Mycobacterial Iron Acquisition Mechanisms - Iron Acquisition by the Genus Mycobacterium - page 42

in 1973 [ 11 ] which like all useful trivial names for complex molecules conveys
information that recalls for the reader the outstanding function, location, or other
relevant property of the molecule. An outstanding chemical asset of siderophores
is their competitive binding affinity for ferric iron but very low affinity for ferrous
iron, allowing the metal to be released from the ferric-siderophore by reduction
once the ferric-siderophore is transported internally by siderophore receptors and
transport systems. The molecular mass (usually about 500-1000 Da) is too large to
move internally across the membrane without a cognate system.
Most siderophores belong to three groups: the catecholate structural group,
which is usually based on 2, 3-dihydroxybenzoic acid (2, 3-DHB) components,
the hydroxamic acids, and mixed types. Production of siderophores is boosted by
decreased environmental iron levels, implying careful cellular monitoring of the
internal iron status. Interestingly, the simple subunit 2, 3-DHB is often released by
catecholate siderophore producers into the extracellular region. In a unique instance,
Bacillus anthracis and microorganisms related to B. anthracis produce the catecho-
late siderophore petrobactin which is based on the phenolate 3, 4-dihydroxybenzoic
acid (3, 4-DHB) [ 12 ]. Like 2, 3-DHB, the 3, 4-DHB subunit of petrobactin is found
external to the microbial cells during iron restriction. In the mycobacteria, excretion
of salicylic acid, a common moiety of cell associated mycobactin and excreted car-
boxymycobactin (see Chap. 2 ), is promoted by iron starvation. It has been proposed
that a modern function of salicylic acid might be to act as an internal acceptor of fer-
rous iron once the metal has been reduced and released from ferric-siderophores [ 13 ].
Similarly, the simple catecholate subunits might be internal acceptors of the ferrous
ion discharged by reduction from ferric-siderophores. If siderophore subunits have
internal ferrous ion acceptor roles, then why is there such a dramatic extracellular
accumulation of these compounds? We have argued above that primordial versions
later became modern iron cofactors or components of iron acquisition processes. As
excreted ferrous iron binding agents, these simple compounds may have encouraged
ferrous uptake by way of early porin-like membrane constituents on an anaerobic
Earth; however, their chelation capacities became inadequate once oxidized condi-
tions predominated the environment and iron was redistributed to the ferric state. It
is possible that from the simple excreted moieties, the complex ferric binding sidero-
phores could have been configured to form ferric chelation centers. In other instances
some of the siderophores are built on a backbone of citric acid, inferring that citric
acid may be a metal ion transporter that was modified to yield some of the high affin-
ity ferric chelating siderophores.
3.2 The “Iron Biofulcrum” of Infectious Diseases
An invading pathogenic microorganism must interrupt the normal flow of iron that
persists in nearly a closed circuit in the vertebrate host. Table 3.1 lists most of the
known host and microbial factors involved in this pivotal struggle [ 14 ]. While iron
acquisition is far from the only trait required for virulence, the pathogen must tilt