Siderocalin Combats Mycobacterial Infections - Iron Acquisition by the Genus Mycobacterium - page 54

Fig. 4.2 Siderophores enterobactin ( top left ) and generic versions of carboxymycobactins ( top
right , n = 3-10) and mycobactins ( bottom , n = 6-17). Both carboxymycobactins and mycobac-
tins have varying alkyl substituents on the backbone that, for simplicity, are not included in this
figure
and display compromised survival [ 5 , 7 ]. The role of Scn as an antimicrobial pro-
tein was further demonstrated by the compatibility of the Scn calyx with a collec-
tion of siderophores from both Gram-positive and Gram-negative bacteria [ 8 - 10 ].
Recent work has also shown that Scn is a mediator of mammalian iron trans-
port, utilizing so-called mammalian siderophores (simple catechols found endog-
enously in the mammalian gut) [ 11 , 12 ]. Scn-mediated iron transport is thought to
occur in kidney embryogenesis or in cases of kidney damage where concentrations
of iron must be strictly regulated to control inflammation. Catechols are iron-bind-
ing moieties found in some natural siderophores (e.g., enterobactin, Fig. 4.2 ) and
can be bound by Scn as either the free ligand or the iron complex. Endogenous
catechols, found as byproducts of either bacterial or human metabolism, are biden-
tate iron chelators. Under physiological conditions, ferric bis catechol complexes
primarily are formed, as determined by speciation calculations [ 11 ]. Scn intercepts
these complexes and recruits a third catechol to fill the iron coordination shell such
that the ferric complex is hexacoordinate. Ferric tris catechol complexes carry a − 3
charge and the additional aromatic catechol optimizes binding by Scn via hybrid
Coulombic and cation-pi interactions. However, not all catechols are mamma-
lian siderophores. Those with substituents on the aromatic ring exhibit a severely
compromised affinity for Scn. The consequent decrease in affinity is due to steric
clashes between catechol substituents and the rigid Scn calyx [ 13 , 14 ].