Abstract
In the human brain, isoquinolines are synthesized from catecholamines, β-phenylethylamine, and indoleamines, and their involvement in the pathogenesis of Parkinson’s disease has been intensively investigated. The Pictet-Spengler reaction nonenzymatically produces racemic isoquinolines, but the predominant occurrence of (R)-enantiomers in the human brain and the selective toxicity suggest the involvement of enantio-specific enzyme system. This paper presents the characteristics of enzymes in the synthesis and bioactivation and the molecular mechanism behind the selective degeneration of dopamine neurons. In the human brain, (R)salsolinol synthase catalyzes the synthesis of (R)salsolinol from dopamine and acetaldehyde or pyruvic acid, N-methyltransferase converts (R)salsolinol into 2(N)-methyl-(R)salsolinol, and an oxidase oxidizes it into toxic cation, 1,2-dimethyl-5,6-dihydroxy-isoquinolinium ion. Dopaminergic neurotoxicity of N-methyl-(R)salsolinol was proven by preparation of a rat model and in cellular models. In parkinsonian patients, N-methyl-(R)salsolinol levels increase in the cerebrospinal and intraventricular fluid, and the toxic 1,2-dimethyl- 5,6-dihydroxyiosquinolinium ion is accumulated in the substantia nigra. The activity of a neural (R)salsolinol N-methyltransferase is significantly higher in parkinsonian lymphocytes than in control. Similar enzymatic processes produce dopaminergic neurotoxins from phenylethylamine-derived isoquinolines and indoleamine-derived β-carbolines. Involvement of the enzyme systems in the pathogenesis of Parkinson’s disease is discussed.
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Abbreviations
- β-CB:
-
β-Carboline
- CSF:
-
Cerebrospinal fluid
- DA:
-
Dopamine
- IQ:
-
Isoquinoline
- IVF:
-
Intraventricular fluid
- MAO-A, MAO-B:
-
Type A and B monoamine oxidase
- Me:
-
Methyl
- N-MT:
-
N-methyltransferase
- NAM:
-
Nicotinamide
- PD:
-
Parkinson’s disease
- PEA:
-
Phenylethylamine
- ROS, RNS:
-
Reactive oxygen and nitrogen species
- Sal:
-
Salsolinol
- SAM:
-
S-adenosyl-L-methionine
- SN:
-
Substantia nigra
- TH:
-
Tyrosine hydroxylase
- UPS:
-
Ubiquitin-proteasome system
- TIQ:
-
1,2,3,4-Tetrahydroisoquinoline
- *:
-
Abbreviations of isoquinolines are presented in Tables 1, 3, and 5.
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Naoi, M., Maruyama, W. (2021). N-Methyl-(R)salsolinol and Enzymes Involved in Enantioselective Biosynthesis, Bioactivation, and Toxicity in Parkinson’s Disease. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_10-1
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