxylating enzymes.
TRENDS BIOCHEM.SCI. 23 56-57 (1998).
 
11. OZOLS, J.
Covalent structure of liver microsomal flavin-containing monooxygenase 
form 1. 
J.BIOL.CHEM. 265 10289-10299 (1990).  
 
12. TREACY, E.P., AKERMAN, B.R., CHOW, L.M.L., YOUIL, R., BIBEAU, C.,
LIN, J., BRUCE, A.G., KNIGHT, M., DANKS, D.M., CASHMAN, J.R. AND
FORREST, S.M. 
Mutations of the flavin-containing monooxygenase gene (FMO3) cause
trimethylaminuria, a defect in detoxication.
HUM.MOL.GENET. 7 839-845 (1998). 

Documentation
Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic-
metabolising enzymes [1]. Using an NADPH cofactor and FAD prosthetic group,
these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen,
sulphur, phosphorous 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 [2-6]: 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 [1]. Following the determination of the
complete nucleotide sequence of S.cerevisiae [7], a novel gene was found
to encode a protein with similarity to mammalian monooygenases.
 
The mRNA encoding FMO3 is abundant in adult liver and is also present, in
low abundance, in some foetal tissues [8]. Thus, like FMO1, FMO3 is subject
to developmental and tissue-specific regulation, with a developmental switch
in the expression of the genes taking place in the liver [8]. 
 
The deduced amino acid sequence of human FM03 includes the putative FAD-
(GxGxxG) and NADP+ pyrophosphate-binding (GxGxxA) sites characteristic of
mammalian FMOs [9], a `FATGY' motif that has also been observed in a range
of siderphore biosynthetic enzymes [10], and a C-terminal hydrophobic 
segment that is believed to anchor the monooxygenase to the microsomal 
membrane [11].
 
Mutations in human FMO3 impair N-oxygenation of xenobiotics and are 
responsible for the trimethylaminuria phenotype [12]. Three disease-causing
mutations have been identified. Nonsense and missense mutations are 
associated with a severe phenotype and are also implicated in impaired
metabolism of other nitrogen- and sulphur-containing substrates, including
biogenic amines, both clinically and when mutated proteins expressed from
cDNA are studied in vitro [12]. Human FMO3 thus plays a critical role in the
metabolism of xenobiotic substrates and endogenous amines.
 
FMOXYGENASE3 is a 7-element fingerprint that provides a signature for type
3 flavin-containing monooxygenases. The fingerprint was derived from an
initial alignment of 3 sequences: the motifs were drawn from conserved
regions spanning virtually the full alignment length, focusing on those
sections that characterise type 3 FMOs but distinguish them from the rest
of the FMO family - motif 7 spans the C-terminal hydrophobic region thought
to act as a membrane anchor. Two iterations on SPTR37_9f were required to
reach convergence, at which point a true set comprising 4 sequences was
identified. 
Summary Information
4 codes involving  7 elements
0 codes involving 6 elements
0 codes involving 5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
74444444
60000000
50000000
40000000
30000000
20000000
1234567
True Positives
FMO3_HUMAN    FMO3_MOUSE    FMO3_RABIT    O60774        
Sequence Titles
FMO3_HUMAN  DIMETHYLANILINE MONOOXYGENASE [N-OXIDE FORMING] 3 (EC 1.14.13.8) (HEPATIC FLAVIN-CONTAINING MONOOXYGENASE 3) (FMO 3) (DIMETHYLANILINE OXIDASE 3) (FMO II) - HOMO SAPIENS (HUMAN). 
FMO3_MOUSE DIMETHYLANILINE MONOOXYGENASE [N-OXIDE FORMING] 3 (EC 1.14.13.8) (HEPATIC FLAVIN-CONTAINING MONOOXYGENASE 3) (FMO 3) (DIMETHYLANILINE OXIDASE 3) - MUS MUSCULUS (MOUSE).
FMO3_RABIT DIMETHYLANILINE MONOOXYGENASE [N-OXIDE FORMING] 3 (EC 1.14.13.8) (HEPATIC FLAVIN-CONTAINING MONOOXYGENASE 3) (FMO 3) (DIMETHYLANILINE OXIDASE 3) (FMO 1D1) (FMO FORM 2) - ORYCTOLAGUS CUNICULUS (RABBIT).
O60774 DJ127D3.2 (FLAVIN-CONTAINING MONOOXYGENASE FAMILY PROTEIN) - HOMO SAPIENS (HUMAN).
Scan History
SPTR37_9f  2  8    NSINGLE    
Initial Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
QEYIIAFAKEKN FMO3_HUMAN 87 87 -
QEYITTFAREKN FMO3_RABIT 87 87 -
QEYITSFAKEKN FMO3_MOUSE 88 88 -

Motif 2 width=10
Element Seqn Id St Int Rpt
TTERDGKKES FMO3_HUMAN 127 28 -
STERNGKKET FMO3_RABIT 127 28 -
TTEKHGKKET FMO3_MOUSE 128 28 -

Motif 3 width=11
Element Seqn Id St Int Rpt
TAISDWLYVKQ FMO3_HUMAN 248 111 -
TAISDWWYVKQ FMO3_RABIT 248 111 -
TAISDWWYTRQ FMO3_MOUSE 249 111 -

Motif 4 width=15
Element Seqn Id St Int Rpt
IIKSRNNEIILFKGV FMO3_HUMAN 341 82 -
IIKSENNKVTLFKGI FMO3_RABIT 341 82 -
IIKSRNNEVTLYKGV FMO3_MOUSE 342 82 -

Motif 5 width=20
Element Seqn Id St Int Rpt
INEKMEKKRKWFGKSETIQT FMO3_HUMAN 408 52 -
IHEKMGTKLKWFGKSETIQT FMO3_RABIT 408 52 -
IDEKMGEKFKWYGNSTTIQT FMO3_MOUSE 409 52 -

Motif 6 width=14
Element Seqn Id St Int Rpt
PMQTRVVGRLQKPC FMO3_HUMAN 495 67 -
PMKTRAVGHLQKPA FMO3_RABIT 495 67 -
PMKTRVVSKVQKSC FMO3_MOUSE 496 67 -

Motif 7 width=21
Element Seqn Id St Int Rpt
FFFHWLKLFAIPILLIAVFLV FMO3_HUMAN 509 0 -
LFSPWLKLLAIAVLLIAAVLV FMO3_RABIT 509 0 -
FYSRLLRLLAVPVLLIALFLV FMO3_MOUSE 512 2 -
Final Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
QEYIIAFAKEKN FMO3_HUMAN 87 87 -
QEYITTFAREKN FMO3_RABIT 87 87 -
QEYITSFAKEKN FMO3_MOUSE 88 88 -
QEYIKTYAQKKD O60774 88 88 -

Motif 2 width=10
Element Seqn Id St Int Rpt
TTERDGKKES FMO3_HUMAN 127 28 -
STERNGKKET FMO3_RABIT 127 28 -
TTEKHGKKET FMO3_MOUSE 128 28 -
VTEKDGKQES O60774 128 28 -

Motif 3 width=11
Element Seqn Id St Int Rpt
TAISDWLYVKQ FMO3_HUMAN 248 111 -
TAISDWWYVKQ FMO3_RABIT 248 111 -
TAISDWWYTRQ FMO3_MOUSE 249 111 -
SFISDWLYVQK O60774 249 111 -

Motif 4 width=15
Element Seqn Id St Int Rpt
IIKSRNNEIILFKGV FMO3_HUMAN 341 82 -
IIKSENNKVTLFKGI FMO3_RABIT 341 82 -
IIKSRNNEVTLYKGV FMO3_MOUSE 342 82 -
IMKSRNNEVTLFKGI O60774 342 82 -

Motif 5 width=20
Element Seqn Id St Int Rpt
INEKMEKKRKWFGKSETIQT FMO3_HUMAN 408 52 -
IHEKMGTKLKWFGKSETIQT FMO3_RABIT 408 52 -
IDEKMGEKFKWYGNSTTIQT FMO3_MOUSE 409 52 -
TDEKMGKKLKCMFSSFFMFG O60774 409 52 -

Motif 6 width=14
Element Seqn Id St Int Rpt
PMQTRVVGRLQKPC FMO3_HUMAN 495 67 -
PMKTRAVGHLQKPA FMO3_RABIT 495 67 -
PMKTRVVSKVQKSC FMO3_MOUSE 496 67 -
PTRTRVVSEVQRPH O60774 503 74 -

Motif 7 width=21
Element Seqn Id St Int Rpt
FFFHWLKLFAIPILLIAVFLV FMO3_HUMAN 509 0 -
LFSPWLKLLAIAVLLIAAVLV FMO3_RABIT 509 0 -
FYSRLLRLLAVPVLLIALFLV FMO3_MOUSE 512 2 -
PFYNLLKMLSFPLLLLAVTLT O60774 517 0 -