Evidence map›Paper›PMID 39332648›Full record

ArticleBioorganic & medicinal chemistry letters2024

AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs.

Nicole Wandrey, Luke Hamilton, Jake Boley, Alexis Haynes, Makenna Redinger, Mackinzi Hill, Mackenzie Hagemeister, Philip A Cole, Michael A Moxley, Allen A Thomas

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry letters, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Hydantion indolinones as AANAT inhibitors.Bioorganic & medicinal chemistry letters · 2026
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Nicole WandreyDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Luke HamiltonDepartment of Biology, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Jake BoleyDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Alexis HaynesDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Makenna RedingerDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Mackinzi HillDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Mackenzie HagemeisterDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Philip A ColeDivision of Genetics, Department of Medicine, Brigham and Women's Hospital; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Michael A MoxleyDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
Allen A ThomasDepartment of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA. Electronic address: thomasaa@unk.edu.

Funding

UNMC Structural Biology CoreP20GM103427 · NIGMS · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI PAUL L SORGEN · 2012 to 2026
$59.2M
Chemical Approaches to Understanding Reversible Lysine ModificationsR35GM149229 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI PHILIP A COLE · 2023 to 2026
$1.9M
Serotonin N-Acetyl-Transferase Inhibitors for Circadian Rhythm DisordersR15HL165700 · NHLBI · UNIVERSITY OF NEBRASKA KEARNEY · PI THOMAS, ALLEN · 2022 to 2022
$395k
NHLBI NIH HHS R15 HL165700NIGMS NIH HHS P20 GM103427NIGMS NIH HHS R35 GM149229
6 · The paper itself

Abstract

Arylalkylamine N-acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT's alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT's alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism.

Indexed as

Arylalkylamine N-AcetyltransferaseTryptaminesDose-Response Relationship, DrugEnzyme InhibitorsHumansKineticsMolecular StructureStructure-Activity RelationshipArylalkylamine N-AcetyltransferaseEnzyme InhibitorstryptamineTryptaminesAcetyl transferaseCircadian rhythmEnzyme modelsMelatonin

Identifiers

PMID39332648
PMCPMC11729038

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.