Flavin reductase

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flavin reductase
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EC no. 1.5.1.30
CAS no. 56626-29-0
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Flavin reductase a class of enzymes. There are a variety of flavin reductases, (i.e. FRP, FRE, FRG, etc.) which bind free flavins and through hydrogen bonding, catalyze the reduction of these molecules to a reduced flavin. Riboflavin, or vitamin B, and flavin mononucleotide are two of the most well known flavins in the body and are used in a variety of processes which include metabolism of fat [1] and ketones [2] and the reduction of methemoglobin in erythrocytes. [3] Flavin reductases are similar and often confused for ferric reductases because of their similar catalytic mechanism and structures. [4]

Contents

In enzymology, a flavin reductase (EC 1.5.1.30) is an enzyme that catalyzes the chemical reaction

riboflavin + NADPH + H+ reduced riboflavin + NADP + H+

Thus, the two products of this enzyme are reduced riboflavin and NADP+, whereas its 3 substrates are riboflavin, NADPH, and H+.

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is reduced-riboflavin:NADP+ oxidoreductase. Other names in common use include NADPH:flavin oxidoreductase, riboflavin mononucleotide (reduced nicotinamide adenine dinucleotide, phosphate) reductase, flavin mononucleotide reductase, flavine mononucleotide reductase, FMN reductase (NADPH), NADPH-dependent FMN reductase, NADPH-flavin reductase, NADPH-FMN reductase, NADPH-specific FMN reductase, riboflavin mononucleotide reductase, riboflavine mononucleotide reductase, NADPH2 dehydrogenase (flavin), and NADPH2:riboflavin oxidoreductase.

Structures of reactants and products

Flavin reductase is a dimer made up of two subunits. Each subunit is similar. Flavin reductase P, FRP, was studied by Tanner, Lei, Tu and Krause and was discovered to have a structure made up of two subunits each containing a sandwich domain and an excursion domain. The excursion domains of each subunit reach out to connect the sandwich domain of the other subunit. This creates a large hydrophobic core in flavin reductase [5] The enzyme has two binding sites, one for NADPH and one for the flavin mononucleotide substrate. The isoalloxazine ring of flavin mononucleotide is where reduction occurs. Therefore, this is where flavin creates a variety of hydrogen bonds to connect to the amino acid side chains of flavin reductase. [6] Side chains 167–169 in FRP block the isoalloxazine ring in FAD from binding the enzyme, making FRP an FMN specific flavin reductase. [5] The placement of methyl groups in the isoalloxazine ring can also have an effect on the binding and specificity of the enzyme for substrate. [7] There is a depletion of a C-terminal extension that allows for the binding of NADPH, and studies show that if it is removed, it is depleted, catalytic activity increases. [8]

Mechanism

The mechanism of the flavin reductase process is described above and most likely follows the ping pong kinetic pattern. [5] This means that it is a bisubstrate-biproduct mechanism. First the flavin reductase enzyme binds NADPH and stabilizes the release of the hydride. Because of sterics, it is not possible for the enzyme to bind both NADPH and the flavin. [5] For this reason, NADP+ is released and then the flavin substrate is bound to the enzyme. In this step, the hydride attacks Nitrogen on the flavin, which allows for another protonation. Then, reduced flavin is released from flavin reductase as the second product. In this way, the reduction of flavin is dependent on flavin reductase binding first to NADPH, or in some cases NADH. [6]

Biological function

Flavin reductases exist in a variety of organisms, including animals and bacteria. In luminous organisms, flavin reductase is important in the luciferase process. [6] In an experiment with P. fischeri and B. harveyi cells, bioluminescence was increased as the in vivo concentration of flavin reductase was increased. This suggests a connection between either a flavin reductase-luciferase complex or reduced flavin and the luminescence process in bacteria. [9] The bacteria oxidize the reduced flavin mononucleotide to oxidized FMN and transfer it through free fusion to generate light. [10]

In humans, flavin reductase often catalyzes an NADPH dependent reduction of flavin mononucleotide which occurs in methemoglobin in erythrocytes and the liver. [11]

It has also been suggested that flavin reductases play a role in the production of hydrogen peroxide. This would be biologically helpful as H2O2 assists the body in maintaining homeostatic microbiota. A study showed that women with lactobacillus that produced hydrogen peroxide were less likely to develop bacterial vaginosis prebirth. [12] It was also seen in Trichomonas vaginalis that decreased levels of flavin reductase increased the cycling of metronidazole because flavin reductase has an antioxidative effect, which decreases oxygen levels, maintaining the metronidazole population. [13]

Future of the enzyme

Currently, it is seen that bacterial flavin reductase can be used to sensitize carcinomas, or tumors to pro drugs. At first, flavin reductases were used to target the hypoxia of tumors. However, current research is showing an interest in these reductase molecules, specifically, MSuE from Pseudomonas aeruginosa which has been shown to increase the effectiveness of the prodrugs for cancerous tumors. [14] A dual flavin reductase has been shown to participate in the activation of anticancer drugs. [15] There are also molecules that when oxidized can be carcinogenic. In this case, it is helpful to have flavin reductase to reduce these molecules, such as carcinogenic chromate. [16]

Related Research Articles

A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as forward reactions, and in some cases this has physiological significance: for example, alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde in animals, but in yeast it catalyzes the production of ethanol from acetaldehyde.

<span class="mw-page-title-main">Flavin group</span> Group of chemical compounds

Flavins refers generally to the class of organic compounds containing the tricyclic heterocycle isoalloxazine or its isomer alloxazine, and derivatives thereof. The biochemical source of flavin is the vitamin riboflavin. The flavin moiety is often attached with an adenosine diphosphate to form flavin adenine dinucleotide (FAD), and, in other circumstances, is found as flavin mononucleotide, a phosphorylated form of riboflavin. It is in one or the other of these forms that flavin is present as a prosthetic group in flavoproteins.

<span class="mw-page-title-main">Flavin adenine dinucleotide</span> Redox-active coenzyme

In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which may be in the form of FAD or flavin mononucleotide (FMN). Many flavoproteins are known: components of the succinate dehydrogenase complex, α-ketoglutarate dehydrogenase, and a component of the pyruvate dehydrogenase complex.

<span class="mw-page-title-main">Flavin mononucleotide</span> Chemical compound

Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as well as cofactor in biological blue-light photo receptors. During the catalytic cycle, a reversible interconversion of the oxidized (FMN), semiquinone (FMNH•), and reduced (FMNH2) forms occurs in the various oxidoreductases. FMN is a stronger oxidizing agent than NAD and is particularly useful because it can take part in both one- and two-electron transfers. In its role as blue-light photo receptor, (oxidized) FMN stands out from the 'conventional' photo receptors as the signaling state and not an E/Z isomerization.

<span class="mw-page-title-main">Flavoprotein</span> Protein family

Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. These proteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair. The flavoproteins are some of the most-studied families of enzymes.

<span class="mw-page-title-main">Shikimate dehydrogenase</span> Enzyme involved in amino acid biosynthesis

In enzymology, a shikimate dehydrogenase (EC 1.1.1.25) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Protochlorophyllide reductase</span>

In enzymology, protochlorophyllide reductases (POR) are enzymes that catalyze the conversion from protochlorophyllide to chlorophyllide a. They are oxidoreductases participating in the biosynthetic pathway to chlorophylls.

In enzymology, an alkanal monooxygenase (FMN-linked) (EC 1.14.14.3) is an enzyme that catalyzes the chemical reaction

In enzymology, a ferredoxin-NADP+ reductase (EC 1.18.1.2) abbreviated FNR, is an enzyme that catalyzes the chemical reaction

In enzymology, an FMN reductase (EC 1.5.1.29) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">NAD(P)H dehydrogenase (quinone)</span>

In enzymology, a NAD(P)H dehydrogenase (quinone) (EC 1.6.5.2) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">NADPH—hemoprotein reductase</span> Enzyme

In enzymology, a NADPH—hemoprotein reductase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Sulfite reductase (NADPH)</span>

Sulfite reductase (NADPH) (EC 1.8.1.2, sulfite (reduced nicotinamide adenine dinucleotide phosphate) reductase, NADPH-sulfite reductase, NADPH-dependent sulfite reductase, H2S-NADP oxidoreductase, sulfite reductase (NADPH2)) is an enzyme with systematic name hydrogen-sulfide:NADP+ oxidoreductase. This enzyme catalises the following chemical reaction

<span class="mw-page-title-main">Riboflavin kinase</span>

In enzymology, a riboflavin kinase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">NDOR1</span> Protein-coding gene in the species Homo sapiens

NADPH-dependent diflavin oxidoreductase 1 is an enzyme that in humans is encoded by the NDOR1 gene.

FMN reductase (NADPH) (EC 1.5.1.38, FRP, flavin reductase P, SsuE) is an enzyme with systematic name FMNH2:NADP+ oxidoreductase. This enzyme catalyses the following chemical reaction:

Riboflavin reductase (NAD(P)H) (EC 1.5.1.41, NAD(P)H-FMN reductase, Fre) is an enzyme with systematic name riboflavin:NAD(P)+ oxidoreductase. This enzyme catalyses the following chemical reaction

Morphinone reductase is an enzyme which catalyzes the NADH-dependent saturation of the carbon-carbon double bond of morphinone and codeinone, yielding hydromorphone and hydrocodone respectively. This saturation reaction is assisted by a FMN cofactor and the enzyme is a member of the α/β-barrel flavoprotein family. The sequence of the enzyme has been obtained from bacteria Pseudomonas putida M10 and has been successfully expressed in yeast and other bacterial species. The enzyme is reported to harbor high sequence and structural similarity to the Old Yellow Enzyme, a large group of flavin-dependent redox biocatalysts of yeast species, and an oestrogen-binding protein of Candida albicans. The enzyme has demonstrated value in biosynthesis of semi-opiate drugs in microorganisms, expanding the chemical diversity of BIA biosynthesis.

<span class="mw-page-title-main">L-ornithine N5 monooxygenase</span> Enzyme

L-ornithine N5 monooxygenase (EC 1.14.13.195 or EC 1.14.13.196) is an enzyme which catalyzes one of the following chemical reactions:

L-ornithine + NADPH + O2 N(5)-hydroxy-L-ornithine + NADP+ + H2O L-ornithine + NAD(P)H + O2 N(5)-hydroxy-L-ornithine + NAD(P)+ + H2O

In enzymology, a prostaglandin-F synthase (PGFS; EC 1.1.1.188) is an enzyme that catalyzes the chemical reaction:

References

  1. ↑ Ceccoli RD, Bianchi DA, Rial DV (6 Feb 2014). "Flavoprotein monooxegenases for oxidative biocatalysis". Front Microbiol. 5: 25. doi: 10.3389/fmicb.2014.00025 . PMC   3915288 . PMID   24567729.
  2. ↑ Kadow M, Balke K, Willetts A, Bornscheuer UT, Bäckvall JE (5 Nov 2013). "Functional Assembly of camphor converting two-component Baeyer–Villiger monooxygenases with a flavin reductase from E. coli". Appl. Microbiol. Biotechnol. 98 (9): 3975–86. doi:10.1007/s00253-013-5338-3. PMID   24190498. S2CID   15295145.
  3. ↑ Yubisui T, Takeshita M, Yoneyama Y (June 1980). "Reduction of methemoglobin through flavin at the physiological concentration by NADPH-flavin reductase of human erythrocytes". J. Biochem. 87 (6): 1715–20. doi:10.1093/oxfordjournals.jbchem.a132915. PMID   7400118.
  4. ↑ Marc Fontecave; Jacques Coves; Jean-Louis Pierre (27 April 1993). "Ferric reductases or flavin reductases". Biometals. 7 (1): 3–8. doi:10.1007/bf00205187. PMID   8118169. S2CID   10007595.
  5. 1 2 3 4 Tanner, JJ; B. Lei; SC Tu; KL Krause (22 Oct 1996). "Flavin Reductase P: Structure of a Dimeric Enzyme That Reduces Flavin". Biochemistry. 35 (42): 13531–9. doi:10.1021/bi961400v. PMID   8885832.
  6. 1 2 3 Takahito Imagawa; Toshiharu Tsurumura; Yasasushi Sugimoto; Kenji Aki; Kazumi Ishido; Seiki Kuramitsu; Hideaki Tsuge (3 Nov 2011). "Structural Basis of Free Reduced Flavin Generation by Flavin Reductase from Thermus Thermophilus". J. Biol. Chem. 286 (51): 44078–85. doi: 10.1074/jbc.M111.257824 . PMC   3243531 . PMID   22052907.
  7. ↑ Fieschi F, Niviere V, Frier C, Decout JL, Fontecave M (22 Dec 1995). "The Mechanism and Substrate specificity of the NADPH:Flavin Oxidoreductase from Escherichia Coli". J. Biol. Chem. 270 (51): 30392–400. doi: 10.1074/jbc.270.51.30392 . PMID   8530465.
  8. ↑ Seo D, Asano T, Komori H, Sakurai T (30 Jan 2014). "Role of the C-terminal extension stacked on the re-face of the isoalloxazine ring moiety of flavin". Plant Physiol. Biochem. 81: 143–8. doi:10.1016/j.plaphy.2014.01.011. hdl: 2297/36899 . PMID   24529496.
  9. ↑ Warren Duane; JW Hastings (10 June 1974). "Flavin Nomonucleotide Reductase of Luminous Bacteria". Mol. Cell. Biochem. 6 (1): 53–64. doi:10.1007/BF01731866. PMID   47604. S2CID   21243671.
  10. ↑ Tinikul R, Pisawong W, Sucharitakul J, Nijvipakul S, Ballou DP, Chaiyen P (1 Oct 2013). "The transfer of reduced flavin mononucleotide from LuxG oxidoreductase to luciferase via free diffusion". Biochemistry. 52 (39): 6834–43. doi:10.1021/bi4006545. PMID   24004065.
  11. ↑ Shalloe F, Elliott G, Ennis O, Mantle TJ (1 Jun 1996). "Evidence that biliverdin-IX beta reductase and flavin reductase are identical". Biochem. J. 316 (2): 385–7. doi:10.1042/bj3160385. PMC   1217361 . PMID   8687377.
  12. ↑ Hertzberger R; Arents Jos; Dekker H; Pridmore R; Gysler C; Kleerebezem M; Teixeira de Mattos M (31 January 2014). "H2O2 Production in species of the lactobacillus acidophilus group, a central role for a novel NADPH dependent flavin reductase". Appl. Environ. Microbiol. 80 (7): 2229–39. Bibcode:2014ApEnM..80.2229H. doi:10.1128/AEM.04272-13. PMC   3993133 . PMID   24487531.
  13. ↑ Leitsch, David; Janssen, Brian D.; Kolarich, Daniel; Johnson, Patricia J.; Duchêne, Michael (2014). "Trichomonas vaginalisflavin reductase 1 and its role in metronidazole resistance". Molecular Microbiology. 91 (1): 198–208. doi:10.1111/mmi.12455. ISSN   0950-382X. PMC   4437529 . PMID   24256032.
  14. ↑ Green LK, Storey MA, Williams EM, Patterson AV, Smaill JB, Copp JN, Ackerley DF (8 Aug 2013). "The Flavin Reductase MsuE is a Novel Nitroreductase that can efficiently Activate two promising next Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy". Cancers (Basel). 5 (3): 985–97. doi: 10.3390/cancers5030985 . PMC   3795375 . PMID   24202330.
  15. ↑ Paine MJ, Garner AP, Powell D, Sibbald J, Sales M, Pratt N, Smith T, Tew DG, Wolf CR (14 Jan 2000). "Cloning and Characterization of a novel human dual flavin reductase". J. Biol. Chem. 275 (2): 1471–8. doi: 10.1074/jbc.275.2.1471 . PMID   10625700.
  16. ↑ Puzon GJ, Petersen JN, Roberts AG, Kramer DM, Xun L (31 May 2002). "A bacterial flavin reductase system reduces chromate to a soluble chromium(III)-NAD(+) complex". Biochem. Biophys. Res. Commun. 294 (1): 76–81. doi:10.1016/S0006-291X(02)00438-2. PMID   12054743.
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