Monoamine oxidase B (MAO-B) is a mitochondrial flavin adenine dinucleotide (FAD)-dependent enzyme that preferentially metabolizes phenylethylamine, benzylamine, and dopamine. It plays a central role in Parkinson's disease pathogenesis and is a major therapeutic target for MAO-B inhibitor drugs used in PD treatment. MAO-B activity increases with age, and its overexpression in the substantia nigra contributes to oxidative stress and dopaminergic neuron degeneration.
MAO-B is structurally similar to MAO-A, requiring FAD as a cofactor. The enzyme exists as a homodimer with each monomer containing a binding site for FAD.
| Property |
Value |
| Gene |
MAOB |
| UniProt |
P27338 |
| Molecular Weight |
~58 kDa (520 amino acids) |
| Subcellular Localization |
Outer mitochondrial membrane |
| Tissue Expression |
Brain (astrocytes, substantia nigra), peripheral tissues |
| Cofactor |
FAD (covalently bound) |
| PDB Structure |
1OJD, 2V5Z |
The active site contains:
- FAD-binding domain: Covalent attachment to cysteine residue
- Substrate cavity: Hydrophobic pocket for phenylethylamine
- Ile/Asn/Val region: Determines substrate specificity (MAO-B prefers phenylethylamine over serotonin)
MAO-B catalyzes the oxidative deamination of monoamines:
- Phenylethylamine (PEA): Primary endogenous substrate — converts to phenylacetaldehyde
- Benzylamine: Trace amine substrate
- Dopamine: With lower affinity than MAO-A
- Methylhistamine: Histamine metabolite
The reaction produces:
- Corresponding aldehyde
- Hydrogen peroxide (H₂O₂) — contributes to oxidative stress
- Ammonia
MAO-B is central to PD pathophysiology:
- Increased Activity: MAO-B activity increases with age (doubles by age 70) and is elevated in PD
- Dopamine Metabolism: Produces toxic byproducts (H₂O₂, aldehydes) that contribute to oxidative stress and mitochondrial dysfunction
- MPTP Toxicity: MAO-B converts MPTP to MPP+, the toxic metabolite that selectively destroys dopaminergic neurons
- Neuroinflammation: MAO-B activity in glial cells contributes to neuroinflammation
- Clinical Target: MAO-B inhibitors (selegiline, rasagiline, safinamide) are standard PD therapy
- DATATOP Study: Demonstrated selegiline slows disease progression in untreated early PD patients
- TEMPO Trial: Rasagiline showed disease-modifying potential in early PD
- Age-Related Increase: MAO-B activity doubles in the aging brain, correlating with increased PD risk
- Oxidative Stress: Contributes to ROS generation
- Amyloid Pathology: Interacts with amyloid processing via shared signaling pathways
- Combination Therapy: MAO-B inhibitors being explored in AD as adjunct therapy
| Drug |
Type |
Clinical Use |
Dose |
Key Points |
| Selegiline |
Irreversible |
Early PD, depression |
5-10 mg/day |
First approved MAO-B inhibitor; also has amphetamine-like metabolites |
| Rasagiline |
Irreversible |
Early/mid PD |
1 mg/day |
More potent than selegiline; single daily dose; TEMPO trial showed benefits |
| Safinamide |
Reversible |
Mid/late PD (add-on) |
50-100 mg/day |
Reversible binding; allows enzymatic activity return on discontinuation |
- Enzyme Inhibition: Covalent (selegiline, rasagiline) or reversible (safinamide) binding to FAD
- Dopamine Preservation: Reduced metabolism → increased synaptic dopamine
- Neuroprotection: Prevents formation of toxic metabolites (H₂O₂, aldehydes)
- Glial Modulation: Reduces MAO-B activity in astrocytes and microglia
- Symptomatic: Increases dopamine via reduced metabolism
- Disease-Modifying: Prevents formation of toxic metabolites
- Motor Fluctuations: Reduces "wearing-off" phenomenon
- Combination Therapy: Used with levodopa/carbidopa in advanced PD
- DATATOP (Selegiline): Pivotal trial showing slowed disease progression
- TEMPO (Rasagiline): Disease modification evidence in early PD
- MOTION (Safinamide): Demonstrated efficacy as add-on therapy
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Ouyang S et al. MAO-B inhibitors in Parkinson's disease: A comprehensive review. Neuropharmacology. 2023
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Chen X et al. MAO-B inhibitors and neuroinflammation in Parkinson's disease. Br J Clin Pharmacol. 2024