Flavin reductase: Difference between revisions
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==Biological Function== |
==Biological Function== |
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Flavin reductases exist in a variety of [[organism|organisms]], including animals and bacteria. In [[luminous]] organisms, flavin reductase is important in the [[luciferase]] process. <ref name="JBC"> {{cite journal | author = Takahito Imagawa, Toshiharu Tsurumura, Yasasushi Sugimoto, Kenji Aki, Kazumi Ishido, Seiki Kuramitsu, Hideaki Tsuge| title = Structural Basis of Free Reduced Flavin Generation by Flavin Reductase from Thermus Thermophilus. | date= 3 Nov. 2011 | pmid = 22052907 }}</ref> |
Flavin reductases exist in a variety of [[organism|organisms]], including animals and bacteria. In [[luminous]] organisms, flavin reductase is important in the [[luciferase]] process. <ref name="JBC"> {{cite journal | author = Takahito Imagawa, Toshiharu Tsurumura, Yasasushi Sugimoto, Kenji Aki, Kazumi Ishido, Seiki Kuramitsu, Hideaki Tsuge| title = Structural Basis of Free Reduced Flavin Generation by Flavin Reductase from Thermus Thermophilus. | date= 3 Nov. 2011 | pmid = 22052907 }}</ref> |
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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]] |
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]]. <ref name="lum"> {{cite journal | author = Warren Duane and JW Hastings| title = Flavin Nomonucleotide Reductase of Luminous Bacteria. | date= 10 June 1974 | pmid = 47604 }}</ref> |
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In humans, flavin reductase often [[catalyze|catalyzes]] an [[NADPH]] dependent reduction of flavin mononucleotide which occurs in [[methemoglobin]] in [[erythrocyte|erythrocytes]] and the [[liver]]. <ref name="identical"> {{cite journal | author = Shalloe F, Elliott G, Ennis O, Mantle TJ.| title = Evidence that biliverdin-IX beta reductase and flavin reductase are identical. | date= 1 Jun. 1996 | pmid = 8687377 }}</ref> |
In humans, flavin reductase often [[catalyze|catalyzes]] an [[NADPH]] dependent reduction of flavin mononucleotide which occurs in [[methemoglobin]] in [[erythrocyte|erythrocytes]] and the [[liver]]. <ref name="identical"> {{cite journal | author = Shalloe F, Elliott G, Ennis O, Mantle TJ.| title = Evidence that biliverdin-IX beta reductase and flavin reductase are identical. | date= 1 Jun. 1996 | pmid = 8687377 }}</ref> |
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==Future of the Enzyme== |
==Future of the Enzyme== |
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Currently, it is seen that bacterial flavin reductase can be used to sensitize [[carcinoma|carcinomas]], or [[tumor|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 |
Currently, it is seen that bacterial flavin reductase can be used to sensitize [[carcinoma|carcinomas]], or [[tumor|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. <ref name="tumors"> {{cite journal | author = Green LK, Storey MA, Williams EM, Patterson AV, Smaill JB, Copp JN, Ackerley DF| title = The Flavin Reductase MsuE is a Novel Nitroreductase that can efficiently Activate two promising next Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy. | date= 8 Aug 2013 | pmid = 24202330 }}</ref> A dual flavin reductase has been shown to participate in the activatio of anticancer drugs. <ref name="future2"> {{cite journal | author = Paine MJ, Garner AP, Powell D, Sibbald J, Sales M, Pratt N, Smith T, Tew DG, Wolf CR| title = Cloning and Characterization of a novel human dual flavin reductase. | date= 14 Jan 2000 | pmid = 10625700 }}</ref> |
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Revision as of 02:19, 28 February 2014
| flavin reductase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 1.5.1.30 | ||||||||
| CAS no. | 56626-29-0 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
Flavin reductase is in a class of enzymes which catalyzes the reduction of a substrate. 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 and the reduction of methemoglobin in erythrocytes (flavin 2).
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.
Structure
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This is the structure of flavin mononucleotide, drawn in ChemBio Draw.
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This is the structure of reduced flavin mononucleotide, drawn in ChemBio Draw.
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Structure of NADPH
Flavin reductase is an 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 [1] 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(JBC). Side chains 167-169 in FRP block the isoalloxazine ring in FAD from binding the enzyme, making FRP an FMN specific flavin reductase (flavin12pm-structure).
Mechanism
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This shows the hydrogen bonding of flavin reductase with flavin mononucleotide. -
Mechanismpingpong
The mechanism of the flavin reductase process is described above and most likely follows the ping pong kinetic pattern(flavin12pm-structure). 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. 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.
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. [2] 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. [3] In humans, flavin reductase often catalyzes an NADPH dependent reduction of flavin mononucleotide which occurs in methemoglobin in erythrocytes and the liver. [4]
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. [5] A dual flavin reductase has been shown to participate in the activatio of anticancer drugs. [6]
References
- ^ Tanner, JJ, B. Lei, SC Tu, and KL Krause (22 Oct. 1996). [PubMed "Flavin Reductase P: Structure of a Dimeric Enzyme That Reduces Flavin"]. National Center for Biotechnology Information. PMID 8885832.
{{cite journal}}: Check|url=value (help); Check date values in:|date=(help); Cite has empty unknown parameter:|1=(help)CS1 maint: multiple names: authors list (link) - ^ 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". PMID 22052907.
{{cite journal}}: Check date values in:|date=(help); Cite journal requires|journal=(help)CS1 maint: multiple names: authors list (link) - ^ Warren Duane and JW Hastings (10 June 1974). "Flavin Nomonucleotide Reductase of Luminous Bacteria". PMID 47604.
{{cite journal}}: Cite journal requires|journal=(help) - ^ Shalloe F, Elliott G, Ennis O, Mantle TJ. (1 Jun. 1996). "Evidence that biliverdin-IX beta reductase and flavin reductase are identical". PMID 8687377.
{{cite journal}}: Check date values in:|date=(help); Cite journal requires|journal=(help)CS1 maint: multiple names: authors list (link) - ^ 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". PMID 24202330.
{{cite journal}}: Cite journal requires|journal=(help)CS1 maint: multiple names: authors list (link) - ^ 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". PMID 10625700.
{{cite journal}}: Cite journal requires|journal=(help)CS1 maint: multiple names: authors list (link)