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.
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)
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.
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.
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”).
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.
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.
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.
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:
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.