Iron acquisition

Iron acquisition for higher education

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Once bacteria have successfully colonised and/or invaded their host, it is essential that they acquire the nutrients required for growth and proliferation. Iron is perhaps the most important micronutrient required for bacteria to proliferate and cause disease.

Iron has several roles within a bacterial cell. It is required to render active many different proteins and enzymes involved in a variety of metabolic processes. It is also essential for expression of many key virulence determinants. Without iron, it is almost impossible for bacteria to establish themselves within the host and cause disease.

Roles in enzymology and cell physiology

Many proteins crucial for bacterial replication and growth require iron to function. These include enzymes/proteins involved in: the neutralisation of harmful oxidative species (superoxide dismutase), synthesis of DNA (ribonucleotide diphosphate reductase - E. coli) and the generation of ATP (cytochromes). Iron deficiency inhibits these processes in bacterial cells, having a deleterious effect and subsequently reducing its ability to cause disease.

iron need

Above- a simplified, diagrammatic explanation of the use of iron in metabolic enzymes. Without iron at the active site of many metabolic proteins, they cannot bind their target substrate, inhibiting whichever pathway they belong to.

Roles in gene expression

Expression of the appropriate virulence-determining genes are essential to a bacteria's ability to cause disease. As we discovered on the infection page, bacteria have an arsenal of different virulence factors and the expression of many of these can be altered by iron. There are many different ways iron can alter gene expression, but for now we will discuss an aspect of iron-mediated gene expression we are interested in at UoL, the fur regulon.

Regulation of gene expression by Fur

The ferric uptake regulator family (Fur) proteins are iron-dependent repressors governing expression of a huge amount of iron regulated genes in a myriad of bacteria. Fur proteins can bind free ferrous (2+) iron, altering their DNA binding properties. In the presence of iron, Fur-Fe2+ acts as a repressor for iron regulated genes. In the absence of ferrous iron then, these genes are de-repressed and can be transcribed. These genes include systems for acquiring iron, and other virulence determinants.

Fur

Above- diagrammatic representation of iron-mediated transcriptional regulation by Fur.

In this example, in Iron limited conditions, the Fur protein will be de-repressed causing expression of genes encoding iron acquisition systems. Bacteria can then acquire the iron they need to proliferate.

The problem with iron- The human body is an extremely iron limiting environment, and what little iron is present is often sequestered in proteins such as haemoglobin. Bacteria therefore need not only a mechanism to obtain iron from the host, but a way in which to outcompete other bacteria also vying for the same source.

Acquisition of iron

Bacteria have evolved several mechanisms to acquire iron from their hosts. These include:

1.) Siderophore systems- Siderophores are large protein molecules that have extremely high affinities for iron (iron chelators). They can therefore outcompete the iron sequestering molecules of the human body. The iron bound to these molecules is then taken up, often through a TonB receptor mediated process. Some bacteria have on their surface receptor uptake systems for siderophores secreted by other bacteria (iron piracy)!

2.) Surface ferric reductases- These proteins on the surface of bacteria can reduce free ferric (3+) iron to ferrous iron which can be taken up and used by the cell.

3.) Haemolysins and cytotoxins- as mentioned above, most iron in the human body is tied up biological molecules such as haemoglobin. Haemolysin breaks down the haemoglobin in red blood cells, freeing up the iron for bacterial uptake. Similarly, cytotoxins can damage and rupture human cells, freeing up intercellular iron.

Note: the mechanisms used will depend upon the organism - Gram-positive and negative organisms will often use different systems.

 

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