Monoamine oxidase B
Encyclopedia
Monoamine oxidase B, also known as MAOB, is a protein
that in humans is encoded by the MAOB gene
.
The protein encoded by this gene belongs to the flavin monoamine oxidase
family. It is an enzyme
located in the mitochondrial outer membrane
. It catalyzes the oxidative deamination
of biogenic and xenobiotic
amine
s and plays an important role in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. This protein preferentially degrades benzylamine
and phenylethylamine. Like MAOA, it also degrades dopamine
.
3. hMAO-A
has a single cavity that exhibits a rounder shape and is larger in volume than the "substrate cavity" of hMAO-B.
The first cavity of hMAO-B has been termed the entrance cavity (290 Å3), the second substrate cavity or active site cavity (~390 Å3) – between both an isoleucine
199 side-chain serves as a gate. Depending on the substrate or bound inhibitor, it can exist in either an open or a closed form, which has been shown to be important in defining the inhibitor specificity of hMAO B. At the end of the substrate cavity is the FAD
coenzyme with sites for favorable amine binding about the flavin involving two nearly parallel tyrosyl (398 and 435) residues that form what has been termed an aromatic cage.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the MAOB gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
The protein encoded by this gene belongs to the flavin monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
family. It is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
located in the mitochondrial outer membrane
Outer membrane
The bacterial outer membrane is found in Gram-negative bacteria. Its composition is distinct from that of the cytoplasmic membrane - among other things, the outer leaflet of the membrane includes a complex lipopolysaccharide whose lipid portion acts as an endotoxin - and it is linked to the cell's...
. It catalyzes the oxidative deamination
Oxidative deamination
Oxidative deamination is a form of deamination that generates oxoacids in the liver.The presence of nitrous acid can cause transition mutations, by converting cytosine to uracil. Primarily occurs in the liver and kidneys.-In Urea cycle:...
of biogenic and xenobiotic
Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s and plays an important role in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. This protein preferentially degrades benzylamine
Benzylamine
Benzylamine is the chemical compound with the formula C6H5CH2NH2. It consists of a benzyl group, C6H5CH2, attached to an amine functional group...
and phenylethylamine. Like MAOA, it also degrades dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
.
Structure
Edmondson et al. described structural features of the human enzyme: it has a hydrophobic bipartite elongated cavity that (for the "open" conformation) occupies a combined volume close to 700 ÅÅngström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
3. hMAO-A
Monoamine Oxidase A
Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAO-A gene. Monoamine oxidase A is an isozyme of monoamine oxidase. It preferentially deaminates norepinephrine , epinephrine , serotonin, and dopamine...
has a single cavity that exhibits a rounder shape and is larger in volume than the "substrate cavity" of hMAO-B.
The first cavity of hMAO-B has been termed the entrance cavity (290 Å3), the second substrate cavity or active site cavity (~390 Å3) – between both an isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
199 side-chain serves as a gate. Depending on the substrate or bound inhibitor, it can exist in either an open or a closed form, which has been shown to be important in defining the inhibitor specificity of hMAO B. At the end of the substrate cavity is the FAD
FAD
In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
coenzyme with sites for favorable amine binding about the flavin involving two nearly parallel tyrosyl (398 and 435) residues that form what has been termed an aromatic cage.
Differences between MAOA and MAOB
In general, Monoamine Oxidase A (MAOA) prefers to metabolize norepinephrine (NE), serotonin (5-HT), and Dopamine (DA) (and other less clinically relevant chemicals). Monoamine Oxidase B, on the other hand, prefers to metabolize Dopamine (DA) (and other less clinically relevant chemicals).The differences between the substrate selectivity of the two enzymes are utilized clinically when treating specific disorders: Monoamine Oxidase A inhibitors have been used in the treatment of depression, and Monoamine Oxidase B inhibitors are used in the treatment of Parkinson's Disease.Selective inhibitors
Species-dependent divergences may hamper the extrapolation of inhibitor potencies.Natural
- GeiparvarinGeiparvarinGeiparvarin is a coumarin derivative found in the leaves of the Australian Willow . It is a monoamine oxidase inhibitor.Several analogues of geiparvarin have been studied for antitumor properties....
- DesmethoxyyangoninDesmethoxyyangoninDesmethoxyyangonin or 5,6-dehydrokawain is one of the six major kavalactones found in the Piper methysticum plant.-Pharmacology:...
, a constituent of kava-kava extract; modest affinity - CatechinCatechinCatechin is a natural phenol antioxidant plant secondary metabolite. The term catechins is also commonly used to refer to the related family of flavonoids and the subgroup flavan-3-ols ....
and epicatechin
Synthetic
- SafinamideSafinamideSafinamide is a candidate drug against Parkinson's disease with multiple methods of action. In 2007, a Phase III clinical trial was started. It is scheduled to run until 2011. The drug will be marketed by Merck-Serono....
and analogs - 5H-Indeno[1,2-c]pyridazin-5-ones (see 3d model)
- Substituted chalcones
- 2-(N-Methyl-N-benzylaminomethyl)-1H-pyrrole
- 1-(4-Arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine
- 2-Thiazolylhydrazone
- 3,5-Diaryl pyrazolePyrazolePyrazole refers both to the class of simple aromatic ring organic compounds of the heterocyclic diazole series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions, and to the unsubstituted parent compound...
- Pyrazoline derivatives
- CoumarinCoumarinCoumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...
s and #C19* (see 3d model) - Phenylcoumarins, extremly subtype selective and further analogs (see 3d model)
- ChromoneChromoneChromone is a derivative of benzopyran with a substituted keto group on the pyran ring. It is an isomer of coumarin.Derivatives of chromone are collectively known as chromones...
-3-phenylcarboxamides - IsatinIsatinIsatin or 1H-indole-2,3-dione is an indole derivative. The compound was first obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo dye by nitric acid and chromic acids...
s - Phthalimides
- 8-Benzyloxycaffeines and CSC analogs
- (E,E)-8-(4-phenylbutadien-1-yl)caffeines, with A2AAdenosine A2A receptorThe adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, but also denotes the human gene encoding it.-Structure:This protein is a member of the G protein-coupled receptor family which possess seven transmembrane alpha helices...
antagonistic component
Irreversible (covalent)
- SelegilineSelegilineSelegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
(Eldepryl, Zelapar, EmsamEmsamEmsam is the trade name of an antidepressant of the monoamine oxidase inhibitor class. Emsam is a transdermal patch containing the MAOI selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment...
) - RasagilineRasagilineRasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....
(Azilect)