[Monoamine oxidase B](/mechanisms/mao-b-pathway) (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](/diseases/parkinsons-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.
Structure
MAO-B is structurally similar to [MAO-A](/proteins/mao-a-protein), requiring FAD as a cofactor. The enzyme exists as a homodimer with each monomer containing a binding site for FAD.
Active Site Architecture
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)
Normal Function
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](/proteins/mao-a-protein)
Methylhistamine: Histamine metabolite
The reaction produces:
Corresponding aldehyde
Hydrogen peroxide (H₂O₂) — contributes to oxidative stress
Ammonia
Role in Neurodegeneration
Parkinson's Disease
MAO-B is central to [PD pathophysiology](/mechanisms/dopamine-metabolism):
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](/mechanisms/oxidative-stress) and [mitochondrial dysfunction](/mechanisms/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](/mechanisms/neuroinflammation-pathway)
Clinical Target: MAO-B inhibitors ([selegiline](/therapeutics/selegiline), [rasagiline](/therapeutics/rasagiline), [safinamide](/therapeutics/safinalide)) are standard PD therapy
Key Evidence
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
Alzheimer's Disease
Oxidative Stress: Contributes to [ROS](/entities/reactive-oxygen-species) generation
Amyloid Pathology: Interacts with amyloid processing via shared signaling pathways
Combination Therapy: MAO-B inhibitors being explored in AD as adjunct therapy
Therapeutic Targeting
Approved MAO-B Inhibitors
Mechanism of Action
Enzyme Inhibition: Covalent (selegiline, rasagiline) or reversible (safinamide) binding to FAD
TEMPO (Rasagiline): Disease modification evidence in early PD
MOTION (Safinamide): Demonstrated efficacy as add-on therapy
Key Publications
[Riederer P, Laux G. MAO-inhibitors in Parkinson's disease. Exp Neurobiol. 2011;20(1):1-17.](https://pubmed.ncbi.nlm.nih.gov/21366356/)
[Mandel S, Grunblatt E, Riederer P, Youdim MB. Neuroprotective strategies in Parkinson's disease: the GPAP approach. Ann N Y Acad Sci. 2003;991:318-330.](https://pubmed.ncbi.nlm.nih.gov/14578002/)
[Tetrud JW, Langston JW. The effect of selegiline (L-deprenyl) on the natural history of Parkinson's disease. Science. 1989;245(4917):519-522.](https://pubmed.ncbi.nlm.nih.gov/2545833/)
[Ouyang S et al. MAO-B inhibitors in Parkinson's disease: A comprehensive review. Neuropharmacology. 2023](https://doi.org/10.1016/j.neuropharm.2023.109480)
[Chen X et al. MAO-B inhibitors and neuroinflammation in Parkinson's disease. Br J Clin Pharmacol. 2024](https://doi.org/10.1111/bcp.16012)