A History of Iron Metabolism in the Mycobacteria - Iron Acquisition by the Genus Mycobacterium - page 5

in any case, covered elsewhere in this monograph. Solving the problems of iron
metabolism is a little like doing a jigsaw puzzle: in this case, however, one is never
sure that one has all the pieces available to provide the final picture. One tries to
provide a coherent and comprehensible view of iron metabolism in the mycobac-
teria from the pieces that can be found. But how many more are still missing? In
spite of us thinking that we now know what the final picture is going to look like,
there is clearly still a long way to go!
2.2 The Trouble with Iron
Iron is an essential trace element for almost all living cells. The only exceptions
appear to be some lactobacilli and the spirochete, Borrelia burgdorferi, that is the
causative agent of Lyme disease. Iron is needed as an essential co-factor in many
enzymes and is also the critical metal ion in all haem compounds, including all the
cytochromes that carry out essential functions in energy metabolism and also are
components of several key enzymes. Iron, however, is unique amongst the nutri-
ents needed for cell growth in that is insoluble at neutral pH values. However, this
needs to be qualified as iron exists in two states: the reduced ferrous form and the
oxidized ferric form. It is the latter form that is insoluble and, although ferrous
salts are water-soluble, they quickly oxidize to the ferric form, a reaction which is
accelerated if the iron is in a chelated form. Although the solubility of ferric iron
at pH 7 has usually been stated to be 10 − 18 M, more recent measurements give
this as about 10 − 9 to 10 − 10 M [ 1 , 2 ]. This revised lower value arises because it is
now appreciated that the principal ionic species that exists in aqueous solution is
FE ( OH ) 2 and not Fe(OH) 3 as previously thought. Even though this revised value
is a billion times higher than the earlier value, it still results in iron being effec-
tively insoluble as 10 − 9 M corresponds to 56 pg/ml. This then effectively renders
iron as being unavailable to cells. Specific mechanisms have therefore evolved so
that cells may acquire iron from the environment and also hold it within them-
selves in a usable form. These mechanisms differ between animals, plants and
microorganisms.
For microbial pathogens, solving the problem of iron acquisition is essential.
If they cannot acquire iron from the sources of iron inside the host that they have
infected, then they will be unable to grow and thus cause disease. As pathogens do
cause disease, we can obviously conclude that all pathogens must have evolved
mechanisms for iron acquisition. The principal sources of iron within an animal
are: transferrin, ferritin, haemoglobin and haem-containing proteins.
Transferrin is the principle iron transporting protein in the blood. There are
related proteins of lactoferrin, found in milk and other extracellular fluids and
secretions, and ovaferrin (formerly known as conalbumin) that is found in eggs.
These are large proteins (~80 kDa) but only have two binding sites for ferric iron.
Ferritin is a protein (~50 kDa) comprising 24 identical subunits that form a
hollow sphere into which up to 4,000 atoms of Fe(III) can be stored. This is the