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Issue 13, 2021
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Metabolic mechanisms of a drug revealed by distortion-free 13C tracer analysis

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Abstract

Metabolomic isotopic tracing can provide flux information useful for understanding drug mechanisms. For that, NMR has the unique advantage of giving positional isotope enrichment information, but the current 13C 1D NMR approach suffers from low sensitivity and high overlaps. We developed a new 2D heteronuclear NMR experiment incorporating J-scaling and distortion-free elements that allows for quantitative analysis of multiplets with high sensitivity and resolution. When applied to an old chemotherapeutic drug, the approach provided a quantitative estimation of TCA-cycle turns, confirming the conventional mechanism of its mitochondrial metabolic enhancement. Additionally, the approach identified a new mechanism of the higher contribution of the pentose phosphate pathway to serine synthesis in the cytosolic compartment, possibly explaining the broad pharmacological activities of the drug. Our approach may prove beneficial in helping to find new usages or metabolic mechanisms of other drugs.

Graphical abstract: Metabolic mechanisms of a drug revealed by distortion-free 13C tracer analysis

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Supplementary files

Article information


Submitted
25 Nov 2020
Accepted
22 Feb 2021
First published
24 Feb 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021,12, 4958-4962
Article type
Edge Article

Metabolic mechanisms of a drug revealed by distortion-free 13C tracer analysis

J. W. Cha, X. Jin, S. Jo, Y. J. An and S. Park, Chem. Sci., 2021, 12, 4958 DOI: 10.1039/D0SC06480G

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