Discoveries – TKTL1

In 1995, I identified a gene that was structurally similar to the gene containing the blueprint for the enzyme transketolase (TKT). Due to this fact, the gene and the enzyme formed from it were given the name Transketolase-like 1 (TKTL1). The numerous molecular and evolutionary insights gained since then have shown that the TKTL1 gene has mutated during vertebrate evolution and that the function of the TKTL1 enzyme has changed fundamentally.

TKTL1 – Enzyme with new function

In contrast to the original transketolase, which catalysis a two-substrate reaction, TKTL1 enables a metabolic pathway that has not yet been described in human biology and medicine textbooks:

A single-substrate reaction in which the five-sugar (pentose, C5 unit) xylulose-5-phosphate is converted to glyceraldehyde-3-phosphate (C3 unit) and a C2 unit. In 2016, researchers at the University of Barcelona¹ confirmed my previous assumption that this C2 unit is acetyl-CoA, which plays a central role in cell metabolism.

Two-substrate reaction: Classical enzyme reaction of transketolase (TKT)

Single-substrate reaction: Newly acquired enzyme reaction of transketolase-like 1 (TKTL1)

Comparison of energy recovery pathways

Respiration Fermentation TKTL1

Cell respiration: oxidative energy metabolism in the mitochondria

Healthy cells with sufficient oxygen supply normally gain their energy by degrading sugars and fatty acids and introducing the resulting degradation products into the “cellular powerhouses”, the mitochondria. There, the degradation products undergo a further transformation process (citrate cycle), which ultimately leads to the energy-producing respiratory chain (oxidative phosphorylation). Oxygen is necessary for this energy production process.

Mitochondrial cell respiration has two major disadvantages:
On the one hand, it contributes to the formation of endogenous radicals. On the other hand, carbon dioxide (6 x CO₂) is formed in the mitochondria during the formation of acetyl-CoA from pyruvate as well as during the citrate cycle, which we breathe out. In this way, all 6 carbon atoms of the original sugar molecule are lost and can no longer be used elsewhere in the cell.

Sugars such as glucose in particular undergo a degradation process known as glycolysis. The C6 unit glucose is split step by step into two C3 units (2 x glycerinaldehyde-3-phosphates) and these are converted into pyruvate over several partial steps. During glycolysis, 4 molecules of ATP (adenosine triphosphate) are already formed, the most important high-energy compound in the body, which is required for a multitude of metabolic processes.

If sufficient oxygen is available in the cell, pyruvate (C3 unit) is further converted to acetyl-CoA (C2 unit). In this process, however, two carbon atoms in the form of CO₂ are irretrievably lost.

Acetyl-CoA then flows into the citrate cycle, a cyclic metabolic process in which reduction equivalents are formed (the remaining four carbon atoms of glucose are lost in the form of CO₂). These in turn give off their electrons in the following respiratory chain (oxidative phosphorylation) and thus initiate a hydrogen proton-mediated process in the membrane of the mitochondria, which serves as a drive for an ATP-producing enzyme complex.

In addition to ATP, water (H₂O) is formed at the end of the respiratory chain by transferring the electrons to oxygen (from the inhaled air) and then reacting with the hydrogen protons. In a small percentage of the reactions, however, the electron transfer is faulty and reactive oxygen species (radicals) such as hydrogen peroxide (H₂O₂), hydroxyl radicals or superoxide radicals are formed instead of water. Under normal circumstances, these cell-damaging substances can be defused by antioxidative enzymes and in the case of excessive formation (e.g. in energy-intensive processes such as rapid growth) they can also lead to sustained cell damage and programmed cell death (apoptosis).

Anaerobic glycolysis: energy metabolism of normal cells in case of oxygen deficiency

In case of poor oxygen supply, the energy production metabolism stops before the mitochondria. The cell temporarily obtains its energy exclusively from the ATP molecules that are formed during sugar degradation (glycolysis). The pyruvate formed at the end of glycolysis is no longer converted to acetyl-CoA but to lactic acid (more precisely its salt lactate and protons H⁺), whereby lactate is ejected, transported to the liver and recycled to glucose. Since this energy production pathway is rather inefficient from an energetic point of view (only 2 ATP instead of 30-32 ATP are produced per glucose molecule, which requires high glucose consumption), the cell switches directly back to mitochondrial cell respiration if there is sufficient oxygen.

Anaerobic glycolysis is used, for example, by muscle cells in which the energy requirement exceeds the oxygen supply from the blood during strenuous physical activity, or by cells that are temporarily cut off from the blood supply due to vascular injuries.

Under these oxygen-poor conditions, a signal substance, the so-called hypoxia-induced factor 1-alpha (HIF-1α), is temporarily activated. This triggers processes that lead, for example, to the increased uptake of glucose, the upregulation of various glycolysis enzymes and the formation of new blood vessels (angiogenesis). This ensures that the increased glucose requirement for energy generation is met in the short term and that the blood system is reconnected in the long term and that the blood vessel system provides a better supply of nutrients and oxygen.

As early as 1861, the French chemist Louis Pasteur observed that yeast cells metabolized glucose to a greater and faster extent when there was a lack of oxygen, thereby producing increased amounts of “lactic acid” or lactate. The “Pasteur effect”, named after him, is stopped as soon as oxygen is supplied – glucose consumption decreases and lactate formation is hardly detectable. Most body cells are also subject to this effect. Exceptions to this are erythrocytes (red blood cells) and sperm cells, which do not possess mitochondria, as well as certain nerve cells, retina cells and sperm-producing cells, which ferment glucose even in the presence of oxygen. In the 1920s, the German physician and biochemist Otto Warburg observed that the fermentation metabolism cannot be stopped even in aggressively growing cancer cells by the supply of oxygen (“Warburg effect”).

TKTL1-mediated fermentation: energy metabolism in cells with active TKTL1

In cells with high TKTL1 activity, such as some nerve cells, retinal cells, sperm cells but also aggressively growing tumor cells, glucose is metabolized predominantly via the non-oxidative part of the pentose phosphate pathway (PPP). In contrast to cells without TKTL1 activity, the TKTL1 reaction is replaced by acetyl-CoA (which is mainly used to build lipids) and glyceraldehyde-3-phosphate (G3P).
For energy production, G3P can be introduced into glycolysis and degraded there to pyruvate and further to lactate (“lactic acid”), where ATP is also formed.

TKTL1 thus enables energy production without radical formation on the one hand and the utilization of all carbon atoms in sugars on the other hand to build up new cell components.

The fermentation metabolism in cells with high TKTL1 activity thus differs from the fermentation metabolism, which takes place e.g. in the case of oxygen deficiency in the muscle cells. In particular, it is independent of the presence of oxygen.

The advantage of TKTL1-mediated fermentation is that on the one hand, as in classical fermentation, the energy-rich ATP can be obtained without the risk of radical formation. At the same time, TKTL1 also enables the formation of acetyl-CoA from sugars, which is an important raw material for the formation of lipids or fatty acids (membrane building blocks) in fast-growing cells.

There are two reasons why TKTL1-positive cancer cells in particular are able to sufficiently cover their enormous energy and building material requirements in this way:
First, TKTL1 stabilizes the hypoxia-induced factor 1 alpha (HIF-1α) so that it remains active even in the presence of oxygen. This increases cellular glucose uptake, regulates glycolysis enzymes and promotes the formation of new blood vessels (angiogenesis).
On the other hand, neither energy nor acetyl-CoA production leads to the loss of carbon (C atoms) from glucose in the form of carbon dioxide (CO₂) (which is either converted into cell building materials such as nucleotides and lipids or recycled back into glucose in the form of lactate).

Advantages of the altered enzyme function

Reduced radical formation

TKTL-mediated fermentation metabolism offers cells the advantage of producing energy from sugar without the formation of radicals.

The activation of TKTL1 thus offers protection against radical cell damage that would lead to loss of function or, in the long term, to programmed cell death (apoptosis).

In conventional cell respiration, which is used by most body cells, energy is produced in the form of the energy carrier ATP in the “cellular powerhouses”, the mitochondria. Under the influence of oxygen (O₂), water (H₂O) is produced as a by-product. Now and then this process does not run correctly and instead of water reactive oxygen species (radicals) such as hydrogen peroxide (H₂O₂), hydroxyl radicals or superoxide radicals are formed. Radicals can attack cell structures such as membrane lipids, structural proteins or the genome and lead to irreparable damage in the long run. If the damage to a cell is too great, programmed cell death (apoptosis) is usually initiated.

In cells with high energy requirements, such as fast-growing cancer cells, the generation of energy in the mitochondria would inevitably lead to increased radical formation. The price for uncontrolled growth would be early apoptosis.

In the TKTL1-mediated reaction, glycerinaldehyde-3-phosphate (G3P) is formed, which can be introduced into the glycolysis. During this process, ATP is formed at two sites as a “by-product” – without the development of radicals. At the same time, pyruvate itself acts as a radical scavenger, further minimizing oxidative stress.

The ATP yield via fermentation is extremely low compared to mitochondrial ATP synthesis and requires a high sugar consumption to cover the energy requirement. Nevertheless, for some cells the advantages of reduced radical load predominate.

Production of building material without

Especially in anabolic – i.e. dividing and growing cells – the activation of the TKTL1 enzyme offers a highly efficient possibility of acetyl-CoA formation from sugars. In contrast to acetyl-CoA formation from pyruvate, no carbon atoms in the form of carbon dioxide (CO₂) are lost in TKTL1-mediated synthesis via the non-oxidative pentose phosphate pathway.

Acetyl-CoA is a central molecule in cell metabolism, which is not only used to generate energy, but also to build up cell components such as lipids and fat. By utilizing all carbon atoms from sugar without losses, TKTL1-mediated acetyl-CoA formation enables the effective conversion of sugar into fats.

Textbooks describe the possibility of acetyl-CoA formation from sugars as the glycolysis pathway (Embden-Meyerhof pathway). Here glucose (C6 unit) is split step by step into two C3 units and these are then converted by the enzyme pyruvate dehydrogenase into one acetyl-CoA molecule each (2 x C2 units). One carbon atom in the form of CO₂ is irreversibly lost. This synthesis pathway is very ineffective for anabolic processes, since only 4 of the 6 carbon atoms of glucose can be used.

In acetyl-CoA synthesis via the TKTL1-mediated metabolic pathway, however, all carbon atoms can be used. Glucose is first converted into a C5 sugar (xylulose-5-phosphate, X5P) in the non-oxidative part of the pentose phosphate metabolic pathway and then converted by TKTL1 into acetyl-CoA and a C3 unit (glycerol aldehyde-3-phosphate, G3P). G3P can then be recycled again in the pentose phosphate pathway and finally returned as X5P to the TKTL1 reaction.

Within the framework of the non-oxidative pentose phosphate pathway, all carbon atoms can be utilized via various conversion reactions and ultimately flow into the TKTL1-mediated reaction to form acetyl-CoA. Thus 3 instead of 2 acetyl-CoA molecules can be formed from each glucose molecule; there is no loss of C atoms via CO₂, so that this metabolic pathway is highly efficient compared to glycolysis.

engl-acetyl-coa-synthesis-glycolysis-ppp

TKTL1 – Protective factor for healthy cells

Unlike oxidative energy generation in the mitochondria, TKTL1-mediated aerobic fermentation metabolism does not produce any cell-damaging radicals. At the same time, the pyruvate formed defuses exogenous radicals. This not only benefits cancer cells but also some healthy cells in particular, so that the development of the TKTL1 gene and the enzyme formed from it can be regarded as a milestone in the evolution of modern humans.

Eyes

Due to the constant incidence of light, the retina cells of the eye are exposed to a strong, UV-induced radical formation. Without a suitable protective mechanism, the resulting damage would quickly lead to blindness. The TKTL1-mediated aerobic fermentation metabolism on the one hand prevents further radical formation via the mitochondria. At the same time, the pyruvate formed during this metabolism supports the neutralization of exogenous radicals which penetrate the retina cells through the incidence of UV light.

Testicles

In order to enable a healthy new life, the genetic material in the sperm must be protected from mutations. Increased TKTL1 activity in the testicles protects the sperm DNA from radical damage and thus prevents malformations in the offspring. The TKTL1 protein is therefore also an important marker for male fertility².

The increased glucose consumption of sperm cells due to the TKTL1 metabolism is also clearly visible in FDG-PET. The testicles also appear in healthy men as tissue with high glucose accumulation (“hot eggs”).

Nerves

Nerve cells benefit not only from TKTL1-induced radical protection. In the course of aerobic fermentation metabolism, reduction equivalents such as NADPH and glutathione are increasingly produced. These reduce the protein cytochrome c and thus prevent it from triggering programmed cell death (apoptosis)³. Thus, fermenting nerve cells survive even if beta-amyloid plaques have already formed in them⁴. The TKTL1-related protection of nerve cells against premature cell death is thus one of the most important evolutionary developments that enables mammals, and in particular humans, to achieve long-lasting brain and cognitive function.

Warburg effect

Already in the 1920s, the German physician, biochemist and later Nobel laureate Otto Heinrich Warburg observed the unusual energy metabolism of cancer cells. In contrast to most healthy cells, which only ferment when there is a lack of oxygen, the cancer cells he investigated still produced large amounts of lactic acid when oxygen was supplied to them – a sign of fermentation metabolism even in the presence of oxygen (aerobic glycolysis).

Based on his observation, Warburg hypothesized that damage to the mitochondria was the cause of cancer. Today we know that he was wrong in his hypothesis and that instead genetic changes (mutations) in certain genes lead to cancer.

His discovery that malignant tumor cells use a lactic acid-producing fermentation metabolism for energy production even in the presence of oxygen (Warburg effect) is, however, confirmed not least by the findings around TKTL1. The associated high glucose consumption of cancer cells is even used for diagnostic purposes in positron emission tomography.

Nevertheless, the aerobic glycolysis described by Warburg must no longer be regarded as a “peculiarity of cancer”, but rather as an important protective mechanism for sensitive tissue due to the latest findings on the function of TKTL1 in cells such as nerve cells, retina cells and sperm.

TKTL1 – Protective factor and survival strategy for cancer cells

Although the TKTL1-mediated aerobic fermentation metabolism is an evolutionarily important protective mechanism for certain body tissues, it also has a downside: an activation of TKTL1 in unwanted, degenerate cells is associated with an increased malignancy. The cell-protective effects of the special metabolism not only promote their unlimited survival. Characteristic of cancer cells – and the difference to benign tumors – is their invasive growth, their ability to destroy surrounding tissue and form metastases in the body. The TKTL1-mediated fermentation metabolism offers advantages that promote these factors and thus increase the aggressiveness of cancer cells.

Cell division Immune system Invasivity/ metastasis Angiogenesis Apoptosis Therapy resistance

Initiation of cell division through the provision of cellular building materials

The activation of TKTL1 in cancer cells is associated with increased proliferation⁵ ⁶ ⁷ ⁸.

Cell division and growth are not only energy-intensive processes, but also require the sufficient supply of building materials such as nucleotides for the amplification of DNA or lipids for the rebuilding of cell and cell organelle membrane.

The TKTL1-mediated reaction in the non-oxidative part of the pentose phosphate pathway enables the effective conversion of sugars to lipids or fatty acids by providing acety-CoA⁹. On the other hand, ribose-5-phosphate is increasingly produced via the pentose phosphate pathway – a basic building block for nucleotides and thus for the production of new DNA. A high supply of ribose-5-phosphate in the cell in turn triggers cell division.

Protection of cancer cells from attack by immune cells

Activation of TKTL1 promotes immunosuppression of cancer cells.
Immune cells are normally able to recognize and eliminate degenerate cells. Protective mechanisms that protect a cell from attack by immune cells therefore offer aggressive cancer cells a significant survival advantage.

The TKTL1-mediated fermentation metabolism produces high concentrations of lactic acid, which are ejected from the cell. In this way, a protective acid shell is formed not only around the tumor tissue but also around individual cancer cells circulating in the bloodstream, which acts as a barrier against immune cells¹⁰ ¹¹.

engl-cancercell-tktl1-matrix-degradation

Promotion of invasive growth and spread in the body

The activity of TKTL1 in cancer cells is associated with an increased tendency to metastasis, particularly in surrounding lymph nodes¹² ¹³.

Invasive growth and the ability to metastasize are basic characteristics of aggressive cancer cells. The lactic acid, which is amplified in the TKTL1-mediated fermentation metabolism, promotes the destruction of the surrounding healthy tissue (matrix degradation) and thus creates space for the spread of tumor tissue. The destruction of cells in nearby vascular walls also forms entry points into the bloodstream and enables cancer cells to spread throughout the body.

engl-cancercell-tktl1-hif-1a-angiogenesis

Stimulation of the formation of new blood vessels (angiogenesis)

The connection to the blood vessel system is crucial for tissue in order to ensure the supply of nutrients and oxygen. In uncontrolled tumor tissue, however, poorly perfused, oxygen-deficient areas quickly develop. The ability to stimulate the formation of new blood vessels (angiogenesis) and thus improve the supply of energy and building materials into the tumor interior is an important factor for the aggressiveness of cancerous ulcers.

TKTL1-mediated fermentation metabolism supports this ability by stabilizing the signaling substance hypoxia-induced factor 1-alpha (HIF-1α) and maintaining its activity even under normal oxygen conditions.

HIF-1α is normally produced during oxygen deficiency and controls processes that are necessary to adapt the cell to the oxygen-deficient condition. This also includes the formation of new blood vessels to restore or improve the supply of oxygen. If sufficient oxygen is available again, HIF-1α is normally degraded and the associated processes are stopped. By stabilizing the factor in TKTL1-positive cells, however, these processes remain active and thus also the stimulating effect on angiogenesis.

Reduced tendency to programmed cell death (apoptosis)

The activation of TKTL1 in cancer cells reduces the apoptosis susceptibility of the cells.
In intracellular (intrinsic) apoptosis, internal signals such as DNA damage cause the release of the protein cytochrome c from the mitochondria. This step initiates a cascade-like process that ultimately leads to the dissolution of the cell. This requires cytochrome c to be oxidized.

In TKTL1-positive cells, the reduction equivalent NADPH is increasingly formed via the oxidative pentose-phosphate pathway, which can transfer its reduction capacity to the cellular antioxidant glutathione. Glutathione can reduce released cytochrome c and thus inactivate it, whereby apoptosis is already stopped in the initial step¹⁴ ¹⁵.

engl-cancercell-tktl1-therapy-resistence

Reduced therapeutic success through resistance formation in aggressive cancer cells

The activation of TKTL1 contributes to the resistance of many cancer cells to radiation and chemotherapy¹⁶ ¹⁷ as well as to a number of targeted therapies such as sorafenib¹⁸, imatinib¹⁹ und cetuximab²⁰ and is therefore associated with a poor treatment prognosis for patients²¹. The reason for this is that many of the processes and metabolic changes associated with TKTL1 therapies take their targets in the malignant tumor cells:

Blocked radical formation by bypassing the energy production pathway in the mitochondria and increased provision of antioxidant substances such as pyruvate, glutathione → Radical-inducing therapies such as radiation remain ineffective²².
Improved repair of DNA damages by increased supply of nucleotides (Ribose 5 phosphate) → DNA-damaging therapies work worse²³.
Lack of apoptosis triggering → Reduced efficacy of therapies designed to induce programmed cell death²⁴ .

TKTL1 as a marker for aggressive cancer cells

The activation of TKTL1 in cancer cells is associated with a number of metabolic changes that significantly increase the aggressiveness and malignancy of malignant cells:

Rapid, invasive growth and facilitated metastasis
Protection against radical cell damage, apoptosis-inducing signals and attack by immune cells
Resistance to a variety of currently available therapies

Patients with TKTL1-positive tumors often show a worse therapy prognosis and significantly shorter survival times²⁵ ²⁶ ²⁷ ²⁸ ²⁹ ³⁰ ³¹.

TKTL1 therefore represents a universal marker for the malignancy of cancer cells and helps to identify patients for whom concomitant treatment that specifically affects the TKTL1 metabolism and inhibits TKTL1 activity or its effects makes sense.

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