Structural role of the active‐site metal in the conformation of <i>Trypanosoma brucei</i> phosphoglycerate mutase

Mercaldi, Gustavo Fernando; Pereira, H.M.; Cordeiro, Artur T.; Michels, Paul A.M.; Thiemann, Otávio Henrique

doi:10.1111/j.1742-4658.2012.08586.x

Cited by 18 publications

(17 citation statements)

References 35 publications

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“…X-ray crystal structures have been obtained for the enzymes derived from two trypanosomatids and several bacterial species8252627.…”

Section: Resultsmentioning

confidence: 99%

“…The glycolytic phosphoglycerate mutase, iPGM is an attractive target for the development of broad spectrum antiparasitic and antibacterial agents owing to its essential metabolic function and evolutionary divergence from the human enzyme1025. Infectious organisms potentially susceptible to an iPGM inhibitor are responsible for diseases ranging from African trypanosomiasis (sleeping sickness), lymphatic filariasis (elephantiasis tropica), onchocerciasis (river blindness), Staphylococcus aureus toxic shock syndrome and Bacillus anthracis intoxication.…”

Section: Discussionmentioning

confidence: 99%

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Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Dranchak

et al. 2017

Nat Commun

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Glycolytic interconversion of phosphoglycerate isomers is catalysed in numerous pathogenic microorganisms by a cofactor-independent mutase (iPGM) structurally distinct from the mammalian cofactor-dependent (dPGM) isozyme. The iPGM active site dynamically assembles through substrate-triggered movement of phosphatase and transferase domains creating a solvent inaccessible cavity. Here we identify alternate ligand binding regions using nematode iPGM to select and enrich lariat-like ligands from an mRNA-display macrocyclic peptide library containing >1012 members. Functional analysis of the ligands, named ipglycermides, demonstrates sub-nanomolar inhibition of iPGM with complete selectivity over dPGM. The crystal structure of an iPGM macrocyclic peptide complex illuminated an allosteric, locked-open inhibition mechanism placing the cyclic peptide at the bi-domain interface. This binding mode aligns the pendant lariat cysteine thiolate for coordination with the iPGM transition metal ion cluster. The extended charged, hydrophilic binding surface interaction rationalizes the persistent challenges these enzymes have presented to small-molecule screening efforts highlighting the important roles of macrocyclic peptides in expanding chemical diversity for ligand discovery.

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“…X-ray crystal structures have been obtained for the enzymes derived from two trypanosomatids and several bacterial species8252627.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Dranchak

et al. 2017

Nat Commun

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“…In the absence of published empirical evidence that nematode iPGAMs can be potently and specifically modulated by drug-like molecules, advancing them as drug targets appears highly challenging and risky. We would also advise caution in the pursuit of non-nematode iPGAMs like the Trypanosoma brucei iPGAM [34], [35] as drug targets, since their druggability remains uncertain.…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structure of the B. stearothermophilus iPGAM does indicate a “gate” region peptide over the active site that could prevent access by potential inhibitors (see above [12], [29]). More recent studies on the crystalized structure of Tryanosoma brucei iPGAM also indicate that when crystalized in the presence of substrate, the substrate is buried and is not solvent-accessible, again suggesting a gate-like fold over the active site [35] that may increase the difficulty of finding inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens

Crowther

Booker²,

et al. 2014

PLoS Negl Trop Dis

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Cofactor-independent phosphoglycerate mutase (iPGAM) is essential for the growth of C. elegans but is absent from humans, suggesting its potential as a drug target in parasitic nematodes such as Brugia malayi, a cause of lymphatic filariasis (LF). iPGAM's active site is small and hydrophilic, implying that it may not be druggable, but another binding site might permit allosteric inhibition. As a comprehensive assessment of iPGAM's druggability, high-throughput screening (HTS) was conducted at two different locations: ∼220,000 compounds were tested against the C. elegans iPGAM by Genzyme Corporation, and ∼160,000 compounds were screened against the B. malayi iPGAM at the National Center for Drug Screening in Shanghai. iPGAM's catalytic activity was coupled to downstream glycolytic enzymes, resulting in NADH consumption, as monitored by a decline in visible-light absorbance at 340 nm. This assay performed well in both screens (Z′-factor >0.50) and identified two novel inhibitors that may be useful as chemical probes. However, these compounds have very modest potency against the B. malayi iPGAM (IC50 >10 µM) and represent isolated singleton hits rather than members of a common scaffold. Thus, despite the other appealing properties of the nematode iPGAMs, their low druggability makes them challenging to pursue as drug targets. This study illustrates a “druggability paradox” of target-based drug discovery: proteins are generally unsuitable for resource-intensive HTS unless they are considered druggable, yet druggability is often difficult to predict in the absence of HTS data.

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“…Oxoacyl acyl-carrier-protein reductase (OAR) 2C07 [198] Peptide deformylase (PDF) 1JYM [199]; 1RL4, 1RQC [200] Peroxisomal targeting signal 1 (PTS1) 3CV0, 3CVL, CVN, 3CVP, 3CVQ [201] Peroxisomal targeting signal 2 (PTS2) 2F2J [110] Phosphethanolamine methyltransferase (PMT) 3UJ6, 3UJ7, 3UJ8, 3UJ9, 3UJA, 3UJB [202] Phosphodiesterase B1 (PDEB1) 2R8Q [203] 4I15 [204] Phosphodiesterase C (PDEC) 3V93 [205]; 3V94 [206] Phosphoenolpyruvate carboxykinase (PEPCH) 1II2 [207] Phosphofructokinase (PFK) 3F5M [208] 6-Phosphoglucolactonase (6PGL) 2J0E [209]; 3E7F, 3EB9 [210] 6-Phosphogluconate dehydrogenase (6PGDH) 1PGJ [211] Phosphoglucose isomerase (PGI) 1Q50, 1T10 [212] 2O2C, 2O2D [213] Phosphoglycerate kinase (PGK) 3OZA, 3OZ7 [214] 13PK [215]; 16PK [216] Phosphoglycerate mutase (PGAM) 3IGY, 3IGZ [217] 3EOZ [218] 3NVL [219] [220] 3F9R [221] Plasmepsin I (PMI) 2R9B [222]; 3QRV, 3QS1 [223];…”

Section: Brucei T Cruzimentioning

confidence: 99%

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

Ogungbe

Setzer

2016

Molecules

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Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp.

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Structural role of the active‐site metal in the conformation of Trypanosoma brucei phosphoglycerate mutase

Cited by 18 publications

References 35 publications

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

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