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Principles of Bioinorganic Chemistry - 2004

The grade for this course will be determined by a term exam (35%), a written research paper with oral presentation (55%), and problem sets (10%). The oral presentations will be held in research conference style at an all-day symposium at MIT on Saturday, October 30th. Please reserve the date for there are no excused absences. Papers are due October 28th. Problem sets are due one week after their assigned date. Recitations are held at 5 PM on Mondays.



Control and Use of Metal Ion Concentrations


  • Homeostasis: maintain [M+] in proper range
  • Detoxification: remove excess and/or unnatural metal ions
    • Extracellular carriers
    • Passive transport
    • Ion channels/pumps
    • Metalloregulation
  • Binding and release of metal ions to receptors controlled by pH and redox changes
  • Ion concentration gradients - used to transmit energy and information

Transferrin and Structural Changes on Fe Binding

Baker, Anderson, and Baker, PNAS, 2003, 100, 3579.


Various Anions Can Bind Transferrin

Nomenclature: Fbp, ferric binding proteins

n, for Neisseria meningitidis

Iron must bind as Fe(III), or the ferric state. If reduced, a bacterial reductase must be involved, thus affording control of iron binding and uptake in the organism (see E1/2 values in the table above.

Crumbliss, et al. PNAS, 2003, 100, 3659.


Mechanism of Transferrin Uptake and Iron Release

in Cells by Receptor-Mediated Endocytosis


Metal Regulation of Gene Expression


  • Metal-mediated protein structure changes affect transcription
  • Metal-mediated protein structure changes affect translation
  • Apo vs holo metalloproteins bind DNA/RNA differently
  • Metalloregulatory protein is the sensor - inorganic chemistry
  • Metal-induced protein structure changes also activate enzymes
  • Metal-induced protein structure changes are metal-specific


  • Iron regulatory proteins (IRPs); control Ft and Tf translation
  • Regulation of a toxic metal, mercury
  • Zinc finger proteins control transcription
  • Ca2+, a second messenger and sentinel at the synapse

Regulation of Iron Levels in Cells

The Players:

  • Ferritin, the iron storage protein: 24-subunits, ~175 aa each; has cubic symmetry; apoFt can house 1000 iron atoms in its central core; a ferroxidase center loads the iron into the protein
  • Transferrin, the uptake protein, discussed previously


  • In bacteria, occurs at the transcriptional level
  • In mammals, the synthesis of apoferritin and of the transferrin receptor are regulated at the level of translation, not transcription

Central dogma of molecular biology:

DNA mRNA Protein




Mixed-valent polyiron oxo cluster prepared as a model for ferritin core formation intermediates.

Taft, et al., Science1993, 259, 1302

Overall formula: [Fe12O2 (OCH3)18(O2CCH3) 6(CH3OH)n]


Reminder: Apo (left) and Holo (right) Forms of Transferrin

Only Iron-Loaded Transferrin Binds to the Receptor


Metalloregulation of Iron Uptake and Storage


A single protein, Fur (for iron uptake regulator), controls the transcription of genes involved in siderophore biosynthesis. Fur is a dimer with subunits of Mr 17 kDa. At high iron levels, the Fur protein has bound metal and interacts specifically with DNA repressing transcription.


Expression of ferritin and the transferrin receptor is regulated at the translational level.


Components of the Metalloregulatory System


Iron-responsive protein (IRP)

Stem-loop structure in the mRNA



Regulation events

High Fe, low TfR, high Ft

Low Fe, high TfR, low Ft



Message translated

Message degraded




Message blocked

Message translated


IRP1 is the Cytosolic Aconitase

Contains an Fe4S4 Cluster

Cluster assembled in

protein, which then dissociates from


Apoprotein stays associated with



Regulation of a Toxic Metal, Mercury

The problem:

Mercury in the environment of industrial plants is converted by bacterial to harmful organomercury compounds. Fish and other plant and animal life assimilate the mercury which ultimately enters the

human food chain. Bacteria defend themselves against

the mercury by using the proteins listed below.

The players:

Organomercurial lyase

Mercuric ion reductase

MerR, the intracellular mercuric ion sensor

The implications:

Transcription of the genes encoding the proteins is

controlled by MerR in response to mercury levels


MerR and Mercuric Ion Reductase Properties

Reductase: no structural or detailed mechanistic information


EXAFS spectroscopy and chemical modification experiments indicate that Hg-MerR has a 3-coordinate, Hg(S-Cys)3

environment with an average Hg–S distance of 2.43 Å.

This unusual tridentate heavy metal receptor site is consistent

with the thermodynamic stability of [Hg(SR) 3]- complexes and may account both for the high affinity of the Hg(II) binding and for

the selectivity for Hg(II) over other soft metal ions that

prefer tetrahedral metal-thiolate coordination.