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N-Methyl-(R)salsolinol and Enzymes Involved in Enantioselective Biosynthesis, Bioactivation, and Toxicity in Parkinson’s Disease

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Handbook of Neurotoxicity

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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 chapter 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

*:

Abbreviations of isoquinolines are presented in Tables 1, 3, and 5.

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

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  1. Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, Nissin, Aichi, Japan

    Makoto Naoi & Wakako Maruyama

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  1. Makoto Naoi
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  2. Wakako Maruyama
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Correspondence to Makoto Naoi .

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  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Naoi, M., Maruyama, W. (2022). 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/10.1007/978-3-031-15080-7_10

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