Probing the ligand preferences of the three types of bacterial pantothenate kinase

Guan, Jinming; Barnard, Leanne; Cresson, Jeanne; Hoegl, Annabelle; Chang, Julia Yu Fong; Strauss, Erick; Auclair, Karine

doi:10.1016/j.bmc.2018.10.042

Cited by 7 publications

(14 citation statements)

References 32 publications

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“…However, pantetheine analogues are important lead compounds as inhibitors of pantothenate kinase, 59,60 a key enzyme in the biosynthesis of CoA which is a validated target for antimicrobial chemotherapy. A range of structural mimics of pantetheine side chains have therefore been developed, 45,48,61,62 and these were used as a starting point for the present study. Prior to the synthesis of further analogues, alternative esterification conditions for the coupling of the tail to the linker moiety were investigated, and it was found that the use of DIC as the coupling agent gave the highest yields.…”

Section: Role Of the Pantetheine Tailmentioning

confidence: 99%

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties

Bellany¹,

Tsuchiya

Tran³

et al. 2020

Bioorganic & Medicinal Chemistry

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The Aurora kinases are a family of highly homologous serine/threonine kinases, 1,2,3 which have welldocumented roles in the control of meiosis, mitosis and cell division. 4 There are three distinct subfamilies, Aurora A, Aurora B and Aurora C, which vary in their function and subcellular location.Since the first observation of the overexpression of Aurora kinases in cancer cell lines by Bischoff et al., 5 they have been regarded as promising drug targets for cancer chemotherapy. Aurora A overexpression is frequently detected in leukemia, breast, prostate and colon cancers, 2,5,6 with a lower overall survival rate seen in colorectal cancer patients with increased Aurora A levels. 7 This has seen a number of Aurora kinase inhibitors progressing through different stages of clinical trials. 3,8,9,10,11 The Aurora kinases are highly homologous, with a highly conserved C-terminal catalytic domain, a short N-terminal domain which varies in size, and an activation loop (Asp274-Glu299) which is conserved between the three family members. 3 The kinase activity of Aurora A is dependent on autophosphorylation of Thr288 (and possibly Thr287), found in the activation loop. In addition, binding of Aurora A to microtubule-associated proteins, in particular TPX2, alters the structure of Aurora A by stabilisation of the activation loop, allowing ATP to bind and driving the kinase into the optimal conformation for catalysis. 1,3,12 Inhibition of Aurora A results in inhibition of this phosphorylation, giving delayed entry into mitosis and the failure of the centrosomes to assemble bipolar spindles, resulting in aneuploidy and mitotic arrest. 13 Different conformational states of Aurora A can be induced or stabilised by different small molecule inhibitors, 14,15,16,17 and in particular the conformation of the activation loop modulates the interaction of Aurora A with its binding partners. 18 Coenzyme A (CoA) is an essential and ubiquitous cofactor made from vitamin B5 (pantothenate), ATP, and cysteine. CoA and its thioester derivatives (Acetyl CoA, Malonyl CoA, HMG CoA among others) are involved in diverse anabolic and catabolic pathways, biosynthesis of neurotransmitters and the regulation of gene expression. 19,20 Dysregulation of CoA biosynthesis or CoA thioester homoeostasis is associated with various human pathologies, including neurodegeneration, cancer and metabolic disorders. [21][22][23][24] Recent studies have uncovered a novel function of CoA in redox regulation, involving covalent modification of cellular proteins by disulphide bond formation, termed CoAlation, in cellular response to oxidative and metabolic stress. 25,26 Protein CoAlation is a widespread and reversible posttranslational modification, which occurs in single-cell and multicellular organisms, and modulates catalytic activity, regulatory interactions, subcellular localization and the stability of modified proteins. [27][28][29][30] Recently, we have reported that CoA is a specific ATP-competitive Aurora A inhibitor in vitro. 31 Using a combination of bioc...

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Section: Role Of the Pantetheine Tailmentioning

confidence: 99%

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties

Bellany¹,

Tsuchiya

Tran³

et al. 2020

Bioorganic & Medicinal Chemistry

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“…In a related study, Guan et al., extended the strategy of probing potential ligand preferences for PanK inhibition and interaction against all three PanK subtypes. However, on this occasion, the modifications focussed on the primary and secondary alcohols, the β‐alanine moiety and the germinal dimethyls . The results of this study indicated that a manner of inhibitory selectivity between type I, II and III could be introduced through subtle modifications to the primary alcohol, as illustrated by preferential binding of compounds 7 ( Ec PanK I), 8 ( Sa PanK II) and 9 ( Pseudomonas aeruginosa PanK III), while diketone 10 , had no preference.…”

Section: Anti‐bacterial Agentsmentioning

confidence: 90%

“…Furthermore, they identified that removal of the geminal methyl moieties ( 11 ) disrupted interactions with PanK I and II, while this compound remained a viable substrate for PanK III. Furthermore, modifications to the β‐alanine portion such as with compound 12 , tended to hinder interaction with PanK II, whilst maintaining interaction with type I and II enzymes, indicating the potential for selective inhibitors…”

Section: Anti‐bacterial Agentsmentioning

confidence: 99%

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

Veale

Müller

2020

ChemMedChem

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Global advancements in biological technologies have vastly increased the variety of and accessibility to bioassay platforms, while simultaneously improving our understanding of druggable chemical space. In the South African context, this has resulted in a rapid expansion in the number of medicinal chemistry programmes currently operating, particularly on university campuses. Furthermore, the modern medicinal chemist has the advantage of being able to incorporate data from numerous related disciplines into the medicinal chemistry process, allowing for informed molecular design to play a far greater role than previously possible. Accordingly, this review focusses on recent highlights in drug-discovery programmes, in which South African medicinal chemistry groups have played a substantive role in the design and optimisation of biologically active compounds which contribute to the search for promising agents for infectious disease.

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“…Structure-activity relationships (SARs) of the antimicrobial activity of pantothenamides however remain complex as they must account for cell permeability, the enzymatic transformation by one or more enzymes and the numerous potential targets of the active product [105]. Pantothenamides have been modified at the primary and secondary alcohols [94,106], the geminal dimethyl group [101,[105][106][107][108][109], the β-alanine chain [79,94,102,106,[110][111], the substituents at the C-1 amide [32,79,81,[94][95][100][101][102]106,109,[112][113], and the amide bond itself has been replaced with other groups [103,[113][114]. Minor alterations are often sufficient to completely shift the spectrum of antimicrobial activity or suppress all activity.…”

Section: Figure 2: Examples Of Pantothenamidesmentioning

confidence: 99%

“…These include numerous pantothenamides with the following C-1 amide modifications accepted by both EcPanKI and SaPanKII: linear or branched chain, with or without heteroatoms, aromatic groups, and bulky rings [94,[101][102]. Substitution of either methyl group of the geminal dimethyl moiety with small or moderately bulky groups are also typically tolerated by EcPanKI and SaPanKII, in contrast to removal of the methyl groups which is not [106]. Shortening the β-alanine chain is acceptable with both enzymes, whereas lengthening the β-alanine chain is not productive with EcPanKI [102,106].…”

Section: Substrate Specificity Of Pank Enzymesmentioning

confidence: 99%

The coenzyme A biosynthetic pathway: A new tool for prodrug bioactivation

Duncan

Auclair

2019

Archives of Biochemistry and Biophysics

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Prodrugs account for more than 5% of pharmaceuticals approved worldwide. Over the past decades several prodrug design strategies have been firmly established; however, only a few functional groups remain amenable to this approach. The aim of this overview is to highlight the use of coenzyme A (CoA) biosynthetic enzymes as a recently explored bioactivation scheme and provide information about its scope of utility. This emerging tool is likely to have a strong impact on future medicinal and biological studies as it offers promiscuity, orthogonal selectivity, and the capability of assembling exceptionally large molecules.

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Probing the ligand preferences of the three types of bacterial pantothenate kinase

Cited by 7 publications

References 32 publications

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

The coenzyme A biosynthetic pathway: A new tool for prodrug bioactivation

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