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PDBsum entry 4zvv
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4zvv
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PDB id:
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| Name: |
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Oxidoreductase/oxidoreductase inhibitor
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Title:
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Lactate dehydrogenase a in complex with a trisubstituted piperidine-2, 4-dione inhibitor gne-140
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Structure:
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L-lactate dehydrogenase a chain. Chain: a, b, c, d. Synonym: ldh-a,cell proliferation-inducing gene 19 protein,ldh muscle subunit,ldh-m,renal carcinoma antigen ny-ren-59. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ldha, pig19. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.20Å
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R-factor:
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0.233
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R-free:
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0.259
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Authors:
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Y.Li,Z.Chen,C.Eigenbrot
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Key ref:
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A.Boudreau
et al.
(2016).
Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.
Nat Chem Biol,
12,
779-786.
PubMed id:
DOI:
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Date:
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18-May-15
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Release date:
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18-May-16
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PROCHECK
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Headers
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References
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P00338
(LDHA_HUMAN) -
L-lactate dehydrogenase A chain from Homo sapiens
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Seq:
Struc:
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332 a.a.
331 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.1.1.1.27
- L-lactate dehydrogenase.
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Reaction:
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(S)-lactate + NAD+ = pyruvate + NADH + H+
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(S)-lactate
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+
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NAD(+)
Bound ligand (Het Group name = )
corresponds exactly
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=
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pyruvate
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+
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NADH
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Nat Chem Biol
12:779-786
(2016)
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PubMed id:
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Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.
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A.Boudreau,
H.E.Purkey,
A.Hitz,
K.Robarge,
D.Peterson,
S.Labadie,
M.Kwong,
R.Hong,
M.Gao,
C.Del Nagro,
R.Pusapati,
S.Ma,
L.Salphati,
J.Pang,
A.Zhou,
T.Lai,
Y.Li,
Z.Chen,
B.Wei,
I.Yen,
S.Sideris,
M.McCleland,
R.Firestein,
L.Corson,
A.Vanderbilt,
S.Williams,
A.Daemen,
M.Belvin,
C.Eigenbrot,
P.K.Jackson,
S.Malek,
G.Hatzivassiliou,
D.Sampath,
M.Evangelista,
T.O'Brien.
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ABSTRACT
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Metabolic reprogramming in tumors represents a potential therapeutic target.
Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA)
inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in
vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected
global metabolism, although cell death only occurred after 2 d of continuous
LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation
(OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could
be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired
resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling
pathway, which led to increased OXPHOS, and inhibitors targeting this pathway
could prevent resistance. Thus, combining an LDHA inhibitor with compounds
targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the
clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but
also reduce the emergence of resistance to LDHA inhibition.
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Links
