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") 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 yellow B ...

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, shortened MetHb) (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 ...

in erythrocytes. Flavin reductases are similar and often confused for ferric reductases because of their similar catalytic mechanism and structures. In

enzymology An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

, a flavin reductase () is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that

catalyzes Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

the

chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...

riboflavin + NADPH + H⁺

\rightleftharpoons

reduced riboflavin + NADP + H⁺ Thus, the two

products Product may refer to: Business * Product (business), an item that can be offered to a market to satisfy the desire or need of a customer. * Product (project management), a deliverable or set of deliverables that contribute to a business solution ...

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 ...

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 N ...

, 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 ut ...

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 semitrivi ...

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 ** TH-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * ...

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 chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

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, as ...

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 (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, covalently bonded to a mo ...

to connect to the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

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

FAD A fad, trend, or craze 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 time period. Fads are objects or behaviors tha ...

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 (economics), a set of rules for a game designed to achieve a certain outcome **Mechanism design, the study of such mechanisms *Mechanism (engineering), rigid bodies connected by joints in order to accomplish 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−), a hydrogen ion with two electrons. In modern usage, this is typically only used for ionic bonds, but it is sometimes (and has been more frequently in the past) applied to all che ...

. Because of

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

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 a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

on the flavin, which allows for another

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

. 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 ade ...

Biological function

Flavin reductases exist in a variety of

organism An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...

s, including animals and bacteria. In luminous 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 emission of light during a chemiluminescence reaction by living organisms. Bioluminescence occurs in multifarious organisms ranging from marine vertebrates and invertebrates, as well as in some Fungus, fungi, microorgani ...

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 (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

. 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 increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

s an

dependent reduction of flavin mononucleotide which occurs in

erythrocyte Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood ce ...

s and the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. 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 viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...

. 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 organism, anaerobic, flagellated protozoan parasite and the causative agent of a Sexually transmitted infection, sexually transmitted disease called trichomoniasis. It is the most common pathogenic protoz ...

that decreased levels of flavin reductase increased the cycling of

metronidazole Metronidazole, sold under the brand name Flagyl and Metrogyl 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 vagino ...

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, mesoder ...

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 agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...

. 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