The flavin-containing monooxygenase (FMO)
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
family specializes in the
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
of
xeno-substrates in order to facilitate the excretion of these compounds from living organisms.
These
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s can oxidize a wide array of
heteroatoms, particularly
soft nucleophiles, such as
amines
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
,
sulfides, and
phosphites
A phosphite anion or phosphite in inorganic chemistry usually refers to PO3sup>2− but includes 2PO3sup>− ( PO2(OH)sup>−). These anions are the conjugate bases of phosphorous acid (H3PO3). The corresponding salts, e.g. sodium phosphite ...
. This reaction requires an oxygen, an
NADPH cofactor, and an
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- ...
prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
.
FMOs share several structural features, such as a
NADPH binding domain,
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- ...
binding domain, and a conserved arginine residue present in the active site. Recently, FMO enzymes have received a great deal of attention from the pharmaceutical industry both as a
drug target
A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
for various diseases and as a means to
metabolize
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
pro-drug compounds into active pharmaceuticals.
These
monooxygenase
Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation o ...
s are often misclassified because they share activity profiles similar to those of
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
(CYP450), which is the major contributor to oxidative xenobiotic
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
. However, a key difference between the two enzymes lies in how they proceed to oxidize their respective substrates; CYP enzymes make use of an oxygenated
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consis ...
prosthetic group, while the FMO family utilizes FAD to oxidize its substrates.
History
Prior to the 1960s, the
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
of
xenotoxic materials was thought to be completely accomplished by
CYP450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
. However, in the early 1970s, Dr. Daniel Ziegler from the University of Texas at Austin discovered a
hepatic
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 is ...
flavoprotein
Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin.
Flavoproteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair. T ...
isolated from pig liver that was found to oxidize a vast array of various
amines
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
to their corresponding
nitro
Nitro may refer to:
Chemistry
*Nitrogen, a chemical element and a gas except at very low temperatures, with which many compounds are formed:
**Nitro compound, an organic compound containing one or more nitro functional groups, -NO2
**Nitroalkene, ...
state. This flavoprotein named "Ziegler's enzyme" exhibited unusual chemical and spectrometric properties. Upon further spectroscopic characterization and investigation of the substrate pool of this enzyme, Dr. Ziegler discovered that this enzyme solely bound FAD molecule that could form a C4a-hydroxyperoxyflavin intermediate, and that this enzyme could oxidize a wide variety of substrates with no common structural features, including
phosphines
Phosphine (IUPAC name: phosphane) is a colorless, flammable, highly toxic compound with the chemical formula , classed as a pnictogen hydride. Pure phosphine is odorless, but technical grade samples have a highly unpleasant odor like rotting ...
,
sulfides,
selenium
Selenium is a chemical element with the symbol Se and atomic number 34. It is a nonmetal (more rarely considered a metalloid) with properties that are intermediate between the elements above and below in the periodic table, sulfur and tellurium, ...
compounds, amongst others. Once this was noticed, Dr. Ziegler's enzyme was reclassified as a broadband flavin
monooxygenase
Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation o ...
.
In 1984, the first evidence for multiple forms of FMOs was elucidated by two different laboratories when two distinct FMOs were isolated from rabbit lungs. Since then, over 150 different FMO enzymes have been successfully isolated from a wide variety of organisms. Up until 2002, only 5 FMO enzymes were successfully isolated from mammals. However, a group of researchers found a sixth FMO gene located on
human chromosome 1. In addition to the sixth FMO discovered as of 2002, the laboratories of Dr. Ian Philips and Elizabeth Sheppard discovered a second gene cluster in humans that consists of 5 additional pseudogenes for FMO on human chromosome 1.
Evolution of FMO gene family
The FMO family of
genes is
conserved across all
phyla that have been studied so far, therefore some form of the FMO gene family can be found in all studied
eukaryotes. FMO genes are characterized by specific structural and functional constraints, which led to the evolution of different types of FMO's in order to perform a variety of functions.
Divergence
In vector calculus, divergence is a vector operator that operates on a vector field, producing a scalar field giving the quantity of the vector field's source at each point. More technically, the divergence represents the volume density of t ...
between the functional types of FMO's (FMO 1–5) occurred before the
amphibians and
mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
diverged into separate
classes. FMO5 found in
vertebrates
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
appears to be evolutionarily older than other types of FMO's, making FMO5 the first functionally distinct member of the FMO family.
Phylogenetic
In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...
studies suggest that FMO1 and FMO3 are the most recent FMO's to evolve into enzymes with distinct functions. Although FMO5 was the first distinct FMO, it is not clear what function it serves since it does not
oxygenate
Oxygenated chemical compounds contain oxygen as a part of their chemical structure. The term usually refers to oxygenated chemical compounds added to fuels. Oxygenates are usually employed as gasoline additives to reduce carbon monoxide and soot ...
the typical FMO substrates involved in
first-pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...
.
Analyses of FMO genes across several species have shown extensive
silent DNA mutations, which indicate that the current FMO gene family exists because of selective pressure at the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
level rather than the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecule ...
level. FMO's found in
invertebrates
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordat ...
are found to have originated
polyphyletically; meaning that a
phenotypically
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
similar gene evolved in invertebrates which was not inherited from a common ancestor.
Classification and characterization
FMOs are one
subfamily of class B external flavoprotein
monooxygenase
Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation o ...
s (EC 1.14.13), which belong to the family of monooxygenase
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 u ...
s, along with the other subfamilies
Baeyer-Villiger monooxygenases and microbial N-hydroxylating monooxygenases.
FMO's are found in fungi, yeast, plants, mammals, and bacteria.
Mammals
Developmental and tissue specific
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
has been studied in several mammalian species, including humans, mice, rats, and rabbits.
However, because FMO expression is unique to each animal species, it is difficult to make conclusions about human FMO regulation and activity based on other mammalian studies.
It is likely that species-specific expression of FMO's contributes to differences in susceptibility to
toxins and
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
as well as the efficiency with excreting among different mammals.
Six functional forms of human FMO genes have been reported. However, FMO6 is considered to be a
pseudogene.
FMOs 1–5 share between 50–58% amino acid identity across the different species.
Recently, five more human FMO genes were discovered, although they fall in the category of pseudogenes.
*
FMO1
Dimethylaniline monooxygenase -oxide-forming1 is an enzyme that in humans is encoded by the ''FMO1'' gene.
Metabolic N-oxidation of the diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an i ...
,
FMO2,
FMO3
Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase -oxide-forming3 and trimethylamine monooxygenase, is a flavoprotein enzyme () that in humans is encoded by the ''FMO3'' gene.
This enzyme catalyzes the follow ...
,
FMO4
Dimethylaniline monooxygenase -oxide-forming4 is an enzyme that in humans is encoded by the ''FMO4'' gene.
Function
Metabolic N-oxidation of the diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is sub ...
,
FMO5,
FMO6
Yeast
Unlike mammals, yeast (''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...
'') do not have several
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
of FMO, but instead only have one called yFMO. This enzyme does not accept
xenobiotic
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
compounds. Instead, yFMO helps to fold proteins that contain
disulfide bonds
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
by catalyzing O
2 and
NADPH-dependent oxidations of biological
thiols
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...
, just like mammalian FMO's.
An example is the oxidation of
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
to
glutathione disulfide, both of which form a
redox
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
buffering system in the cell between the
endoplasmic reticulum and the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
. yFMO is localized in the cytoplasm in order to maintain the optimum redox buffer ratio necessary for proteins containing disulfide bonds to fold properly.
This non-xenobiotic role of yFMO may represent the original role of the FMO's before the rise of the modern FMO family of enzymes found in mammals.
Plants
Plant FMO's play a role in defending against
pathogens
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...
and catalyze specific steps in the
biosynthesis of
auxin, a
plant hormone. Plant FMO's also play a role in the metabolism of
glucosinolates
Glucosinolates are natural components of many pungent plants such as mustard, cabbage, and horseradish. The pungency of those plants is due to mustard oils produced from glucosinolates when the plant material is chewed, cut, or otherwise damaged. T ...
. These non-xenobiotic roles of plant FMO's suggest that other FMO functions could be identified in non-plant organisms.
Structure
Crystal structures have been determined for yeast (''
Schizosaccharomyces pombe
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measur ...
'') FMO
PDB: 1VQW and bacterial (''
Methylophaga aminisulfidivorans'') FMO
PDB: 2XVH.
The crystal structures are similar to each other and they share 27% sequence identity.
These enzymes share 22% and 31%
sequence identity
In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Ali ...
with human FMOs, respectively.
![BacterialFMOactivesite](https://upload.wikimedia.org/wikipedia/commons/a/aa/BacterialFMOactivesite.png)
FMOs have a tightly bound
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- ...
prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
and a binding
NADPH cofactor.
Both
dinucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules with ...
binding motifs form
Rossmann fold
The Rossmann fold is a tertiary fold found in proteins that bind nucleotides, such as enzyme cofactors FAD, NAD+, and NADP+. This fold is composed of alternating beta strands and alpha helical segments where the beta strands are hydrogen bonde ...
s. The yeast FMO and bacterial FMO are
dimers, with each
monomer
In chemistry, a monomer ( ; '' mono-'', "one" + ''-mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
...
consisting of two structural
domains: the smaller NADPH binding domain and the larger FAD-binding domain. The two domains are connected by a double linker. A channel between the two domains leads to the active site where NADPH binds both domains and occupies a cleft that blocks access to the
flavin group
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 wit ...
of FAD, which is bound to the large domain along the channel together with a water molecule.
The
nicotinamide
Niacinamide or Nicotinamide (NAM) is a form of vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) may ...
group of NADPH interacts with the flavin group of FAD, and the NADPH binding site overlaps with the substrate
binding site
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 ...
on the flavin group.
FMOs contain several
sequence motifs
In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an ''N''-glycosylation site motif can be defined as ''A ...
that are conserved across all
domains:
* FAD-binding motif (GXGXXG)
* FMO identifying motif (FXGXXXHXXXF/Y)
* NADPH-binding motif (GXSXXA)
* F/LATGY motif
*
arginine residue in the active site
The FMO identifying motif interacts with the flavin of FAD.
The F/LATGY motif is a sequence motif common in ''N''-hydroxylating enzymes.
The arginine residue interacts with the
phosphate group
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosph ...
of NADPH.
Function
![FMOrxns2](https://upload.wikimedia.org/wikipedia/commons/7/72/FMOrxns2.png)
The general function of these enzymes is to
metabolise
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
.
Hence, they are considered to be xenobiotic detoxication
catalysts
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 ...
. These proteins catalyze the
oxygenation of multiple
heteroatom
In chemistry, a heteroatom () is, strictly, any atom that is not carbon or hydrogen.
Organic chemistry
In practice, the term is usually used more specifically to indicate that non-carbon atoms have replaced carbon in the backbone of the molecula ...
-containing compounds that are present in our diet, such as
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen
Hydrogen is the chemical element wi ...
-,
sulfide-,
phosphorus
Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white phosphorus and red phosphorus, but because it is highly reactive, phosphorus is never found as a free element on Ear ...
-, and other
nucleophilic
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
heteroatom-containing compounds. FMOs have been implicated in the metabolism of a number of pharmaceuticals, pesticides and toxicants, by converting the
lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
xenobiotics into
polar
Polar may refer to:
Geography
Polar may refer to:
* Geographical pole, either of two fixed points on the surface of a rotating body or planet, at 90 degrees from the equator, based on the axis around which a body rotates
* Polar climate, the c ...
, oxygenated, and readily excreted metabolites.
Substrate diversity
FMO substrates are structurally diverse compounds. However, they all share similar characteristics:
*
Soft nucleophiles (basic amines, sulfides, Se- or P-containing compounds)
* Neutral or single-positively charged
Zwitterions
In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups.
: With amino acids, for example, in solution a chemical equilibrium wi ...
,
anions
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
and
dications are considered to be unfavorable substrates. There are several drugs reported to be typical substrates for FMOs.
The majority of drugs function as alternate
substrate competitive inhibitors to FMOs (i.e. good nucleophiles that compete with the drug for FMO
oxygenation), since they are not likely to serve as FMO substrates.
Only a few true FMO competitive inhibitors have been reported. Those include indole-3-carbinol and ''N'',''N''-dimethylamino stilbene carboxylates. A well-known FMO inhibitor is
methimazole (MMI).
Mechanism
![Catalytic Cycle of FMOs](https://upload.wikimedia.org/wikipedia/commons/0/0b/Catalytic_Cycle_of_FMOs.png)
The FMO
catalytic cycle
In chemistry, a catalytic cycle is a multistep reaction mechanism that involves a catalyst. The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, bioinorganic chemistry, materials s ...
proceeds as follows:
# The
cofactor NADPH binds to the
oxidized state of the
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- ...
prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
, reducing it to FADH
2.
# Molecular
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
binds to the formed NADP
+-FADH
2-enzyme complex and is reduced, resulting in 4a-hydroperoxyflavin (4a-HPF or FADH-OOH). This species is stabilized by NADP
+ in the
catalytic site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
of the enzyme. These first two steps in the cycle are fast.
# In the presence of a substrate (S), a
nucleophilic attack
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
occurs on the distal O-atom of the prosthetic group. The substrate is oxygenated to SO, forming the 4a-hydroxyflavin (FADH-OH). Only when the flavin is in the hydroperoxy form is when the xenobiotic substrate will react.
# The flavin product then breaks down with release of water to reform FAD.
# Due to the low
dissociation constant of the NADP
+-enzyme complex, NADP
+ is released by the end of the cycle and the enzyme returns to its original state. The
rate-limiting step
In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of th ...
involves either the breakdown of FADH-OH to water or the release of NADP
+.
#
Quantum mechanics
Quantum mechanics is a fundamental theory in physics that provides a description of the physical properties of nature at the scale of atoms and subatomic particles. It is the foundation of all quantum physics including quantum chemistr ...
simulations showed the N-hydroxylation catalyzed by flavin-containing monooxygenases initiated by
homolysis of the O-O bond in the C4a-hydroperoxyflavin intermediate resulting in the formation of an internal hydrogen bonded hydroxyl radical.
Cellular expression in humans
Expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of each type of FMO relies on several factors including,
cofactor supply, physiological & environmental factors, as well as
diet
Diet may refer to:
Food
* Diet (nutrition), the sum of the food consumed by an organism or group
* Dieting, the deliberate selection of food to control body weight or nutrient intake
** Diet food, foods that aid in creating a diet for weight loss ...
. Because of these factors, each type of FMO is expressed differently depending on the species and tissue. In humans, expression of FMO's is mainly concentrated to the human liver, lungs, and kidneys, where most of the metabolism of
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
occur. However, FMO's can also be found in the human brain and small intestine. While FMO1-5 can be found in the brain, liver, kidneys, lungs, and small intestine, the distribution of each type of FMO differs depending on the tissue and the developmental stage of the person.
Expression in adult tissues
In an adult, FMO1 is predominately expressed in the
kidneys
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
and to a lesser extent in the
lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side ...
and
small intestine. FMO2 is the most abundant of the FMO's and is mostly expressed in the lungs and kidneys, with lower expression in 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 ...
and small intestine. FMO3 is highly concentrated in the liver, but is also expressed in the lungs. FMO4 is expressed mostly in the liver and kidneys. FMO5 is highly expressed in the liver, but also has substantial expression in the lungs and small intestine. Though FMO2 is the most expressed FMO in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, it only constitutes about 1% of that found in the lungs, making FMO expression in the brain fairly low.
Expression in fetal Tissues
The distribution of FMO's in various types of tissues changes as a person continues to develop, making the fetal distribution of FMO's quite different than adult distribution of FMO's. While the adult liver is dominated by the expression of FMO3 and FMO5, the fetal liver is dominated by the expression of FMO1 and FMO5. Another difference is in the brain, where adults mostly express FMO2 and fetuses mostly express FMO1.
Clinical significance
Drug development
Drug metabolism
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set o ...
is one of the most important factors to consider when developing new drugs for
therapeutic
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
applications. The degradation rate of these new drugs in an organism's system determines the duration and intensity of their
pharmacological action. During the past few years, FMOs have gained a lot of attention in
drug development
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
since these enzymes are not readily induced or
inhibited by the chemicals or drugs surrounding their environment.
CYPs are the primary enzymes involved in drug metabolism. However, recent efforts have been directed towards the development of drug candidates that incorporate
functional groups
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
that can be metabolized by FMOs. By doing this, the number of potential adverse
drug-drug interactions is minimized and the reliance on CYP450 metabolism is decreased. Several approaches have been made to screen potential drug interactions. One of them includes human FMO3 (hFMO3), which is described as the most vital FMO regarding drug interactions. In order to successfully screen hFMO3 in a high throughput fashion hFMO3 was successfully fixed to
graphene oxide
An oxide () is a chemical compound that contains at least one oxygen atom and one other element in its chemical formula. "Oxide" itself is the dianion of oxygen, an O2– (molecular) ion. with oxygen in the oxidation state of −2. Most of the ...
chips in order to measure the change in
electrical potential
The electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is defined as the amount of work energy needed to move a unit of electric charge from a reference point to the specific point in ...
generated as a result of the drug being oxidized when it interacts with the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
.
Hypertension
There is evidence that FMOs are associated to the
regulation
Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...
of
blood pressure. FMO3 is involved in the formation of
TMA N-oxides (TMAO). Some studies indicate that
hypertension can develop when there are no organic
osmolytes (i.e. TMAO) that can counteract an increase in
osmotic pressure and
peripheral resistance
Vascular resistance is the resistance that must be overcome to push blood through the circulatory system and create flow. The resistance offered by the systemic circulation is known as the systemic vascular resistance (SVR) or may sometimes be cal ...
. Individuals with deficient FMO3 activity have a higher prevalence of hypertension and other
cardiovascular diseases
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...
, since there is a decrease in formation of TMA N-oxides to counterbalance the effects of a higher osmotic pressure and peripheral resistance.
Fish odor syndrome
The
trimethylaminuria disorder, also known as fish odor syndrome, causes abnormal FMO3-mediated metabolism or a deficiency of this enzyme in an individual. A person with this disorder has a low capacity to oxidize the
trimethylamine
Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a colorless, hygroscopic, and flammable tertiary amine. It is a gas at room temperature but is usually sold as a 40% solution in water. (It is also sold in pressurized ...
(TMA) that comes from their diet to its odourless metabolite TMAO. When this happens, large amounts of TMA are excreted through the individual's urine, sweat, and breath, with a strong fish-like odor. As of today, there is no known cure or treatment for this disorder. However, doctors recommend patients to avoid foods containing
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...
,
carnitine,
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 se ...
,
sulfur and
lecithin.
Other diseases
FMOs have also been associated with other diseases, such as
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
and
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
.
Yet, additional studies are imperative to elucidate what is the relationship between FMO function and these diseases, as well as to define these enzymes’ clinical relevance.
References
External links
*
*
Research information on FMO1 (WikiGenes)
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EC 1.14.13
Oxidoreductases