C-Labeled Diethyl Ketoglutarate Derivatives As Hyperpolarized Probes of 2-Ketoglutarate Dehydrogenase Activity

Overview

Journal Anal Sens

Specialty Biochemistry

Date 2022 Jun 7

PMID 35669533

Authors

Jaspal Singh

Eul Hyun Suh

Gaurav Sharma

Jun Chen

Edward P Hackett

Xiaodong Wen

A Dean Sherry

Chalermchai Khemtong

Craig R Malloy

Jae Mo Park

Zoltan Kovacs

Affiliations

Soon will be listed here.

Abstract

The TCA cycle is a central metabolic pathway for energy production and biosynthesis. A major control point of metabolic flux through the cycle is the decarboxylation of 2-ketoglutarate by the TCA cycle enzyme 2-ketoglutarate dehydrogenase (2-KGDH). In this project, we developed C labeled 2-ketoglutarate derivatives to monitor 2-KGDH activity in vivo. C NMR analysis of liver extracts revealed that uniformly C labeled 2-ketogutarate, in its cell permeable ester form, was rapidly taken up and hydrolyzed in liver and underwent extensive metabolism to produce labeled glutamate, succinate, lactate and other metabolites. Diethyl [1,2-C]-2-ketoglutarate was successfully polarized by dynamic nuclear polarization and within seconds after injection into rats, the probe produced hyperpolarized [C]bicarbonate in the liver reflecting flux through the TCA cycle. These experiments demonstrate that this tracer offers the possibility of directly monitoring flux through 2-KGDH in vivo.

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