Inhibition of pyruvate decarboxylase from Z. mobilis by novel analogues of thiamine pyrophosphate: investigating pyrophosphate mimics

Erixon, Karl M.; Dabalos, Chester L.; Leeper, Finian J.

doi:10.1039/b615861g

Cited by 19 publications

(19 citation statements)

References 22 publications

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“…Compound 6 thus obtained displayed proton and 13 C NMR spectra identical to the described values 20. Finally, formation of the pyrimidine ring was accomplished in two steps 19,26. The aldehyde was condensed with β-anilinopropionitrile to give α,β-unsaturated nitrile 7 , as a Z isomer.…”

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confidence: 75%

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A protecting group-free synthesis of deazathiamine: A step toward inhibitor design

Zhao

Carvalho

Nathan

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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The discovery of 3-deazathiamine diphosphate (deazaThDP) as a potent inhibitor analog of the cofactor thiamine diphosphate (ThDP) has highlighted the need for an efficient and scalable synthesis of deazaThDP. Such a method would facilitate development of analogs with the ability to inhibit individual ThDP-dependent enzymes selectively. Toward the goal of developing selective inhibitors of the mycobacterial enzyme 2-hydroxy-3-oxoadipate synthase (HOAS), we report an improved synthesis of deazaThDP without use of protecting groups. Tribromo-3-methylthiophene served as a versatile starting material whose selective functionalization permitted access to deazaThDP in five steps, with potential to make other analogs accessible in substantial amounts.The emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis poses a global threat.1 , 2 New anti-infectives are needed to combat tuberculosis and other infectious diseases that are becoming resistant to the current arsenal of drugs. An estimated one-third of the global population is infected with Mycobacterium tuberculosis. Although most hosts do not develop active disease, tuberculosis kills almost two million people worldwide every year.3 M. tuberculosis adapts its metabolism to survive under adverse conditions in the host, such as nutrient deprivation, hypoxia, acidification and oxidative stress.4 One approach to finding new anti-infectives against tuberculosis is to design inhibitors that target biochemical pathways used by the pathogen to survive in the host.It was recently demonstrated that M. tuberculosis organizes a tricarboxylic acid (TCA) cycle that lacks the α-ketoglutarate dehydrogenase complex (KDH).5 The TCA cycle is an essential pathway used by aerobic organisms to metabolize carbohydrates, amino acids and fatty acids to produce energy, reducing power and biosynthetic precursors. In the canonical TCA cycle, KDH carries out decarboxylation of α-ketoglutarate, producing succinyl-CoA, which is then converted to succinate. Lack of KDH activity is a TCA cycle variant common among anaerobic bacteria and microaerophiles.6 It was initially proposed that the M. tuberculosis enzyme Rv1248c converts α-ketoglutarate to succinate via an α-ketoglutarate © 2010 Elsevier Ltd. All rights reserved.Correspondence to: Ouathek Ouerfelli. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript decarboxylase (Kgd)-mediated decarboxylation of α-ketoglutarate to succinic semialdehyde (SSA), followed by ox...

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confidence: 75%

“…We have developed a concise and general synthetic route to deazaTh. This report is a formal synthesis of deazaThDP since the transformation of the former to the latter has been described previously18,19 and worked in our hands.…”

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confidence: 87%

A protecting group-free synthesis of deazathiamine: A step toward inhibitor design

Zhao

Carvalho

Nathan

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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“…These side effects may rely on interactions with enzymes involved in thiamine pyrophosphate metabolic pathways. Indeed it has been shown that triazole-derivatives of thiamine pyrophosphate inhibit enzymes involved in the biosynthesis of TPP in vitro (Erixon and Dabalos, 2007). …”

Section: Discussionmentioning

confidence: 99%

Novel TPP-riboswitch activators bypass metabolic enzyme dependency

et al. 2014

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Riboswitches are conserved regions within mRNA molecules that bind specific metabolites and regulate gene expression. TPP-riboswitches, which respond to thiamine pyrophosphate (TPP), are involved in the regulation of thiamine metabolism in numerous bacteria. As these regulatory RNAs are often modulating essential biosynthesis pathways they have become increasingly interesting as promising antibacterial targets. Here, we describe thiamine analogs containing a central 1,2,3-triazole group to induce repression of thiM-riboswitch dependent gene expression in different E. coli strains. Additionally, we show that compound activation is dependent on proteins involved in the metabolic pathways of thiamine uptake and synthesis. The most promising molecule, triazolethiamine (TT), shows concentration dependent reporter gene repression that is dependent on the presence of thiamine kinase ThiK, whereas the effect of pyrithiamine (PT), a known TPP-riboswitch modulator, is ThiK independent. We further show that this dependence can be bypassed by triazolethiamine-derivatives that bear phosphate-mimicking moieties. As triazolethiamine reveals superior activity compared to pyrithiamine, it represents a very promising starting point for developing novel antibacterial compounds that target TPP-riboswitches. Riboswitch-targeting compounds engage diverse endogenous mechanisms to attain in vivo activity. These findings are of importance for the understanding of compounds that require metabolic activation to achieve effective riboswitch modulation and they enable the design of novel compound generations that are independent of endogenous activation mechanisms.

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“…Two inhibitors with marginally less potency than 3‐deazaThDP but which can be obtained much more easily in four synthetic steps are the triazole analogues 6 ( K i = 20 p m ) and 7 ( K i = 30 p m against Zm PDC) (Fig. 6) [37]. A disadvantage of these triazole compounds is that they cannot be functionalized at the 2‐position to produce analogues of reaction intermediates.…”

Section: Modifications To the Thiazolium Ringmentioning

confidence: 99%

“…With this in mind, a number of analogues of ThDP have been synthesized with isosteres of the diphosphate group (Fig. 8) [37].…”

Section: Diphosphate Group Mimicsmentioning

confidence: 99%

Thiamin diphosphate in biological chemistry: analogues of thiamin diphosphate in studies of enzymes and riboswitches

Agyei-Owusu

Leeper

2009

The FEBS Journal

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The role of thiamin diphosphate (ThDP) as a cofactor for enzymes has been known for many decades. This minireview covers the progress made in understanding the catalytic mechanism of ThDP‐dependent enzymes through the use of ThDP analogues. Many such analogues have been synthesized and have provided information on the functional groups necessary for the binding and catalytic activity of the cofactor. Through these studies, the important role of hydrophobic interactions in stabilizing reaction intermediates in the catalytic cycle has been recognized. Stable analogues of intermediates in the ThDP‐catalysed reaction mechanism have also been synthesized and crystallographic studies using these analogues have allowed enzyme structures to be solved that represent snapshots of the reaction in progress. As well as providing mechanistic information about ThDP‐dependent enzymes, many analogues are potent inhibitors of these enzymes. The potential of these compounds as therapeutic targets and as important herbicidal agents is discussed. More recently, the way that ThDP regulates the genes for its own biosynthesis through the action of riboswitches has been discovered. This opens a new branch of thiamin research with the potential to provide new therapeutic targets in the fight against infection.

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Inhibition of pyruvate decarboxylase from Z. mobilis by novel analogues of thiamine pyrophosphate: investigating pyrophosphate mimics

Abstract: Replacement of the thiazolium ring of thiamine pyrophosphate with a triazole gives extremely potent inhibitors of pyruvate decarboxylase from Z. mobilis, with K(I) values down to 20 pM; this system was used to explore pyrophosphate mimics and several effective analogues were discovered.

Cited by 19 publications

References 22 publications

A protecting group-free synthesis of deazathiamine: A step toward inhibitor design

A protecting group-free synthesis of deazathiamine: A step toward inhibitor design

Novel TPP-riboswitch activators bypass metabolic enzyme dependency

Thiamin diphosphate in biological chemistry: analogues of thiamin diphosphate in studies of enzymes and riboswitches

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