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Heme, heme, is oxygen here?

You have probably heard that aristocrats have blue blood, right? Of course, it is not true. We all have blood of a beautiful red color, thanks to a protein called hemoglobin – the blood pigment. This protein has a non-protein part called heme, which carries oxygen in our blood from lungs to a whole body. Besides being an oxygen carrier, heme has a much wider set of tasks in various proteins of many organisms. For example, bacteria use heme in oxygen sensor proteins to orient themselves in the environment. The team of Assoc. Prof. Markéta Martínková from the Faculty of Science, Charles University has recently published a new mini-review focused on the mechanisms of action of those proteins.
The chemical structure of heme.
source: Wikipedia

The existence of the blood pigment has been known for a long time, but what does its chemical structure look like? This question was answered by William Küster in 1912. Thus, his discovery celebrates 110 years nowadays. Küster was nominated for the Nobel Prize in 1913. However, the prize for heme structure discovery wasn´t awarded until 1930 when Hans Fisher obtained it for the synthesis of heme and proving its structure in 1926. William Küster might have gotten the prize as well but unfortunately, he died beforehand. So, the structure of heme was known but what about the structure of the whole hemoglobin? Max Perutz and John Kendrew managed to resolve this while solving structures of complex proteins and they were awarded the Nobel prize exactly 60 years ago, in 1962. Assoc. Prof. Martínková´s review was published in a special issue of the Biological Chemistry journal to celebrate these two anniversaries.

Heme-containing proteins (hemoproteins) have many different functions in various organisms. The basic ones are the transportation and storage of oxygen (through the above-mentioned hemoglobin), but other than that heme can be active in an electron transport or catalysis of oxygenation reactions. Uncommonly, in smaller amounts, heme can be found even outside of proteins. In general, “free” heme is quite toxic for cells so its concentration must be closely monitored and regulated. Therefore, it does work as a signaling molecule to which heme sensor proteins can respond by reversible binding of “free” heme and thus changing their properties. Processes like DNA transcription and translation (crucial for expressing our genetic information) and activities of some ion channels or enzymes can also be regulated this way.

Moreover, gas sensor proteins cleverly use unique properties of heme, specifically the ability to bind diatomic molecules (oxygen, nitrogen, or carbon monoxide) by its central iron atom. Such sensors are proteins that contain heme in one part and a functional unit in the second part. The binding of a gas molecule to heme initializes structural changes of the first part which are than transduce through the whole protein to activate or deactivate its functional unit.

For some time now, scientists have been interested in bacterial oxygen sensors. Thanks to the quick reaction of those sensors, bacteria can sense even the smallest changes in oxygen concentrations in their environment enabling an adaptation to these changes and survive even in less suitable conditions (such as environments lacking oxygen). Although there is a high variability among sensor proteins from different bacteria, they all share some common features. Therefore, understanding a function of at least some oxygen sensor proteins is of a great importance.

The review focuses mainly on two bacterial sensors whose mechanisms of oxygen detection are well characterized. Special attention is given to a detailed description of structural changes taking place upon oxygen binding to the heme molecule, signal transduction from the one part of the protein (containing the heme molecule) to the other leading to an activation/deactivation of the functional domain.

Escherichia coli (E. coli), the source bacteria of one of the investigated heme sensor protein.
source: Wikipedia

Provided that scientists would manage to understand how exactly the sensors work, it would be possible to modulate those systems (set them out of order for example), thus disorienting the bacteria and keeping them from adapting to the environment so that it would be easier to destroy them. The oxygen sensors thus represent an attractive therapeutic target for the development of new antibiotics aside from those used now as these battle the rising antibiotic resistance. Targeting bacterial oxygen sensors is also convenient as the human body uses a completely different mechanism for detecting oxygen.

The understanding of heme sensor proteins has rapidly increased in the last few years. The research has revealed several key functional features common to all known gas sensor proteins. Acquired knowledge could open new pathways for applications in medicine and pharmacology, which are urgently needed in times of rising bacterial antibiotic resistance.

Vávra J, Sergunin A, Jeřábek P, Shimizu T, Martínková M. Signal transduction mechanisms in heme-based globin-coupled oxygen sensors with a focus on a histidine kinase (AfGcHK) and a diguanylate cyclase (YddV or EcDosC). Biol Chem. 2022 Sep 27;403(11-12):1031-1042.

Magda Křelinová

Published: Dec 18, 2022 05:45 PM

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