Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, The resulting acetyl-CoA enters the citric acid cycle (or Krebs Cycle ), where the acetyl group of the acetyl-CoA is converted into carbon dioxide by two. La citrate synthase (CS) est une acyltransférase qui catalyse la réaction: acétyl- CoA + H2O + oxaloacétate → citrate + CoA. Cette enzyme intervient à la 1re. This could arise from glutamate oxidation to a-ketoglutarate entry into the Krebs cycle and direct conversion to OAA as is described for tumour cell glutaminolysis .

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The re-emergence of interest in intermediary metabolism and the development of metabolomics in relation to cancer and other diseases provide a timely reason to revisit issues of tumour cell metabolism. In this review, we address the issue of the role of high aerobic glycolysis, which is commonly associated with the metabolism of many tumour cells.

The concept presented emphasises the importance of the glycolysis-citrate-lipogenesis pathway in providing the synthetic and bioenergetic requirements that are essential for the growth and proliferation of tumour cells.

We hope that our discussion will be informative and instructive, and will stimulate interest and research regarding the intermediary metabolism and its regulation in tumour cells. We express our appreciation to the many pioneering and contemporary researchers whose studies provide much of the basis for this presentation. With great respect, we borrow the question raised by the distinguished biochemist, Dr.

Only few investigators studied this phenomenon and for 50 years no answer was forthcoming to the basic question: Why do tumour cells glycolyse? The question was raised by Racker and Spector in regard to the issue of the mechanism responsible for the acceleration of aerobic glycolysis in tumour cells.


We employ this question to address a different issue; namely, what is the importance of or reason for the transition to a high aerobic metabolism by tumour cells. This too has been an intriguing question that over the ccle 70 years has been addressed in numerous and excellent reports e.

The current re-emergence of interest in intermediary metabolism kerbs the development of metabolomics in relation to cancer and other diseases provide a timely reason to revisit this issue of tumour metabolism. The question, while important, is essentially rhetorical for which a definitive answer cannot be proven.

Concurrence or disagreement with the viewpoint that will be presented becomes the decision of the reader. Moreover, we hope and welcome concurring and opposing responses; as well as expanded information that we might have omitted due to krbes and space limitations of this presentation. The intermediary metabolism of any cell is determined by and geared to the activities of the cell. As such, it has one function in life.

Its purpose is to grow and proliferate. It lives to reproduce; to insure its generational propagation. It does so at the expense and destruction of its host. These are the criteria of a parasitic life-style. To do so place tumour cells in the same category as normal undifferentiated cells e. Stem cells, like tumour ells, also exist to grow and proliferate; but they do so for the purpose of differentiating into specialised cells that perform specific functions.

They proliferate to maintain a continual population for further differentiation. The primary purpose of the intermediary metabolism of the tumour cell must be to facilitate the major purpose of its existence; krebss is its dedication to a parasitic existence of reproduction, i. There is no other purpose or function of tumour cells!

Essentially all the malignant activities of tumour cells e. The intermediary metabolism must provide the bioenergetic and synthetic requirements that are most important to support growth and proliferation of the parasitic tumour cell. The increase in total cell mass kebs the proliferating dd cells necessitates a net increase te lipid biosynthesis, especially for increased membranogenesis. In other words, proliferating tumour cells are prolific lipogenic cells.



Indeed, the importance of increased lipogenesis to cancer cell existence is well exemplified in the recent thoughtful paper of Menendez et al. To address this question, we propose that new metabolism definitions are essential.

However, under aerobic conditions glycolysis is defined as the conversion of glucose to pyruvate, and occurs in essentially all mammalian cells. The difference is whether pyruvate is reduced to lactic acid as the cyclw or if pyruvate is further metabolised. However, contemporarily, the two pathways are commonly used synonymously.

For the following discussion, we will re-define the terminology of ey pathways of glucose utilisation in cells in relation to their tissue environment. Based on these relationships, the following pathways and bioenergetics of glucose utilisation are relevant to the question at hand.

In contrast, the extensive review by Pedersen [ cyvle ] leads to the conclusion that highly glycolytic tumour cells do retain shuttle capacity for oxidation of glycolytic generated NADH.

Difference Between Glycolysis and Krebs (citric acid) Cycle

However, neither pathway 1 nor 2 is applicable to the metabolism of proliferating tumour cells. These cells require a pathway in which citrate production is an end-product of glucose utilisation. Consequently, a third pathway must be defined. Therefore, this pathway exists in these cells in a hypoxic environment. We cannot imply that limited cellular oxygen availability is the direct cause of the failure of citrate oxidation. cyle

It is possible that hypoxic induced signalling pathways are involved. It is also possible for this pathway to exist under normoxic conditions, as it does in normal citrate-producing prostate epithelial cells [ 14 — 18 ]. In those cells, m-aconitase activity is inhibited by mitochondrial zinc, which prevents citrate oxidation. A replaceable source of OAA is required in this metabolic pathway.

In prostate epithelial cells, mitochondrial aspartate transamination with glutamate provides the source of OAA [ 141517 ]. In those cells, citrate is the major end-product of intermediary metabolism and involves the loss of six carbons from the metabolic pool. In contrast, the incorporation of citrate for lipogenesis results in the utilisation of two carbons AcCoA ; so that a four-carbon source of OAA can be regenerated for additional citrate synthesis.

Therefore, the critical pathway in tumour cells becomes. If not, a new source of OAA must be provided.

This could arise from glutamate oxidation to a-ketoglutarate entry into the Krebs cycle and direct conversion to OAA as is described for tumour cell glutaminolysis. An alternative pathway involves the transamination of glutamate with aspartate as a source of OAA as shown below. This is the pathway of net citrate production Fig. The overall reaction is.

We relate tumour cell metabolism to normal prostate cell krebbs as both being cyclee cells. The essential difference is that the fate of citrate in the prostate cells is its accumulation for secretion rather than for utilisation in lipogenesis. Df operation of this pathway depends upon the utilisation and depletion of OAA, and a continual available source of aspartate. Otherwise the direction of the mAAT reaction will be reversed.

Prostate cells contain a high-affinity aspartate transporter that provides for cellular import of aspartate to maintain its high cellular availability for citrate production. For this pathway to occur in tumour cells would require that any operation of glutaminolysis does not involve the glutamate-OAA transaminase reaction. The pathway of net citrate glycooyse in normal prostate epithelial cells. Zinc inhibits m-aconitase activity. Aspartate transamination provides the source of OAA and glucose provides acetyl CoA for continued citrate synthesis.


The tumour cell glucose utilisation would have to increase fold to achieve the same bioenergetic results of the normoxic glycolytic pathway. This is the nature of a successful parasitic existence.

The tumour cells efficiently extract glucose from and at the expense of the host, and then employ effective adaptive metabolic activities suited to their circumstances.

This could provide the bioenergetic requirements for the interim survival of the tumour cells in an arrested state while awaiting a forthcoming oxygenating environment. We propose that the accelerated aerobic glycolysis exists primarily for the purpose of providing a readily available source of AcCoA for mitochondrial synthesis of citrate.

The citrate then provides the source of cytosolic AcCoA for the lipogenic demands of the tumour cells for their avid purpose of growth and proliferation.

A number of relationships provide support for this concept Fig. The thick solid arrows represent the pathway in which the lipogenic carbon source is totally derived from glucose.

The thin arrows represent the aspartate-glutamate transamination pathway as an alternate source of OAA as occurs in normal prostate cells, Fig. The dotted arrows represent a pathway of glutaminolysis as a source of OAA.

Once synthesised, the fate of ef citrate becomes critical. There are two alternatives for mitochondrial citrate utilisation: This leads to another consideration. If m-aconitase activity is not limiting in tumour cells, the intramitochondrial citrate is subjected to both oxidation and export.

Parlo and Coleman [ 819 ee suggest that the up-regulation and rapidity of the citrate exporter depletes the availability of citrate for oxidation via the Krebs cycle. However, if m-aconitase activity is glycolysw limiting, the intramitochondrial citrate will exist in equilibrium with isocitrate, which is rapidly oxidised by IDH. Under these conditions, the extent of citrate availability for export will be dependent upon the rapidity of the export process.

Therefore, both citrate oxidation for energy production and citrate export for lipogenesis will co-exist. The combination of both events would become dependent upon the rate of citrate synthesis. To maintain a continual citrate availability to sustain its oxidation and export will require an increased production of pyruvate and OAA and a non-limiting citrate synthase activity.

Citrate synthase — Wikipédia

The consideration of these relationships leads to some dilemma. The stoichiometery of glucose utilised and products produced needs to be addressed.

Then one would expect that the major end-products of glucose utilisation would be some combination of lactic acid, citrate, and CO 2. As best that we could ascertain from a literature search, no such information has been reported. There are many reports of product-formation from glucose, but apparently none that provides this stoichiometry.

A simple measurement of the existing level of cit-rate even with CO 2 production would not be equivalent to the level of citrate production.

This reflects the major metabolic adaptation and priority of tumour cells to optimise their capability to import and glycolytically utilise glucose; i. The accelerated rate of conversion of glucose to pyruvate exceeds the rate of pyruvate oxidation. As concluded by Pedersen [ 9 ], this accumulating pyruvate is subjected to reduction of lactate. The oxidation of pyruvate might be further impaired by the export g,ycolyse citrate. The truncated Krebs cycle eliminates the re-cycling of OAA, which is essential for condensation of the acetyl CoA produced by pyruvate oxidation.

The AcCoA imposes a product inhibition on pyruvate dehydrogenase activity. Therefore, the further oxidation of g,ycolyse must await the production of OAA from an alternative source. Until then, the excess pyruvate is reduced to lactic acid.