Discovery of a natural thiamine adenine nucleotide

Bettendorff, Lucien; Wirtzfeld, Barbara; Makarchikov, Alexander F; Mazzucchelli, Gabriel; Frédérich, Michel; Gigliobianco, Tiziana; Gangolf, Marjorie; Pauw, Edwin De; Angenot, Luc; Wins, Pierre

doi:10.1038/nchembio867

Cited by 101 publications

(139 citation statements)

References 8 publications

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“…AThTP was synthesized according to the method described by Bettendorff et al ( 9 ) The compound was initially purified by solid phase extraction on a MEGA Bond Elut ® C 18 (Varian Inc., Harbor City, CA, USA) cartridge. After passage of the water solution of the crude compound, the cartridge was washed with water.…”

Section: Methodsmentioning

confidence: 99%

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Tanaka

Yamamoto

Sato

et al. 2011

J Nutr Sci Vitaminol

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Summary Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been demonstrated to result in various stress-related diseases, including diabetes mellitus. Deficiency of cellular nicotinamide adenine dinucleotide (NAD ϩ ) content, consumed by PARP-1 to add ADP-ribose moieties onto target proteins, contributes to pathophysiological conditions. Adenosine thiamine triphosphate (AThTP) exists in small amounts in mammals; however, the function(s) of this metabolite remains unresolved. The structure of AThTP resembles NAD Substantial recent experimental studies demonstrate beneficial impacts of high-dose thiamine on diabetic complications, such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and diabetic cardiomyopathy ( 1-4 ). However, the pharmacological relevance of high-dose thiamine treatments remains unknown.Chronic hyperglycemia results in diabetic complications in target organs. The pathogenic effect of high glucose is, at least partially, mediated to a significant extent through increased production of reactive oxygen species and reactive nitrogen species and subsequent oxidative stress (reviewed in Evans et al. ( 5 )). Increased oxidative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 activation depletes its substrate, nicotinamide adenine dinucleotide (NAD ϩ ), and also covalently attaches branched nucleic acid-like polymers of poly(ADP-ribose) to various acceptor proteins (reviewed in Kiss and Szabó ( 6 )). A covalently attached ADP-ribose polymer, poly(ADP-ribosylation, affects the function of target proteins. The involvement of PARP-1 activation in the pathogenesis of diabetes and its complications has recently been emphasized by both in vivo and in vitro studies (reviewed in Pacher and Szabó ( 7 ), and Szabó ( 8 )). NAD ϩ , used as substrate for PARP-1, consists of two nucleotides joined through their phosphate groups, with one nucleotide containing an adenine base and the other containing nicotinamide.Adenosine thiamine triphosphate (AThTP), a new thiamine derivative, was recently identified in Escherichia coli ( 9 ), followed by the identification in small amounts in mouse brain, heart, skeletal muscle, liver and kidneys ( 10 ). AThTP is composed of two molecules, an adenine base and thiamine, which are joined through phosphate groups. The structure of AThTP appears to closely resemble NAD ϩ . Although the biological role of AThTP is unknown, the existence of noncoenzyme functions of thiamine derivatives has been speculated (11)(12)(13)(14).In the context of 1) structural resemblance of AThTP to NAD ϩ , 2) the experimental evidence implicating PARP-1 as a causative factor in the pathogenesis of diabetes and diabetic complications in vitro and in vivo (reviewed in Szabó ( 8 )), and 3) beneficial effects of highdose thiamine on diabetic complications, we hypothesized that AThTP could interact with PARP-1 and mod-E-mail: t.tanaka.md@gmail.com Abbreviations: AThTP, adenosine thiamine triphosphate; NAD ϩ , nicotinamide adenine dinucleotide; PARP...

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Section: Methodsmentioning

confidence: 99%

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Tanaka

Yamamoto

Sato

et al. 2011

J Nutr Sci Vitaminol

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“…Moreover, intracellular thiamine and thiamine phosphate pools are regulated by various stress conditions in Z. mays and A. thaliana seedlings; it was suggested that thiamine is a signalling molecule important for the adaptation to various stress conditions 47,48 . Interestingly, such a signalling role is assigned to unphosphorylated thiamine in plants, while it should be assigned to ThTP and AThTP in E. coli 5,6,12 (see above). Note that in Arabidopsis leaves, ThTP accumulates during withering 49 .…”

Section: Thiamine In Stress Diabetes and Neurodegenerative Diseasesmentioning

confidence: 99%

“…2): thiamine monophosphate (ThMP), thiamine triphosphate (ThTP), adenosine thiamine triphosphate (AThTP) and adenosine thiamine diphosphate 5,6 . The existence of such forms in many living cells would suggest that they also have some biological role(s).…”

Section: Introductionmentioning

confidence: 99%

Biological functions of thiamine derivatives: Focus on non-coenzyme roles

Bettendorff¹,

Wins²

2013

OA Biochemistry

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“…The pyrimidine nucleus also establishes the major part of vital molecules including vitamins such as thiamine, 4 riboflavin, 5 and folic acid. 6 Derivatives of pyrimidine have a long and distinguished history extending from the days of their discovery as important constituents of nucleic acids to their current use in the chemotherapy of acquired immunodeficiency syndrome (AIDS).…”

Section: 3mentioning

confidence: 99%

The Antifungal Effect of some 4-Chloro-6-Methoxy-N, N-Dimethylpyrimidin-2-Amine Derivatives Containing a Heterocyclic Compound on the Important types of Fungi

Jafar¹,

Mahdi²,

Hadwan³

et al. 2017

JYP

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Objective: 4-methoxy-N, N-dimethyl-6-(phenylthio) pyrimidin-2-amine, 4-(benzo [d]thiazol-2-ylthio)-6-methoxy-N,N-dimethylpyrimidin-2-amine, 4-(4-(1,2,3-selenadiazol-4-yl)phenoxy)-6-methoxy-N,N-dimethylpyrimidin-2-amine and 4-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-6-methoxy-N,N-dimethylpyrimidin-2-amine have been synthesized. Method: The prepared compounds were synthesized by nucleophilic displacement of chloride substituted in pyrimidine heterocyclic ring. Results: The synthesized compounds were being identified by different methods included TLC technique, IR, 1H-NMR and 13C-NMR spectrophotometers. All compounds confirmed by elemental analysis. The biological activity of these new compounds investigated against some fungi like Aspergillus terreus and Aspergillus niger, the results was Aspergillus terreus more effected by antifungal compare with Aspergillus niger, the effect ration 0.98, 1.32 with 200µM respectively and the compound number (2) has more effect than other compounds. Conclusion: It is concluded that synthesized dimethylpyrimidin-derivatives are biologically active and developed into useful Antifungal agents. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Discovery of a natural thiamine adenine nucleotide

Cited by 101 publications

References 8 publications

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Biological functions of thiamine derivatives: Focus on non-coenzyme roles

The Antifungal Effect of some 4-Chloro-6-Methoxy-N, N-Dimethylpyrimidin-2-Amine Derivatives Containing a Heterocyclic Compound on the Important types of Fungi

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