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De Novo Acetate Production is Coupled to Central Carbon Metabolism in Mammals

29 Pages Posted: 4 Apr 2018 Sneak Peek Status: Published

See all articles by Xiaojing Liu

Xiaojing Liu

Duke University - Department of Pharmacology and Cancer Biology

Daniel E. Cooper

Duke University - Department of Radiation Oncology

Ahmad A. Cluntun

Duke University - Department of Pharmacology and Cancer Biology

Marc O. Warmoes

Duke University - Department of Pharmacology and Cancer Biology

Steven Zhao

University of Pennsylvania - Department of Cancer Biology

Michael A. Reid

Duke University - Department of Pharmacology and Cancer Biology

Juan Liu

Duke University - Department of Pharmacology and Cancer Biology

Kathryn E. Wellen

University of Pennsylvania - Department of Cancer Biology

David G. Kirsch

Duke University - Department of Radiation Oncology

Jason W. Locasale

Duke University - Department of Pharmacology and Cancer Biology

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Abstract

In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient not presently known to be produced de novo in mammals. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.

Suggested Citation

Liu, Xiaojing and Cooper, Daniel E. and Cluntun, Ahmad A. and Warmoes, Marc O. and Zhao, Steven and Reid, Michael A. and Liu, Juan and Wellen, Kathryn E. and Kirsch, David G. and Locasale, Jason W., De Novo Acetate Production is Coupled to Central Carbon Metabolism in Mammals (2018). Available at SSRN: https://ssrn.com/abstract=3155509 or http://dx.doi.org/10.2139/ssrn.3155509
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Xiaojing Liu

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Daniel E. Cooper

Duke University - Department of Radiation Oncology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Ahmad A. Cluntun

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Marc O. Warmoes

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Steven Zhao

University of Pennsylvania - Department of Cancer Biology

Philadelphia, PA 19104
United States

Michael A. Reid

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Juan Liu

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Kathryn E. Wellen

University of Pennsylvania - Department of Cancer Biology ( email )

Philadelphia, PA 19104
United States

David G. Kirsch

Duke University - Department of Radiation Oncology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Jason W. Locasale (Contact Author)

Duke University - Department of Pharmacology and Cancer Biology ( email )

100 Fuqua Drive
Durham, NC 27708-0204
United States

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