Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug.

Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug. Research Abstract Details 

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Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug. Abstract Text:

Yousang Hwang,Surajit Ganguly,Anthony K Ho,David C Klein,Philip A Cole,

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) regulates the daily rhythm in the production of melatonin and is therefore an attractive target for pharmacologic modulation of the synthesis of this hormone. Previously prepared bisubstrate analogs show potent inhibition of AANAT but have unfavorable pharmacokinetic properties due to the presence of phosphate groups which prevents transfer across the plasma membrane. Here, we examine a bis-pivaloyloxymethylene (POM)-tryptamine-phosphopantetheine prodrug (2) and its biotransformations in vitro by homogenates and pineal cells. Compound 2 is an efficient porcine liver esterase substrate for POM cleavage in vitro although cyclization of the phosphate moiety is a potential side product. Tryptamine phosphopantetheine (3) is converted to tryptamine-coenzyme A (CoA) bisubstrate analog (1) by human phosphoribosyl pyrophosphate amidotransferase (PPAT) and dephosphocoenzyme A kinase (DPCK) in vitro. Compound 2 was found to inhibit melatonin production in rat pineal cell culture. It was also found that the POM groups are readily removed to generate 3; however, further processing to tryptamine-CoA (1) is much slower in pineal extracts or cell culture. Implications for CoA prodrug development based on the strategy used here are discussed.

Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug. Publishing Authors By Initials

Y Hwang,S Ganguly,AK Ho,DC Klein,PA Cole,

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Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Intr

Journal: Bioorganic & medicinal chemistry

VOLUME: 15

Page Numbers: 2147-55

Journal Abbreviation: Bioorg. Med. Chem.

ISSN: 0968-0896

DAY: 13

MONTH: 12

YEAR: 2006

Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9413298

Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug. Keywords Mesh Terms:

KEYWORDS: Spectrometry, Mass, Electrospray Ionizat

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug. Information

Substance Name: Arylalkylamine N-Acetyltransferase

Registry Number: EC 2.3.1.87

Grant and Affiliation Information for Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug.

AFFILIATION: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Country: England

AGENCY: United States NIA

GRANT: R01 AG019186-06

ACRONYM: AG

MEDLINETA: Bioorg Med Chem

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