Differential 3-bromopyruvate inhibition of cytosolic and mitochondrial human serine hydroxymethyltransferase isoforms, key enzymes in cancer metabolic reprogramming

Paiardini, Alessandro; Tramonti, Angela; Schirch, Doug; Guiducci, Giulia; Salvo, Martino L. di; Fiascarelli, Alessio; Giorgi, Alessandra; Maras, Bruno; Cutruzzolà, Francesca; Contestabile, Roberto

doi:10.1016/j.bbapap.2016.08.010

Cited by 41 publications

(34 citation statements)

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“…Moreover, specific alkylation of proteins by 3-BP is dependent on biochemical properties of target amino acids to create nucleophilic site [43]. Alkylation-dependent inhibition of target enzymes by 3-BP could mostly implicate modification of substrate binding active site [15,44,45] In case of enzymes with lower dissociation constants namely SDH and PGK, the H-bonding involved Gly 52 and Arg 398 and Arg 39 and Gly 397 whereas for PDH it was through Tyr 89 . An overall analysis of amino acids involved in docking revealed the implication of Arg, Asn.…”

Section: Resultsmentioning

confidence: 99%

“…However, the precise mechanisms underlying the antitumor actions are still under extensive investigation. The main mechanism by which 3-BP is understood to exert its antineoplastic action is by hampering ATP generation, which is generally attributed to the wide spectrum of metabolic targets inhibited by 3-BP including: hexokinase 2 (HK 2), 3-phosphoglycerate kinase (PGK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH), pyruvate dehydrogenase complex (PDC), succinate dehydrogenase (SDH), α-ketoglutarate dehydrogenase, isocitrate dehydrogenase (IDH), glyoxalase 1 & 2 and serine hydroxyethyltransferase [10,12–15]. Further, most of these target enzymes of 3-BP are found to be specifically up-regulated in cancer cells [1,2].…”

Section: Introductionmentioning

confidence: 99%

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Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: Implication in designing of novel anticancer therapeutic strategies

et al. 2017

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Altered metabolism is an emerging hallmark of cancer, as malignant cells display a mammoth up-regulation of enzymes responsible for steering their bioenergetic and biosynthetic machinery. Thus, the recent anticancer therapeutic strategies focus on the targeting of metabolic enzymes, which has led to the identification of specific metabolic inhibitors. One of such inhibitors is 3-bromopyruvate (3-BP), with broad spectrum of anticancer activity due to its ability to inhibit multiple metabolic enzymes. However, the molecular characterization of its binding to the wide spectrum of target enzymes remains largely elusive. Therefore, in the present study we undertook in silico investigations to decipher the molecular nature of the docking of 3-BP with key target enzymes of glycolysis and TCA cycle by PatchDock and YASARA docking tools. Additionally, derivatives of 3-BP, dibromopyruvate (DBPA) and propionic acid (PA), with reported biological activity, were also investigated for docking to important target metabolic enzymes of 3-BP, in order to predict their therapeutic efficacy versus that of 3-BP. A comparison of the docking scores with respect to 3-BP indicated that both of these derivatives display a better binding strength to metabolic enzymes. Further, analysis of the drug likeness of 3-BP, DBPA and PA by Lipinski filter, admetSAR and FAF Drug3 indicated that all of these agents showed desirable drug-like criteria. The outcome of this investigation sheds light on the molecular characteristics of the binding of 3-BP and its derivatives with metabolic enzymes and thus may significantly contribute in designing and optimizing therapeutic strategies against cancer by using these agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: Implication in designing of novel anticancer therapeutic strategies

et al. 2017

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“…Tumour cells recycle one-carbon units from different amino acids within the folate and methionine cycles to produce the building blocks needed to sustain high proliferation rates [1][2][3]. Given its pivotal role in OCM, it is not surprising that SHMT is considered a potential drug target for cancer therapy [4][5][6][7]. Serine fuels the folate cycle through the reaction catalysed by serine hydroxymethyltransferase (SHMT) that reversibly interconverts serine and tetrahydrofolate (THF) to glycine and 5,10-methylene-THF (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1). Given its pivotal role in OCM, it is not surprising that SHMT is considered a potential drug target for cancer therapy [4][5][6][7]. SHMT is a pyridoxal-5 0 -phosphate (PLP)dependent enzyme that exists in two main isoforms, which localize in the cytosol (SHMT1) and in the mitochondria (SHMT2).…”

Section: Introductionmentioning

confidence: 99%

The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells

et al. 2018

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“…(FU et al, 2005;HOPKINS;SCHIRCH, 1986), e assim identificar semelhanças e diferenças entre TcSHMT e as enzimas de humanos. Esse tipo de estudo tem demonstrado que possíveis inibidores podem ter efeitos diferentes entre isoformas de SHMTs do mesmo organismo ou entre SHMTs de espécies do mesmo gênero (CHANG et al, 2007;PAIARDINI et al, 2016;. Este tipo de abordagem seria interessante e pode no futuro validar TcSHMT como um atraente alvo quimioterápico, como já tem sido feito para diversos tipos de tumores (HISHIDA et al, 2003;BAUMANN, 1998;WANG et al, 2014) e para outros protozoários parasitas (MAENPUEN et al, 2009).…”

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Metabolismo de serina: caracterização de serina hidroximetiltransferase de <i>Trypanosoma cruzi</i>.

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Chagas' disease is a disorder caused by the protozoan parasite Trypanosoma cruzi, which affects about 10 million people, mainly in the Americas. T. cruzi uses amino acids as an important energy source and in several biological processes such as differentiation, resistance to stress conditions and in the host-cell invasion. Serine is involved in many biosynthetic pathways. One of the relevant functions of serine is the formation of C1 compounds for the biosynthesis of nucleotides. The use of serine for that purpose is initiated by Serine Hydroxymethyltransferase, whose activity was detected in T. cruzi but its role in the biology of parasite remains poorly explored. In this work we identified a putative gene encoding a SHMT with dual localization, cytoplasmic and mitochondrial. We generated a single knockout cell line by homologous recombination in which one allele of SHMT was replaced by the neomycin phosphotransferase gene. Knockout parasites showed no difference in epimastigote growth rate or in in vitro metacyclogenesis. However, knockout parasites showed a significant decrease in both, infection index and in the number of trypomastigotes released from CHO-K1cells infected with knockout metacyclic forms.

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Differential 3-bromopyruvate inhibition of cytosolic and mitochondrial human serine hydroxymethyltransferase isoforms, key enzymes in cancer metabolic reprogramming

Cited by 41 publications

References 58 publications

Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: Implication in designing of novel anticancer therapeutic strategies

Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: Implication in designing of novel anticancer therapeutic strategies

The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells

Metabolismo de serina: caracterização de serina hidroximetiltransferase de <i>Trypanosoma cruzi</i>.

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