Glutaminolysis: a result of the truncyted citrate cycle

In differentiated tissues acetyl CoA is converted to CO2 and energy via the citrate cycle.

Metabolic scheme

In tumor cells, the citrate cycle is truncated due to a selective inactivation of the Fe2+ - containing aconitase and the NADH dehydrogenases (complexes I and III of the respiratory chain) by reactive oxygen species (ROS), such as OH, O2- and 1O2.

In normal cells, superoxide radicals are immediately inactivated by high activities of mitochondrial (Mn SOD) and cytosolic (CuZn SOD) superoxide dismutase and glutathione peroxidase, which are greatly reduced during tumor formation.

Overexpression of the mitochondrial superoxid dismutase reduces cell proliferation and tumor specific morphology.

Overexpression of cytosolic dismutase induces senescence.

On the other hand, tumor pre-stages, polyps and tumor cells over - express mitochondrial phosphate-dependent and phosphate-independent glutaminase.

Phosphate-dependent and -independent glutaminase are responsible for the deamination of glutamine to glutamate which opens up the possibility of a new energy - producing pathway: the degradation of glutamine to lactate.

Cytosolic glutamine synthetase, the enzyme that catalyzes the reverse reaction (amination of glutamate to glutamine), is consistently reduced in tumor cells.

A further enzymatic characteristic of tumor cells is the low glutamate dehydrogenase activity, whereby the mitochondrial isoenzyme is totally lost.

Data

Since glutamate pyruvate transaminase activity is low in tumor cells, the release of NH3 from glutamate mainly takes place via the following transaminase reactions:

- glutamate oxaloacetate transaminase
The amino group of glutamate is transferred to oxaloacetate under the production of aspartate.
Aspartate is the precursor of nucleic acid synthesis.

Metabolic scheme

- serine pyruvate transaminase
The amino group of serine is transferred to pyruvate under the production of alanine. Alanine is released.

- 3-phosphohydroxypyruvate glutamate transaminase
The amino group of glutamate is transferred to 3-phosphohydroxypyruvate under the production of P-serine. P-serine is dephosphorylated to serine which can be further converted to glycine and C1 groups. Glycine and C1 groups are precursor for nucleic acid synthesis. A part of the amino acids glycine and serine are released.

Metabolic scheme

Glycine is immunosuppresive and may protect tumor cells from immune attack.

Due to the special enzymatic characteristics of tumor cells, one of the following two consequences for the citrate cycle can occur depending upon the oxygen supply:

Consequences for the citrate cycle under physiological pO2

Consequences for the citrate cycle at low pO2