Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A

Friberg, Anders; Rehwinkel, Hartmut; Nguyen, Duy Duc; Pütter, Vera; Quanz, Maria; Weiske, Jörg; Eberspächer, Uwe; Heisler, Iring; Langer, Gernot

doi:10.1021/acsomega.0c00715

Cited by 25 publications

(21 citation statements)

References 45 publications

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“…This inhibitor was highly selective towards LDH-5, which is coherent with the lower stability of LDH-5 J o u r n a l P r e -p r o o f tetrameric complex. 36 Such selectivity profile is also consistent with the higher destabilizing effect that LP-22 displays on LDH-5 compared to LDH-1. Consistently with our previous report on LDH tetramer disruptors, 16 LDH destabilization was also dependent on protein concentration, as an increasing amount of subunit reverted the effect ( Figure S2).…”

Section: Identification Of Peptide Ligands Of the Ldh Tetrameric Intesupporting

confidence: 73%

“…29,34 Recently, new advances in the development of ligands targeting LDH oligomeric interface have offered new avenues towards LDH inhibition. 16,35,36 Targeting protein self-association is an emerging concept in drug design that can bring several advantages over classical orthosteric inhibition. First, targeting the LDH oligomeric interface could unravel new allosteric sites, potentially leading to compounds displaying improved drug-like features compare to LDH active site inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…To this end, tool compounds able to target the LDH oligomeric interface instead of its active site have been recently developed. 16,[35][36][37] Targeting a protein oligomeric state is still an underexplored strategy that can provide several benefits over active-site targeting, and could thus overcome the existing difficulties encountered with LDH orthosteric inhibitors. Targeting LDH selfassembly could indeed lead to the identification of new and potentially more druggable allosteric sites.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides

Thabault

Liberelle

Koruza

et al. 2021

Journal of Biological Chemistry

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Section: Identification Of Peptide Ligands Of the Ldh Tetrameric Intesupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides

Thabault

Liberelle

Koruza

et al. 2021

Journal of Biological Chemistry

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“…These inhibitors bound to an allosteric site located at the interface between two monomers, a region less conserved compared with the cofactor and pyruvate-binding sites. 33 In our study, the xanthine derivatives were highly selective for MTHFD2 over MTHFD1. They bound to an allosteric site with a low sequence identity between MTHFD2 and MTHFD1.…”

Section: Discussionmentioning

confidence: 49%

Xanthine Derivatives Reveal an Allosteric Binding Site in Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2)

et al. 2021

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Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in one-carbon metabolism. The MTHFD2 gene is upregulated in various cancers but very low or undetectable in normal proliferating cells, and therefore a potential target for cancer treatment. In this study, we present the structure of MTHFD2 in complex with xanthine derivative 15 , which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by 15 . Allosteric inhibitors often provide good selectivity and, indeed, xanthine derivatives are highly selective for MTHFD2. Moreover, several conformational changes were observed upon the binding of 15 , which impeded the binding of the cofactor and phosphate to MTHFD2. To the best of our knowledge, this is the first study to identify allosteric inhibitors targeting the MTHFD family and our results would provide insights on the inhibition mechanism of MTHFD proteins and the development of novel inhibitors.

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“…However, its binding conformation of MA remains controversial because steric clashes of the protein-ligand interactions have been observed. Recently, selective allosteric inhibitors of the human LDHA isoenzyme with submicromolar activity in vitro 41 . Two compounds with selectivity against LDHA are bound to a novel binding site adjacent 20 / to the active site.…”

Section: Discussionmentioning

confidence: 99%

Identification of the First Highly Selective inhibitor of Human Lactate Dehydrogenase B

Shibata¹,

Sogabe²,

Miwa³

et al. 2021

Preprint

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Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+ and has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have yet to be reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. The screening campaign identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography identified its binding with the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers was critical for enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.

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Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A

Cited by 25 publications

References 45 publications

Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides

Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides

Xanthine Derivatives Reveal an Allosteric Binding Site in Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2)

Identification of the First Highly Selective inhibitor of Human Lactate Dehydrogenase B

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