Metal Ions in Biological Systems (Bioinorganic
Chemistry)
Metal ions play an indispensable role in
a multitude of cellular events (e.g. metabolism,
respiration, photosynthesis, nitrogen fixation,
signal transduction, and many more), pivotal
not only to the sustenance but also to the
propagation of living systems. Hence, it
is not surprising that approximately one
third of all biologically active systems
depend on metal ion(s) for their function.
Research in our laboratory focuses primarily
on zinc and group VI transition metals [Mo,
W, (Cr)] in biological systems:
1. Zinc is a crucial component of
many proteins involved in virtually all
aspects of metabolism and the transmission
of genetic information. Research in this
field centers on two distinct Zn(II)-hydrolases,
(i) the anthrax lethal factor (LF), which
constitutes one of three components of the
anthrax toxin, and (ii) metallo-b-lactamases
(MBLs), enzymes involved in the emergence
of microbial resistance to
b-lactam
antibiotics. In particular, the role of
metal ion(s) in the catalytic events leading
to the hydrolysis of MAPK kinases (the substrates
for LF), and the inactivation of
b-lactams
(the substrates of MBLs) are investigated.
Furthermore, inhibitors of these enzymes
are studied with respect to their mode of
action. Insights gained from such investigations
may lead to the development of potent and
clinically useful inhibitors of these enzymes.
2. Molybdenum is an essential element
for many forms of life due to its participation
in redox processes such as nitrogen reduction,
oxygen atom transfer and hydroxylation reactions.
Tungsten, on the other hand, has
only recently been recognized to be essential
for a number of (hyper)thermophilic microorganisms.
Research in this field pertains to the identification
of Mo/W-containing precursors that are utilized
in the synthesis of cofactors containing
these metals. The mechanisms underlying
the insertion of Mo/W into the cofactor(s),
as well as the transport and storage of
molybdenum (and tungsten) in the cell are
also being investigated.
Instrumental techniques used to achieve
our research objectives include UV/VIS,
fluorescence and EPR spectroscopy, as well
as mass spectrometry. Stopped-flow, cell
culture and protein isolation methods are
also employed.
Selected
recent publications:
Siemann,
S., Schneider, K., Oley, M. & Müller,
A. (2003) Characterization of a tungsten-substituted
nitrogenase isolated from Rhodobacter
capsulatus. Biochemistry 42,
3846-3857. [Pdf]
Siemann, S., Clarke, A. J., Viswanatha,
T. & Dmitrienko, G. I. (2003) Thiols
as classical and slow-binding inhibitors
of IMP-1 and other binuclear metallo-b-lactamases.
Biochemistry 42, 1673-1683.
[Pdf]
Siemann, S., Evanoff, D., Marrone, L., Clarke,
A. J., Viswanatha, T. & Dmitrienko,
G. I. (2002) N-Arylsulfonyl hydrazones as inhibitors of IMP-1
metallo-b-lactamase. Antimicrob. Agents Chemother. 46, 2450-2457. [Pdf]
Siemann, S., Brewer, D., Clarke, A. J.,
Dmitrienko, G. I., Lajoie, G. & Viswanatha,
T. (2002) IMP-1
metallo-b-lactamase:
effect of chelators and assessment of metal
requirement by electrospray mass spectrometry.
Biochim. Biophys. Acta 1571,
190-200. [pdf]
Siemann, S., Schneider, K., Dröttboom,
M. & Müller, A. (2002)
The Fe-only nitrogenase and the Mo nitrogenase
from Rhodobacter capsulatus: A comparative
study on the redox properties of the metal
clusters present in the dinitrogenase components.
Eur. J. Biochem. 269, 1650-1661.
[Pdf]
Siemann,
S., Schneider, K., Behrens, K. Knöchel,
A., Klipp, W. & Müller, A. (2001) FeMo
cofactor biosynthesis in a nifE mutant
of Rhodobacter capsulatus. Eur.
J. Biochem. 268, 1940-1952. [Pdf]
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