What are monoamine oxidases (MAOs), and what is their fundamental enzymatic function?

Monoamine oxidases (MAOs) are a family of enzymes, classified under EC 1.4.3.4, that catalyze the oxidation of monoamines. Their primary function involves using oxygen to remove the amine group from these molecules.

Where are monoamine oxidases primarily located within cells?

Monoamine oxidases are typically found bound to the outer membrane of mitochondria in most cell types throughout the body. This cellular localization is crucial for their metabolic functions.

When and by whom was the first monoamine oxidase enzyme discovered, and what was its initial name?

The first monoamine oxidase enzyme was discovered in 1928 by Mary Bernheim in the liver. It was initially named tyramine oxidase.

To which protein family do monoamine oxidases belong?

Monoamine oxidases belong to the protein family of flavin-containing amine oxidoreductases, indicating their reliance on flavin adenine dinucleotide (FAD) as a cofactor.

What are the two main roles of monoamine oxidases in the body concerning monoamines?

MAOs play a dual role: they help break down monoamines ingested from food and also serve to inactivate monoamine neurotransmitters within the body, thereby regulating their levels.

How are monoamine oxidases clinically relevant in the context of neurological and psychiatric disorders?

MAOs are involved in various psychiatric and neurological diseases because they regulate the levels of monoamine neurotransmitters. Certain conditions can be treated using monoamine oxidase inhibitors (MAOIs), which block the action of these enzymes.

What are the two primary subtypes of monoamine oxidase found in humans?

In humans, the two main subtypes of monoamine oxidase are MAO-A and MAO-B.

Where are MAO-A and MAO-B enzymes found within the central nervous system?

Both MAO-A and MAO-B are found within neurons and astroglia in the central nervous system.

Outside the central nervous system, what are the primary locations where MAO-A is found?

Beyond the CNS, MAO-A is also present in the liver, the pulmonary vascular endothelium, the gastrointestinal tract, and the placenta.

Where is MAO-B primarily found outside of the central nervous system?

Outside the central nervous system, MAO-B is predominantly found in blood platelets.

How do the levels of MAO-A and MAO-B differ between infants and adults, particularly in the brain?

MAO-A levels are approximately 80% of adult levels at birth and increase slightly in the first four years of life, whereas MAO-B is nearly undetectable in the infant brain.

Describe the regional distribution of MAO-A and MAO-B within the human brain.

Both MAO-A and MAO-B are found in very high concentrations in the hypothalamus and the hippocampal uncus. The striatum and globus pallidus have significant amounts of MAO-B with very little MAO-A, while the cortex generally has high MAO-A levels, with exceptions in certain cingulate cortex areas that contain a balance of both.

What correlations have been observed between MAO subtypes and specific neurotransmitter systems in the brain?

Studies on autopsied brains indicated that MAO-A concentrations correlate with regions rich in serotonergic neurotransmission, whereas MAO-B levels correlated with norepinephrine.

What is the catalytic mechanism of monoamine oxidases?

Monoamine oxidases catalyze oxidative deamination, a process where the cofactor FAD oxidizes the monoamine substrate to form an imine. This imine is then hydrolyzed into an aldehyde or ketone and ammonia. Oxygen is required to regenerate the active FAD cofactor from its reduced form, FADH2.

What is known about the structural similarities and binding sites of MAO-A and MAO-B?

MAO-A and MAO-B share approximately 70% of their structure and both possess substrate binding sites that are largely hydrophobic. Specific tyrosine residues within these binding pockets are thought to be important for orienting substrates.

What recent findings (as of 2021) have shed new light on the role of MAO-B in the brain?

Recent research suggests that MAO-B in the rodent striatum does not primarily degrade dopamine but instead participates in synthesizing GABA from putrescine, which then inhibits dopaminergic neurons. It also plays a role in GABA synthesis within astrocytes in various brain regions.

Which monoamine neurotransmitters are primarily metabolized by MAO-A?

MAO-A is primarily responsible for the catabolism of serotonin, norepinephrine, and epinephrine.

Which monoamines are metabolized by both MAO-A and MAO-B?

Both MAO-A and MAO-B metabolize dopamine, tyramine, and tryptamine, although evidence suggests MAO-B might not be significantly involved in dopamine degradation.

What are some examples of endogenous compounds, besides major neurotransmitters, that are substrates for MAO?

Besides neurotransmitters, MAOs also act on endogenous compounds like telemethylhistamine (a histamine metabolite) and N-acetylputrescine, which is involved in GABA synthesis.

Name several examples of exogenous compounds and drugs that are substrates for MAO enzymes.

Various exogenous compounds and drugs are substrates for MAOs, including sympathomimetics like phenylephrine, sympatholytics like propranolol, substituted tryptamines like dimethyltryptamine (DMT) and sumatriptan, and other medications such as sertraline and ticlopidine.

How can MAO dysfunction contribute to psychiatric and neurological disorders?

MAO dysfunction, whether through excessively high or low activity, is believed to contribute to disorders such as schizophrenia, depression, attention deficit disorder, substance abuse, and migraines, due to its role in neurotransmitter inactivation.

What are monoamine oxidase inhibitors (MAOIs) and why are they often considered last-line treatments for depression?

MAOIs are a class of drugs that block the action of MAO enzymes and are used to treat depression. They are often reserved for last-line treatment due to potential interactions with certain foods (like aged cheeses, leading to the "cheese effect") and other medications, which can cause dangerous side effects like hypertensive crisis.

What are the distinct therapeutic applications of MAO-A inhibitors versus MAO-B inhibitors?

MAO-A inhibitors generally act as antidepressant and anti-anxiety agents. In contrast, MAO-B inhibitors are used, often in combination therapies, for treating conditions like Alzheimer's disease and Parkinson's disease.

How can African trypanosomiasis, or sleeping sickness, be linked to monoamine oxidase activity?

The sleep disruption caused by African trypanosomiasis is partly attributed to the trypanosomes' ability to interfere with MAO activity within the orexin system of the host.

What significant difference in dopamine metabolism has been observed between rats and humans/vervet monkeys regarding MAO subtypes?

In rats, dopamine is primarily deaminated by MAO-A, whereas in vervet monkeys and humans, MAO-B is the primary enzyme responsible for dopamine deamination.

What behavioral traits have been observed in mice lacking functional MAO-A or MAO-B?

Mice that are unable to produce either MAO-A or MAO-B exhibit autistic-like traits and show an increased response to stress.

How do MAO enzymes function in insects, and what is their relevance to insecticides?

Insect brains express MAOs, and certain insecticides function by inhibiting these enzymes. For example, chlordimeform is known to inhibit MAO activity in some insect species.

Where are the genes for MAO-A and MAO-B located, and what is their relationship?

The genes encoding MAO-A and MAO-B are situated adjacent to each other on the short arm of the X chromosome and share approximately 70% sequence similarity.

What genetic condition is associated with rare mutations in the MAO-A gene?

Rare mutations in the MAO-A gene are associated with Brunner syndrome.

What did the Dunedin cohort study suggest about the interaction between MAO-A gene variants and childhood maltreatment?

The Dunedin cohort study suggested that maltreated children with a low-activity polymorphism in the MAO-A gene promoter were more likely to develop antisocial conduct disorders compared to maltreated children with the high-activity variant.

What is the proposed biological mechanism linking low MAO-A activity to antisocial behavior in maltreated individuals?

The proposed mechanism is that individuals with low MAO-A activity may have a reduced ability to efficiently degrade norepinephrine, a neurotransmitter involved in arousal and rage, potentially leading to heightened sympathetic responses.

What criticism has been raised regarding the link between MAO-A genotype, maltreatment, and antisocial behavior?

A criticism is that genetic predispositions to antisocial behavior might be inherited from abusive parents through other genes, rather than solely being a consequence of the MAO-A genotype interacting with maltreatment.

Is there a known association between MAO-A gene variants and personality traits?

Yes, a possible link has been found between a specific MAO-A gene variant, sometimes called the "warrior gene" in popular culture, and predisposition to novelty seeking.

How does MAO-B activity change with aging, and what is the potential impact?

MAO-B activity increases in the brain and pineal gland during aging in humans and other mammals. This increase may contribute to the decrease in monoamine levels commonly seen in the brains of older individuals.

What is the EC number for monoamine oxidase?

The EC number for monoamine oxidase is 1.4.3.4.

What is the CAS registry number for monoamine oxidase?

The CAS registry number for monoamine oxidase is 9001-66-5.

What is the gene symbol for monoamine oxidase A?

The gene symbol for monoamine oxidase A is MAOA.

What is the gene symbol for monoamine oxidase B?

The gene symbol for monoamine oxidase B is MAOB.

On which human chromosome are the genes for MAO-A and MAO-B located?

The genes for MAO-A and MAO-B are located on the X chromosome, specifically on the short arm (p11.4-p11.3).

What specific reaction does monoamine oxidase catalyze, involving FAD?

Monoamine oxidase catalyzes the oxidative deamination of monoamines, a reaction where the cofactor FAD oxidizes the substrate, leading to the formation of an imine and the reduced cofactor FADH2.

What are the potential consequences of excessive levels of catecholamines or serotonin in the body, related to MAO function?

Excessive levels of catecholamines (like epinephrine, norepinephrine, and dopamine) can lead to a hypertensive crisis, while excessive serotonin levels can result in serotonin syndrome.

What is the significance of the tyrosine residues (e.g., Tyr398, Tyr435 in MAO-B) in the binding pocket of MAO enzymes?

These tyrosine residues are hypothesized to be important for orienting substrates within the binding pocket, and mutations in these residues have been linked to mental health conditions.

What are the four proposed models for the mechanism of electron transfer in monoamine oxidases?

The four proposed models for electron transfer are single electron transfer, hydrogen atom transfer, the nucleophilic model, and hydride transfer, though evidence is insufficient to strongly support any single model.

What is the "cheese effect" in relation to monoamine oxidase inhibitors?

The "cheese effect" refers to the hypertensive crisis that can occur if MAOIs, particularly non-selective ones, are taken concurrently with certain foods high in tyramine (like aged cheeses). MAO normally breaks down tyramine, and its inhibition allows tyramine levels to rise, triggering a dangerous increase in blood pressure.

What is the role of MAO-B in the synthesis of GABA from putrescine in astrocytes?

MAO-B facilitates the conversion of putrescine into GABA within astrocytes, a process that is important for regulating neuronal activity in various brain regions.

What are the potential implications of MAO-B's role in GABA synthesis for treating Parkinson's disease?

The discovery of MAO-B's role in GABA synthesis may necessitate a re-evaluation of how MAO-B inhibitors are used in treating Parkinson's disease, as their effects might extend beyond dopamine metabolism.

What are some of the specific aldehyde products formed from the oxidative deamination of monoamines by MAO?

MAO catalyzes the formation of various aldehyde products, such as 5-hydroxyindoleacetaldehyde from serotonin, 3,4-dihydroxyphenylacetaldehyde (DOPAL) from dopamine, and 3,4-dihydroxymandelaldehyde (DHMAL) from norepinephrine and epinephrine.

What is the relationship between MAO-A activity and the risk of developing adolescent conduct disorder in maltreated children, according to some studies?

Some studies suggest that maltreated children with a low-activity variant of the MAO-A gene promoter may have a higher likelihood of developing adolescent conduct disorder, potentially due to impaired neurotransmitter breakdown.

How might MAO-B activity in aging contribute to changes in monoamine levels?

The observed increase in MAO-B activity during aging might contribute to the decrease in monoamine levels commonly seen in the brains of older individuals.

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Defining Monoamine Oxidase

Enzymatic Function

Monoamine oxidases (MAOs), classified under EC 1.4.3.4, are a family of enzymes responsible for catalyzing the oxidative deamination of monoamines. This process involves the oxidation of monoamines, utilizing oxygen to cleave the amine group. They are integral components of the flavin-containing amine oxidoreductase protein family.

Cellular Localization

MAOs are primarily located on the outer mitochondrial membrane in most cell types throughout the body. This strategic positioning allows them to efficiently metabolize monoamines, both those ingested through diet and endogenous neurotransmitters.

Historical Context

The first MAO enzyme was identified in 1928 by Mary Bernheim in liver tissue and was initially named tyramine oxidase. Its discovery marked a significant step in understanding metabolic pathways involving amines.

Identification

Key identifiers for Monoamine Oxidase include:

Identifier	Value
EC Number	1.4.3.4
CAS Number	9001-66-5
Pfam	PF01593
InterPro	IPR001613

MAO Subtypes and Distribution

MAO-A

Monoamine oxidase A (MAO-A) is predominantly involved in the catabolism of neurotransmitters such as serotonin, norepinephrine, and epinephrine. It is expressed in neurons and glia, as well as in the liver, pulmonary vascular endothelium, gastrointestinal tract, and placenta. MAO-A levels reach adult concentrations shortly after birth.

MAO-B

Monoamine oxidase B (MAO-B) primarily metabolizes phenethylamine and benzylamine. While also found in neurons and glia, it is predominantly localized in blood platelets outside the central nervous system. MAO-B activity increases with age, particularly in the brain and pineal gland.

Tissue Distribution

Both MAO-A and MAO-B exhibit distinct regional distributions within the brain. High levels of both are found in the hypothalamus and hippocampal uncus. The striatum and globus pallidus show high MAO-B activity with minimal MAO-A, whereas the cortex has higher MAO-A levels, with exceptions in the cingulate cortex.

Mechanism of Action

Oxidative Deamination

MAOs catalyze oxidative deamination. The process begins with the oxidation of the substrate by the flavin adenine dinucleotide (FAD) cofactor, generating a reduced FADH2 form. The resulting imine intermediate is then hydrolyzed non-enzymatically into an aldehyde and ammonia. Molecular oxygen is required to regenerate the active FAD cofactor.

Structural Homology

MAO-A and MAO-B share approximately 70% structural similarity. Their substrate binding sites are largely hydrophobic. Key tyrosine residues within these sites are hypothesized to play a role in substrate orientation and inhibitor interactions, potentially linking to mental health conditions.

Novel Roles of MAO-B

Recent findings suggest MAO-B's role extends beyond neurotransmitter breakdown. In rodents, MAO-B participates in striatal GABA synthesis from putrescine, influencing dopaminergic neuron activity. This pathway, mediated by MAO-B in astrocytes, is observed across various brain regions and may necessitate a re-evaluation of MAO-B inhibitor therapies for conditions like Parkinson's disease.

Substrates and Specificities

MAO-A Substrates

MAO-A preferentially catabolizes:

Serotonin
Norepinephrine
Epinephrine
Tryptamine
Tyramine
Dopamine

MAO-A inhibitors are primarily used as antidepressants and anti-anxiety agents.

MAO-B Substrates

MAO-B preferentially catabolizes:

Phenethylamine
Benzylamine
Tryptamine
Tyramine
Dopamine

MAO-B inhibitors are utilized in managing Parkinson's disease and Alzheimer's disease.

Exogenous Compounds

Beyond endogenous monoamines, MAOs metabolize numerous exogenous compounds and drugs. These include various sympathomimetics, sympatholytics, serotonergic agents (e.g., DMT, sumatriptan), and other pharmaceuticals like citalopram, nomifensine, and sertraline. Some drugs, like haloperidol, may form neurotoxic metabolites via MAO activity.

Clinical Significance

MAO Activity and Disease

Dysregulation of MAO activity (either excessive or deficient) is implicated in various psychiatric and neurological disorders. Altered MAO levels have been associated with schizophrenia, depression, attention deficit disorders, substance abuse, and migraines. MAO-A inhibitors are prescribed for depression, while MAO-B inhibitors are used for neurodegenerative diseases.

MAOI Interactions

Monoamine oxidase inhibitors (MAOIs) require careful management due to potential interactions. Excessive levels of catecholamines (epinephrine, norepinephrine, dopamine) can precipitate a hypertensive crisis, while excessive serotonin can lead to serotonin syndrome. Dietary restrictions (avoiding tyramine-rich foods) are crucial when using MAO-A inhibitors.

Parasites and Insects

MAO activity is relevant in host-parasite interactions. For instance, trypanosomes causing sleeping sickness disrupt MAO activity in the orexin system, affecting sleep patterns. Furthermore, certain insecticides function by inhibiting insect MAOs, highlighting the enzyme's conserved biological importance.

Genetic Basis of MAO

Gene Location and Polymorphisms

The genes encoding MAO-A and MAO-B are located adjacently on the X chromosome (Xp11.4-p11.3). They exhibit significant sequence similarity. Rare mutations in the MAO-A gene are linked to Brunner syndrome. Promoter region polymorphisms, particularly the low-activity variant of MAO-A, have been studied in relation to antisocial behavior, although findings suggest environmental factors (maltreatment) play a more significant role, and genetic predisposition may be inherited alongside abusive environments.

Behavior and Genetics

Research suggests a potential link between MAO-A gene variants and personality traits like novelty seeking. Variations in MAO-A gene frequencies exist across different ethnic groups. The popular press has termed certain variants the "warrior gene," though this requires careful interpretation due to the complex interplay of genetics and environment.

MAO Activity and Aging

Age-Related Changes

Unlike many enzymes, MAO-B activity demonstrates an increase with age in mammalian brains, including humans. This phenomenon is also observed in the pineal gland of aging rats. The elevated MAO-B activity may contribute to reduced monoamine levels observed in the aged brain and pineal gland.

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MAO Unveiled

💡 Dive in with Flashcard Learning! 💡

Defining Monoamine Oxidase 🔬

⚙️ Enzymatic Function

📍 Cellular Localization

📜 Historical Context

🆔 Identification

MAO Subtypes and Distribution 🧠

🅰️ MAO-A

🅱️ MAO-B

🌐 Tissue Distribution

Mechanism of Action ⚛️

⚡ Oxidative Deamination

🔗 Structural Homology

🔄 Novel Roles of MAO-B

Substrates and Specificities 🧪

⬆️ MAO-A Substrates

⬇️ MAO-B Substrates

💊 Exogenous Compounds

Clinical Significance ⚕️

⚖️ MAO Activity and Disease

⚠️ MAOI Interactions

🦠 Parasites and Insects

Genetic Basis of MAO 🧬

🔗 Gene Location and Polymorphisms

💡 Behavior and Genetics

MAO Activity and Aging ⏳

📈 Age-Related Changes

Teacher's Corner 🧑‍🏫

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📜 References

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📜 Important Notice

Dive in with Flashcard Learning!

Defining Monoamine Oxidase

Enzymatic Function

Cellular Localization

Historical Context

Identification

MAO Subtypes and Distribution

MAO-A

MAO-B

Tissue Distribution

Mechanism of Action

Oxidative Deamination

Structural Homology

Novel Roles of MAO-B

Substrates and Specificities

MAO-A Substrates

MAO-B Substrates

Exogenous Compounds

Clinical Significance

MAO Activity and Disease

MAOI Interactions

Parasites and Insects

Genetic Basis of MAO

Gene Location and Polymorphisms

Behavior and Genetics

MAO Activity and Aging

Age-Related Changes

Teacher's Corner

True or False?

Test Your Knowledge!

Gamer's Corner

Discover other topics to study!

References

Feedback & Support

Academic Disclaimer

Important Notice