The Krebs cycle, discovered by Hans Krebs (1900-1981), is located halfway between the processes that lead to the oxidation of nutrients (which will then provide the acetyl groups of acetyl-CoA) and oxidative phosphorylation. The proper functioning of the Krebs Cycle is essential to optimize the beginning of the production of cellular energy and therefore of the vital energy of every single cell in the body, be it muscular, neuronal, cardiac, etc.
The functional integrity of this cycle is necessary for the overall health of the organism and to enable it to cope with emotional or work stress at its best, in full force, with sufficient energy and power.
The Krebs cycle produces only one molecule of ATP (adenosine triphosphate, or the “energy currency” of the cell) for each of its “turns”, but also generates a large flow of electrons, which enter the respiratory chain and lead to the formation of a large number of ATP molecules during the oxidative phosphorylation process.
The Krebs cycle is an example of indirect interaction between vitamins and amino acids; in fact, an alteration of this cycle due to vitamin and / or lipoic acid deficiencies can also lead to an alteration of protein synthesis and many other biological functions.
Citric acid, for example, naturally contained in lemon juice, is the building block of the Krebs cycle. Alpha lipoic acid is an endogenous molecule, produced in our body, and part of the pyruvate dehydrogenase complex, an enzyme complex necessary to optimize the Krebs cycle. In fact, pyruvate is converted by this enzyme, through the oxidative decarboxylation process, into Acetyl-CoA and the latter is the fundamental stone of the citric acid cycle.
In order for the oxidative decarboxylation reaction to take place, thanks to the “pyruvate dehydrogenase complex”, some co-factors are indispensable; the cofactor is a small non-protein molecule or a metal ion that is associated with the enzyme and makes its enzymatic activity possible. Among these we find: Vitamin B1 or thiamine, Vitamin B2 or riboflavin, Vitamin B3 or PP niacin, Pantothenic acid for coenzyme A.
Conversely, starting from some intermediates of the Krebs cycle it is possible to obtain amino acids that are important for our organism: a known intermediate of the Krebs cycle is the alpha-ketoglutarate (AKG), which converts into glutamate and subtracts the dangerous ammonia produced in our body to form glutamine. Glutamine is an amino acid that modulates the immune system, nourishes and hydrates muscle mass, skeleton, kidneys, liver and intestines.
Another equally important intermediate product of the Krebs cycle is oxaloacetate which, by converting into phosphoenolpyruvate, provides a substrate for the endogenous formation of important amino acids such as serine, cysteine, tyrosine, phenylalanine and many others.
NUTRITIONAL DEFICIENCY OF VITAMIN B1 AND Beri Beri
We have seen that among the fundamental cofactors for oxidative decarboxylation there is vitamin B1.
Vitamin B1, or thiamine, is called the “moral vitamin” due to its ability to positively influence people’s mental attitude. Vitamin B1 deficiency causes wasting, as much as its right presence causes attention span and even individual learning. For this reason it is considered a fundamental vitamin in the period of growth of children. In addition, like vitamin B2, vitamin B1 contributes to the important process of converting glucose into energy.
It is part of the so-called water-soluble vitamins, those that cannot be accumulated in the body, but must be regularly consumed through food: it is widespread in both plant and animal foods; in particular it is found in cereals, legumes, eggs, pork, yeast.
A nutritional deficiency of thiamine causes Beri Beri, a disease that affects the nervous and cardiovascular systems.
Damage to the peripheral nervous system manifests itself in the form of pain in the limbs, weakness of the muscles and impaired skin sensitivity. Hence the denomination Beri Beri which means “sheep”; in fact, individuals affected by this disease, walking with trembling knees and unsteady legs, have a gait similar to that of sheep.
The disease continues to be a serious health problem in the Far East, as rice, the main component of the diet of those populations, has a low content of thiamine because it is deprived of the outer layer in which it is contained, i.e. brown rice is made into white rice.
“DEFECTS” OF THE KREBS CYCLE AND CANCER
The most recent research shows that defects in the enzymes of the citric acid cycle can have significant effects on the regulation of some metabolic pathways. Some of these enzymes accumulating in the mitochondria can spill over into the cytoplasm. Here they contribute to increasing the speed of aerobic glycolysis and the consequent development of cancer due to variations that alter gene expression and stimulate uncontrolled cell growth.
Recent discoveries on the role of the mitochondrial enzyme acetyl-CoA acetyltransferase indicate that, under normal conditions, this enzyme produces ketone bodies that serve as fuel for some tissues and are an indispensable source of energy for the whole organism in conditions of prolonged fasting. In certain types of cancer, the aforementioned modified enzyme is “diverted” from its normal role in the formation of ketone bodies to the further growth of the tumor, a truly unique phenomenon. The enzyme destined for the new role could be an exceptional therapeutic target, in order to block tumor growth.
All these observations that link the Krebs cycle to cancer also suggest that cancer is not simply a disease resulting from mutations in the growth factors and proteins that control the cell cycle, but it is also a metabolic disease. Having become aware that there is also a metabolic component in cancer opens the way to new ways of thinking about the control of this disease.
In fact, the results obtained from recent experiments, although still completely preliminary, show that cancer cells that are turning towards the use of aerobic glycolysis lose their malignancy if they are pharmacologically forced to use oxidative phosphorylation.
It is also interesting to note that the citric acid cycle, which has been studied for decades, still today is the custodian of secrets that will have to be revealed by the biochemists of the future.
- Antiaging e lo stile di vita integrato; Tecniche Nuove, M. Spattini
- Biochimica, 2020 Zanichelli, L. Stryer et al.