Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922
Letunic et al. (2020) Nucleic Acids Res doi: 10.1093/nar/gkaa937

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Flavin_Reduct Flavin reductase like domain

SMART accession number:	SM00903
Description:	This entry represents the FMN-binding domain found in NAD(P)H-flavin oxidoreductases (flavin reductases), a class of enzymes capable of producing reduced flavin for bacterial bioluminescence and other biological processes. This domain is also found in various other oxidoreductase and monooxygenase enzymes (PUBMED:12829278), (PUBMED:15461461), (PUBMED:11017201). This domain consists of a beta-barrel with Greek key topology, and is related to the ferredoxin reductase-like FAD-binding domain. The flavin reductases have a different dimerisation mode than that found in the PNP oxidase-like family, which also carries an FMN-binding domain with a similar topology.
Interpro abstract (IPR002563):	This domain can be found in NAD(P)H-flavin oxidoreductases (flavin reductases), a class of enzymes capable of producing reduced flavin for bacterial bioluminescence and other biological processes, and various other oxidoreductase and monooxygenase enzymes [ (PUBMED:12829278) (PUBMED:15461461) (PUBMED:11017201) ]. This domain consists of a beta-barrel with Greek key topology, and is related to the ferredoxin reductase-like FAD-binding domain. The flavin reductases have a different dimerisation mode than that found in the PNP oxidase-like family, which also carries an FMN-binding domain with a similar topology.
GO function:	FMN binding (GO:0010181)
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 44735 Flavin_Reduct domains in 44733 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Taxonomic distribution of proteins containing Flavin_Reduct domain.

  This tree includes only several representative species. The complete taxonomic breakdown of all proteins with Flavin_Reduct domain is also avaliable.

  Click on the protein counts, or double click on taxonomic names to display all proteins containing Flavin_Reduct domain in the selected taxonomic class.

• Cellular role (predicted cellular role)

• Cellular role: metabolism
  

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Russell TR, Tu SC
  • Aminobacter aminovorans NADH:flavin oxidoreductase His140: a highlyconserved residue critical for NADH binding and utilization.
  • Biochemistry. 2004; 43: 12887-93
  • Display abstract

  • Homodimeric FRD(Aa) Class I is an NADH:flavin oxidoreductase fromAminobacter aminovorans. It is unusual because it contains an FMN cofactorbut utilizes a sequential-ordered kinetic mechanism. Because little isknown about NADH-specific flavin reductases in general and FRD(Aa) inparticular, this study aimed to further explore FRD(Aa) by identifying thefunctionalities of a key residue. A sequence alignment of FRD(Aa) withseveral known and hypothetical flavoproteins in the same subfamily revealswithin the flavin reductase active-site domain a conserved GDH motif,which is believed to be responsible for the enzyme and NADH interaction.Mutation of the His140 in this GDH motif to alanine reduced FRD(Aa)activity to <3%. An ultrafiltration assay and fluorescence quenchingdemonstrated that H140A FRD(Aa) binds FMN in the same 1:1 stoichiometricratio as the wild-type enzyme, but with slightly weakened affinity (K(d) =0.9 microM). Anaerobic stopped-flow studies were carried out using boththe native and mutated FRD(Aa). Similar to the native enzyme, H140AFRD(Aa) was also able to reduce the FMN cofactor by NADH although muchless efficiently. Kinetic analysis of anaerobic reduction measurementsindicated that the His140 residue of FRD(Aa) was essential to NADHbinding, as well as important for the reduction of the FMN cofactor. Forthe native enzyme, the cofactor reduction was followed by at least oneslower step in the catalytic pathway.

  • Schroder I, Johnson E, de Vries S
  • Microbial ferric iron reductases.
  • FEMS Microbiol Rev. 2003; 27: 427-47
  • Display abstract

  • Almost all organisms require iron for enzymes involved in essentialcellular reactions. Aerobic microbes living at neutral or alkaline pHencounter poor iron availability due to the insolubility of ferric iron.Assimilatory ferric reductases are essential components of the ironassimilatory pathway that generate the more soluble ferrous iron, which isthen incorporated into cellular proteins. Dissimilatory ferric reductasesare essential terminal reductases of the iron respiratory pathway iniron-reducing bacteria. While our understanding of dissimilatory ferricreductases is still limited, it is clear that these enzymes are distinctfrom the assimilatory-type ferric reductases. Research over the last 10years has revealed that most bacterial assimilatory ferric reductases areflavin reductases, which can serve several physiological roles. Thisarticle reviews the physiological function and structure of assimilatoryand dissimilatory ferric reductases present in the Bacteria, Archaea andYeast. Ferric reductases do not form a single family, but appear to bedistinct enzymes suggesting that several independent strategies for ironreduction may have evolved.

  • Christendat D et al.
  • Structural proteomics of an archaeon.
  • Nat Struct Biol. 2000; 7: 903-9
  • Display abstract

  • A set of 424 nonmembrane proteins from Methanobacteriumthermoautotrophicum were cloned, expressed and purified for structuralstudies. Of these, approximately 20% were found to be suitable candidatesfor X-ray crystallographic or NMR spectroscopic analysis without furtheroptimization of conditions, providing an estimate of the number of themost accessible structural targets in the proteome. A retrospectiveanalysis of the experimental behavior of these proteins suggested somesimple relations between sequence and solubility, implying that data basesof protein properties will be useful in optimizing high throughputstrategies. Of the first 10 structures determined, several provided cluesto biochemical functions that were not detectable from sequence analysis,and in many cases these putative functions could be readily confirmed bybiochemical methods. This demonstrates that structural proteomics isfeasible and can play a central role in functional genomics.

  • Parry RJ, Li W
  • An NADPH:FAD oxidoreductase from the valanimycin producer, Streptomycesviridifaciens. Cloning, analysis, and overexpression.
  • J Biol Chem. 1997; 272: 23303-11
  • Display abstract

  • The valanimycin producer Streptomyces viridifaciens contains atwo-component enzyme system that catalyzes the oxidation of isobutylamineto isobutylhydroxylamine. One component of this enzyme system isisobutylamine hydroxylase, and the other component is a flavin reductase.The gene (vlmR) encoding the flavin reductase required by isobutylaminehydroxylase has been cloned from S. viridifaciens by chromosome walking.The gene codes for a protein of 194 amino acids with a calculated mass of21,265 Da and a calculated pI of 10.2. Overexpression of the vlmR gene inEscherichia coli as an N-terminal His-tag derivative yielded a solubleprotein that was purified to homogeneity. Removal of the N-terminalHis-tag from the overexpressed protein by thrombin cleavage also produceda soluble protein. Both forms of the protein exhibited a high degree offlavin reductase activity, and the thrombin-cleaved form functioned incombination with isobutylamine hydroxylase to catalyze the conversion ofisobutylamine to isobutylhydroxylamine. Kinetic data indicate that theoverexpressed protein utilizes FAD and NADPH in preference to FMN,riboflavin, and NADH. The deduced amino acid sequence of the VlmR proteinexhibited similarity to several other flavin reductases that mayconstitute a new family of flavin reductases.

  • Blanc V, Lagneaux D, Didier P, Gil P, Lacroix P, Crouzet J
  • Cloning and analysis of structural genes from Streptomycespristinaespiralis encoding enzymes involved in the conversion ofpristinamycin IIB to pristinamycin IIA (PIIA): PIIA synthase andNADH:riboflavin 5'-phosphate oxidoreductase.
  • J Bacteriol. 1995; 177: 5206-14
  • Display abstract

  • In Streptomyces pristinaespiralis, two enzymes are necessary forconversion of pristinamycin IIB (PIIB) to pristinamycin IIA (PIIA), themajor component of pristinamycin (D. Thibaut, N. Ratet, D. Bisch, D.Faucher, L. Debussche, and F. Blanche, J. Bacteriol. 177:5199-5205, 1995);these enzymes are PIIA synthase, a heterodimer composed of the SnaA andSnaB proteins, which catalyzes the oxidation of PIIB to PIIA, and theNADH:riboflavin 5'-phosphate oxidoreductase (hereafter called FMNreductase), the SnaC protein, which provides the reduced form of flavinmononucleotide for the reaction. By using oligonucleotide probes designedfrom limited peptide sequence information of the purified proteins, thecorresponding genes were cloned from a genomic library of S.pristinaespiralis. SnaA and SnaB showed no significant similarity withproteins from databases, but SnaA and SnaB had similar protein domains.Disruption of the snaA gene in S. pristinaespiralis led to accumulation ofPIIB. Complementation of a S. pristinaespiralis PIIA-PIIB+ mutant with thesnaA and snaB genes, cloned in a low-copy-number plasmid, partiallyrestored production of PIIA. The deduced amino acid sequence of the snaCgene showed no similarity to the sequences of other FMN reductases but was39% identical with the product of the actVB gene of the actinorhodincluster of Streptomyces coelicolor A(3)2, likely to be involved in thedimerization step of actinorhodin biosynthesis. Furthermore, an S.coelicolor A(3)2 mutant blocked in this step was successfully complementedby the snaC gene, restoring the production of actinorhodin.

• Structure (3D structures containing this domain)

• 3D Structures of Flavin_Reduct domains in PDB

  PDB code	Main view	Title
  1eje		CRYSTAL STRUCTURE OF AN FMN-BINDING PROTEIN
  1i0r		CRYSTAL STRUCTURE OF FERRIC REDUCTASE FROM ARCHAEOGLOBUS FULGIDUS
  1i0s		ARCHAEOGLOBUS FULGIDUS FERRIC REDUCTASE COMPLEX WITH NADP+
  1rz0		Flavin reductase PheA2 in native state
  1rz1		Reduced flavin reductase PheA2 in complex with NAD
  1usc		PUTATIVE STYRENE MONOOXYGENASE SMALL COMPONENT
  1usf		PUTATIVE STYRENE MONOOXYGENASE SMALL COMPONENT WITH BOUND NADP+
  1wgb		Crystal structure of a probable flavoprotein from Thermus thermophilus HB8
  1yoa		Crystal structure of a probable flavoprotein from Thermus thermophilus HB8
  2d36		The Crystal Structure of Flavin Reductase HpaC
  2d37		The Crystal Structure of Flavin Reductase HpaC complexed with NAD+
  2d38		The Crystal Structure of Flavin Reductase HpaC complexed with NADP+
  2d5m		Flavoredoxin of Desulfovibrio vulgaris (Miyazaki F)
  2ecr		Crystal structure of the ligand-free form of the flavin reductase component (HpaC) of 4-hydroxyphenylacetate 3-monooxygenase
  2ecu		Crystal structure of flavin reductase component (HpaC) of 4-hydroxyphenylacetate 3-monooxygenase
  2ed4		Crystal structure of flavin reductase HpaC complexed with FAD and NAD
  2qck		Crystal structure of flavin reductase domain protein (YP_831077.1) from Arthrobacter sp. FB24 at 1.90 A resolution
  2r0x		Crystal structure of a putative flavin reductase (ycdh, hs_1225) from haemophilus somnus 129pt at 1.06 A resolution
  2r6v		Crystal structure of FMN-binding protein (NP_142786.1) from Pyrococcus horikoshii at 1.35 A resolution
  3bnk		X-ray crystal structure of Flavoredoxin from Methanosarcina acetivorans
  3bpk		Crystal structure of nitrilotriacetate monooxygenase component B from Bacillus cereus
  3cb0		CobR
  3e4v		Crystal structure of NADH:FMN oxidoreductase like protein in complex with FMN (YP_544701.1) from METHYLOBACILLUS FLAGELLATUS KT at 1.40 A resolution
  3hmz		CRYSTAL STRUCTURE OF A FMN-BINDING DOMAIN OF FLAVIN REDUCTASES-LIKE ENZYME (SBAL_0626) FROM SHEWANELLA BALTICA OS155 AT 1.50 A RESOLUTION
  3k86		Crystal structure of NADH:FAD oxidoreductase (TftC) - apo form
  3k87		Crystal structure of NADH:FAD oxidoreductase (TftC) - FAD complex
  3k88		Crystal structure of NADH:FAD oxidoreductase (TftC) - FAD, NADH complex
  3nfw		Crystal structure of nitrilotriacetate monooxygenase component B (A0R521 homolog) from Mycobacterium thermoresistibile
  3pft		Crystal Structure of Untagged C54A Mutant Flavin Reductase (DszD) in Complex with FMN From Mycobacterium goodii
  3rh7		Crystal structure of a hypothetical oxidoreductase (SMA0793) from sinorhizobium meliloti 1021 at 3.00 A resolution
  3zoc		Crystal structure of FMN-binding protein (NP_142786.1) from Pyrococcus horikoshii with bound p-hydroxybenzaldehyde
  3zod		Crystal structure of FMN-binding protein (NP_142786.1) from Pyrococcus horikoshii with bound benzene-1,4-diol
  3zoe		Crystal structure of FMN-binding protein (YP_005476) from Thermus thermophilus with bound p-hydroxybenzaldehyde
  3zof		Crystal structure of FMN-binding protein (YP_005476) from Thermus thermophilus with bound benzene-1,4-diol
  3zog		Crystal structure of FMN-binding protein (NP_142786.1) from Pyrococcus horikoshii with bound 1-Cyclohex-2-enone
  3zoh		Crystal structure of FMN-binding protein (YP_005476) from Thermus thermophilus with bound 1-Cyclohex-2-enone
  4f07		Structure of the Styrene Monooxygenase Flavin Reductase (SMOB) from Pseudomonas putida S12
  4hx6		The crystal structure of an oxidoreductase (SgcE6)from Streptomyces globisporus
  4ira		CobR in complex with FAD
  4l82		Structure of a putative oxidoreductase from Rickettsia felis
  4r82		4R82
  4xhy		4XHY
  4xj2		4XJ2
  4ywn		4YWN
  4z85		4Z85
  5cho		5CHO

• Links (links to other resources describing this domain)

• INTERPRO	IPR002563
  PFAM	Flavin_Reduct

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