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 Flavins (from Latin ''flavus'', "yellow") are organic compounds, like their base, pteridine. They are formed by the tricyclic heterocycle isoalloxazine. The biochemical source is the vitamin riboflavin. The flavin moiety is often attached wi ...

in the body and are used in a variety of processes which include metabolism of fat and ketones and the reduction of

methemoglobin Methemoglobin (British: methaemoglobin) (pronounced "met-hemoglobin") is a hemoglobin ''in the form of metalloprotein'', in which the iron in the heme group is in the Fe3+ (ferric) state, not the Fe2+ (ferrous) of normal hemoglobin. Sometimes, it i ...

in erythrocytes. Flavin reductases are similar and often confused for ferric reductases because of their similar catalytic mechanism and structures. In enzymology, a flavin reductase () is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

that

catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycl ...

the

chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...

riboflavin + NADPH + H⁺

\rightleftharpoons

reduced riboflavin + NADP + H⁺ Thus, the two

products Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...

of this enzyme are reduced riboflavin and NADP⁺, whereas its 3 substrates are

riboflavin Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in e ...

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADP ...

, and H⁺. This enzyme belongs to the family of

oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ...

s, specifically those acting on the CH-NH group of donors with NAD⁺ or NADP⁺ as acceptor. The

systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...

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

File:Flavin mononucleotide.png, This is the structure of flavin mononucleotide. File:Flavin mononucleotide reduced.svg, This is the structure of reduced flavin mononucleotide. File:NADP+ structure.svg, This is the structure of NADP+ Flavin reductase is a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius 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 In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...

core in flavin reductase The

has two

binding sites In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

, one for

and one for the

flavin mononucleotide 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, a ...

substrate. The isoalloxazine ring of flavin mononucleotide is where reduction occurs. Therefore, this is where flavin creates a variety of

hydrogen bonds In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

to connect to the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

side chains of flavin reductase. Side chains 167–169 in FRP block the isoalloxazine ring in

FAD A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period. Fads are objects or behaviors that achieve short- ...

from binding the enzyme, making FRP an FMN specific flavin reductase. The placement of methyl groups in the isoalloxazine ring can also have an effect on the binding and specificity of the enzyme for substrate. 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.

Mechanism

File:Enzyme with FMN.png, This shows the hydrogen bonding of flavin reductase with flavin mononucleotide. File:Mechanismpingpong.png, The ping pong mechanism is shown with NADPH binding first and leaving as NADP+ before FMN is bound by Flavin Reductase. The

mechanism Mechanism may refer to: *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission *Mechanism (biology), explaining how a feature is created *Mechanism (philosophy), a theory that a ...

of the flavin reductase process is described above and most likely follows the ping pong kinetic pattern. This means that it is a bisubstrate-biproduct mechanism. First the flavin reductase enzyme binds

and stabilizes the release of the

hydride In chemistry, a hydride is formally the anion of hydrogen( H−). The term is applied loosely. At one extreme, all compounds containing covalently bound H atoms are called hydrides: water (H2O) is a hydride of oxygen, ammonia is a hydride of ...

. Because of

steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

s, it is not possible for the enzyme to bind both NADPH and the flavin. For this reason,

NADP+ Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...

is released and then the flavin substrate is bound to the enzyme. In this step, the hydride attacks

Nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...

on the flavin, which allows for another

protonation In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid ...

. 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

, or in some cases

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...

Biological function

Flavin reductases exist in a variety of

organism In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), taxonomy into groups such as Multicellular o ...

s, including animals and bacteria. In

luminous Luminous may refer to: * Luminous flame, a flame emitting visible light Music * Luminous (group), a South Korean boy band * ''Luminous'' (EP), an EP by Cesium 137 * ''Luminous'' (John Hicks and Elise Wood album), 1985–88 * Luminous (The Hor ...

organisms, flavin reductase is important in the

luciferase Luciferase is a generic term for the class of oxidative enzymes that produce bioluminescence, and is usually distinguished from a photoprotein. The name was first used by Raphaël Dubois who invented the words '' luciferin'' and ''luciferase'' ...

process. In an experiment with ''P. fischeri'' and ''B. harveyi'' cells,

bioluminescence Bioluminescence is the production and emission of light by living organisms. It is a form of chemiluminescence. Bioluminescence occurs widely in marine vertebrates and invertebrates, as well as in some fungi, microorganisms including some ...

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 Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

. The bacteria oxidize the reduced flavin mononucleotide to oxidized FMN and transfer it through free fusion to generate light. In humans, flavin reductase often

catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

s an

dependent reduction of flavin mononucleotide which occurs in

erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

s and the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. It has also been suggested that flavin reductases play a role in the production of

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...

. 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. It was also seen in

Trichomonas vaginalis ''Trichomonas vaginalis'' is an anaerobic, flagellated protozoan parasite and the causative agent of a sexually transmitted disease called trichomoniasis. It is the most common pathogenic protozoan that infects humans in industrialized countries ...

that decreased levels of flavin reductase increased the cycling of

metronidazole Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is e ...

because flavin reductase has an antioxidative effect, which decreases oxygen levels, maintaining the metronidazole population.

Future of the enzyme

Currently, it is seen that bacterial flavin reductase can be used to sensitize

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoderma ...

s, or

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s 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. A dual flavin reductase has been shown to participate in the activation of anticancer drugs. There are also molecules that when oxidized can be

carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...

. In this case, it is helpful to have flavin reductase to reduce these molecules, such as carcinogenic chromate.

References

{{Portal bar, Biology, border=no EC 1.5.1 NADPH-dependent enzymes Enzymes of unknown structure