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Structures of Lactate Dehydrogenase A (LDHA) In Apo, Ternary an Inhibitor-Bound Forms

Resource type
Date created
2015-02-09
Authors/Contributors
Abstract
Lactate dehydrogenase (LDH) is an essential metabolic enzyme that catalyzes the interconversion of pyruvate and lactate using NADH/NAD + as a co-substrate. Many cancer cells exhibit a glycolytic phenotype known as the Warburg effect, in which elevated LDH levels enhance the conversion of glucose to lactate, making LDH an attractive therapeutic target for oncology. Two known inhibitors of the human muscle LDH isoform, LDHA, designated 1 and 2 , were selected, and their IC 50 values were determined to be 14.4 ± 3.77 and 2.20 ± 0.15 µ M , respectively. The X-ray crystal structures of LDHA in complex with each inhibitor were determined; both inhibitors bind to a site overlapping with the NADH-binding site. Further, an apo LDHA crystal structure solved in a new space group is reported, as well as a complex with both NADH and the substrate analogue oxalate bound in seven of the eight molecules and an oxalate only bound in the eighth molecule in the asymmetric unit. In this latter structure, a kanamycin molecule is located in the inhibitor-binding site, thereby blocking NADH binding. These structures provide insights into LDHA enzyme mechanism and inhibition and a framework for structure-assisted drug design that may contribute to new cancer therapies
Document
Identifier
DOI: 10.1107/S1399004714024791
Published as
Kolappan, S., Shen, D. L., Mosi, R., Sun, J., McEachern, E. J., Vocadlo, D. J., & Craig, L. (2015). Structures of lactate dehydrogenase A (LDHA) in apo, ternary and inhibitor-bound forms. Acta Crystallographica Section D, 71(2), 185–195. https://doi.org/10.1107/S1399004714024791.
Publication title
Acta Crystallographica Section D
Document title
Structures of Lactate Dehydrogenase A (LDHA) In Apo, Ternary an Inhibitor-Bound Forms
Date
2015
Volume
71
Issue
2
First page
185
Last page
195
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language
English

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