TY - JOUR
T1 - Hyperpolarized [5-13C,4,4-2H2,5-15N]-L-glutamine provides a means of annotating in vivo metabolic utilization of glutamine
AU - Eskandari, Roozbeh
AU - Kim, Nathaniel
AU - Mamakhanyan, Arsen
AU - Saoi, Michelle
AU - Zhang, Guannan
AU - Berishaj, Marjan
AU - Granlund, Kristin L.
AU - Poot, Alex J.
AU - Cross, Justin
AU - Thompson, Craig B.
AU - Keshari, Kayvan R.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Elisa de Stanchina and the antitumor assessment core for assistance with tumor xenograft experiments and in vivo tracing experiments. We thank George Sukenick and Rong Wang for assistance with NMR and high resolution mass spectrometry characterization. This work was supported in part by the NIH (R01CA237466 to K.R.K. and P30CA008748 to Memorial Sloan Kettering Cancer Center); the Center for Molecular Imaging and Nanotechnology at Memorial Sloan Kettering Cancer Center (Tow Foundation Postdoctoral Fellowship to R.E.); the Geoffrey Beene Award (to K.R.K. and C.B.T.); and the Thompson Family Foundation (to K.R.K.).
Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/5/10
Y1 - 2022/5/10
N2 - Glutamine is consumed by rapidly proliferating cells and can provide the carbon and nitrogen required for growth through various metabolic pathways. However, delineating the metabolic fate of glutamine is challenging to interrogate in vivo. Hyperpolarized magnetic resonance, by providing high transient nuclear magnetic resonance signals, provides an approach to measure fast biochemical processes in vivo. Aminohydrolysis of glutamine at carbon-5 plays an important role in providing nitrogen and carbon for multiple pathways. Here, we provide a synthetic strategy for isotope-enriched forms of glutamine that prolongs glutamine-C5 relaxation times and thereby reveals in vivo reactions involving carbon-5. We investigate multiple enrichment states, finding [5-13C,4,4-2H2,5-15N]-L-glutamine to be optimal for hyperpolarized measurement of glutamine conversion to glutamate in vivo. Leveraging this compound, we explore pancreatic cancer glutamine metabolism in vivo. Taken together, this work provides a means for studying glutamine metabolic flux in vivo and demonstrates on-target effects of metabolic enzyme inhibitors.
AB - Glutamine is consumed by rapidly proliferating cells and can provide the carbon and nitrogen required for growth through various metabolic pathways. However, delineating the metabolic fate of glutamine is challenging to interrogate in vivo. Hyperpolarized magnetic resonance, by providing high transient nuclear magnetic resonance signals, provides an approach to measure fast biochemical processes in vivo. Aminohydrolysis of glutamine at carbon-5 plays an important role in providing nitrogen and carbon for multiple pathways. Here, we provide a synthetic strategy for isotope-enriched forms of glutamine that prolongs glutamine-C5 relaxation times and thereby reveals in vivo reactions involving carbon-5. We investigate multiple enrichment states, finding [5-13C,4,4-2H2,5-15N]-L-glutamine to be optimal for hyperpolarized measurement of glutamine conversion to glutamate in vivo. Leveraging this compound, we explore pancreatic cancer glutamine metabolism in vivo. Taken together, this work provides a means for studying glutamine metabolic flux in vivo and demonstrates on-target effects of metabolic enzyme inhibitors.
KW - cancer metabolism
KW - magnetic resonance imaging
KW - pancreatic cancer
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U2 - 10.1073/pnas.2120595119
DO - 10.1073/pnas.2120595119
M3 - Article
C2 - 35512101
AN - SCOPUS:85129396416
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
M1 - e2120595119
ER -
