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or Hg(II) can replace Zn(II) in order to maintain the thermal stability of the Cu(II)-free
apoenzyme [65]. Overall, the apoenzyme is more sensitive to inactivating processes com-
pared to the holoenzyme. Stability is also affected by the oxidation state of the bound
copper. DSC measurements of dithionite reduced native SOD1 containing Cu
þ
and Zn
2þ
reveal one peak at 96
C while native SOD1 containing Cu
2þ
and Zn
2þ
exhibits two melt-
ing transitions at 89 and 96
C wherein the transition at 89
C is affected by oxygen in the
solution [66]. The effect of metal binding in protein stabilization is not unique to SOD1.
For example the Cu-binding in
P. aeruginosa
azurin stabilizes the protein, whereas in
beta-2-macroglobulin it causes native-state destabilization [67].
Taken together, the presence and identity of the metal ion bound to SOD1 and the status
of the disulfide bonds in SOD1 have significant effects on the folding, stability, and cata-
lytic efficiency of the enzyme. Destabilization and misfolding of this enzyme may result
in the formation of aggregations in neural tissues and cause neurodegeneration and ALS.
The above sections have briefly described the folding, structure, and function of several
natural metallofoldamers-metalloproteins, which serve as a foundation for the further
design and investigation of synthetic metallofoldamers.
1.3 Metallopeptides
Analogous to the metalloproteins discussed above which inspired the design and synthe-
ses of metallofoldamers, a number of simple natural products such as oligopeptides and
oligoketides and some antibiotics also adopt secondary or specific structures upon binding
with metal ion(s) and can serve as templates for functional metallofoldamers. Metal ions
play a key role in the actions of synthetic and natural metallopeptides [68,69] and are
involved in specific interactions with proteins, membranes, nucleic acids, and other bio-
molecules. For example, Fe/Co-bleomycin binds DNA, which impairs DNA function and
may also result in DNA cleavage; metallobacitracin binds the sugar-carrying undecaiso-
prenyl pyrophosphate to inhibit cell wall synthesis; and the specific binding of metal ions
to ionophores or siderophores results in their transport through the cell membrane either
causing disruption of the potential across the membrane or enabling microorganisms to
acquire Fe from the environment.
In addition to the a-helical and b-sheet secondary structures, the b-turn is another impor-
tant secondary structure in peptides and proteins, in which Pro frequently found at the
“break point” [70] and the b-turns [71] to afford an anti-parallel b-sheet structure. In addi-
tion to Pro, Gly is also a “structure breaker” and frequently associated with Pro to form a
turn [72] as observed at the G12-P13 b-turninCu,Zn-superoxidedismutase (Figure 1.10).
Combining with His, a metal-binding site can form near the turn in metalloproteins, such as
the Pro86 turn in the copper site of plastocyanin (Figure 1.10, blue). Peptides are prototypi-
cal molecules which can adopt secondary structures to exhibit broad biological activities by
interacting with specific receptors or target proteins, including a large number of G protein-
coupled receptors, wherein a general “turn motif” is associated with the binding [73]. Pep-
tides are involved in many physiological regulations and bioactivities, such as the opioid
peptides dynorphin, endorphin, and enkephalin, galanin (which may regulate nociception),
ghrelin (which may stimulate hunger), Ca
2þ
-regulating calcitonin, adrenocorticotrophic hor-
mone, and some neurotoxins. Such peptide-associated activities have triggered the design
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