Oxygen facts | Why is oxygen the most important element?

Oxygen is one of the most important elements on Earth, what is special about oxygen?

Oxygen is one of the most important elements on Earth

Appearing initially as a toxic waste of photosynthetic microorganisms, free oxygen now makes up about 20% of the atmosphere of our planet. 

Over the years of its existence, life on Earth has adapted to the oxygen atmosphere, and now most eukaryotic organisms use oxygen to receive energy in the process of respiration. Nobel Prize in Physiology or Medicine for 2019 received Gregg Semenza (Gregg L. Semenza), Sir Peter Ratcliffe (Sir Peter J. Ratcliffe) and William Calin (William G. Kaelin Jr) for his fundamental work, revealing the details of how eukaryotic cells perceive oxygen from the environment and adapt to its level.
For bacteria and mitochondria, oxygen is an important end link in the system of protein electrical "wires", which scientists call the electron transport chain. This chain is used to oxidize food molecules to carbon dioxide, and the energy released in the process is used by the body. 
In this case, oxygen takes on the electrons taken from carbon and in this form is part of the water. Without it, electrons from food can trigger a variety of spontaneous chemical reactions in the cell and lead to its death. Therefore, it is critical that any “breathing” 1  cell of the body constantly has access to this element in sufficient quantities.


Gregg Semenza.  Photo by Will Kirk / Johns Hopkins University
Gregg Semenza. Photo by Will Kirk / Johns Hopkins University

The human body is very sensitive to the amount of oxygen. If it becomes insufficient in the blood for one reason or another, the kidneys begin to secrete the hormone erythropoietin, which causes the bone marrow to produce more red blood cells - cells that carry oxygen from the lungs to tissues through the blood. The first among the laureates of this year, Gregg Semenza, wanted to understand how the system of erythropoietin synthesis in kidney cells works.
The first question that needed to be answered was what is the transcription factor of the erythropoietin gene. Transcription factors are called proteins that trigger the work of a particular gene. As a rule, near the gene on the chromosome there is a landing region for such proteins. And if it is usually very easy to find a gene, then finding the site of planting of its transcription factor is a less trivial task. Semenza used genetically modified mice, which randomly changed the part of the chromosome in which he expected to find the site of the landing factor. At some point, he found this site, and also managed to determine the protein that plays the role of a transcription factor. He called this previously unknown protein “hypoxia-induced factor”, or HIF-1α.


Sir Peter Ratcliffe.  Photo from Oxford University from erc.europa.eu
Sir Peter Ratcliffe. Photo from Oxford University from erc.europa.eu

Semyonza and Sir Peter Ratcliffe, who worked on the same topic at the same time, found that HIF-1α is expressed not only in the kidneys, but also in almost all body tissues. This transcription factor triggered, for example, the growth of new vessels during the destruction of old ones. As the level of oxygen in the environment decreased, the amount of HIF-1α began to increase. And what led to this growth was unclear.
The answer to this important question came from an unexpected place. Oncologist William Calin has been researching Hippel-Lindau disease (VHL). In this condition, vascular growth is impaired in patients, and tumors often appear, in particular, in the kidneys. Calin discovered that the disease is caused by mutations in the VHL gene, which normally suppresses tumor growth. He studied cells with a disrupted VHL gene and showed that there was a significantly increased amount of HIF-1α, which was also independent of oxygen levels. The introduction of the normal VHL gene into cancer cells restored the concentration of HIF-1α to normal values.


William Calin  Photo by Sam Ogden, Dana-Farber Cancer Institute (twitter.com/NobelPrize)
William Calin Photo by Sam Ogden, Dana-Farber Cancer Institute ( twitter.com/NobelPrize )

The product of the VHL gene turned out to be ubiquitin ligase. Here it is worth explaining separately what protein modifications are. Proteins in cells perform almost all tasks - from the perception of the environment to chemical transformations. And the cell must be able to control these proteins. In the course of evolution, many different variants of such control appeared, one of which is the operational change in the structure and shape of the protein molecule by attaching various add-ons to it. They can have a very different chemical nature - from relatively simple compounds like phosphoric acid to large protein or carbohydrate molecules. Modifications of proteins can “turn off” or “turn on” their work, cause them to move to the desired part of the cell, and so on.
Proteins of the ubiquitin ligase class are involved in modifying other proteins with ubiquitin. Transport proteins recognize ubiquitin chains and send their labeled protein for degradation, thereby reducing its concentration. Calin found that the VHL protein he was studying had the ability to ubiquitinylate HIF-1α and thereby reduce its amount in the cell. 
Moreover, its activity increased in the presence of oxygen. During hypoxia, VHL stopped ubiquitinating HIF-1α, and the cell switched to a new mode of operation. Mutations of the VHL gene led to disruption of this function, and HIF-1α continued to be present in the cell even when it was no longer needed.


Image Mattias Karlén (twitter.com/NobelPrize)
Image Mattias Karlén ( twitter.com/NobelPrize )

When this fact was revealed, much fell into place. But there was another area in which not everything was clear. How exactly did the VHL protein “feel” oxygen? Together, Ratcliffe and Calin were able to answer this question. 
It turned out that in the VHL protein, work was regulated using a previously unknown modification - proline hydroxylation. The prolyl hydroxylase enzymes responsible for this modification contain iron ion. Like hemoglobin, they are able to bind oxygen with iron and become activated in this form. Activated prolyl hydroxylase modifies the VHL structure, which begins to lower the concentration of HIF-1α. In subsequent years, many such prolyl hydroxylases have been discovered.
So why did they give the Nobel Prize this year? Why was this discovery so important that the Nobel Committee found it worthy of an award? There are several answers to this. First, details of the universal mechanism that is present in almost all cells have been disclosed. 
Secondly, it quickly turned out that many different diseases, both oncological and other, are tied to this mechanism. And understanding the mechanism is already half the way to treatment. And finally, a new mechanism of protein modification, previously unknown, was discovered. And this is a full-fledged fundamental discovery. So the researchers have definitely earned their well-deserved Nobel.
1  Some cells, such as red blood cells, do not have mitochondria and do not receive energy by respiration. This does not allow them to efficiently use nutrients, but their metabolism does not require this. How many needs does a cell have, which simply flows with a blood stream and does not need either movement or active protein synthesis?