1. 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 30 th. Please reserve the date for there are no excused absences. Papers are due October 28 th. WEB SITE: web.mit.edu/5.062/www/

2. Principles of Bioinorganic Chemistry Two Main Avenues of Study Understand the roles of naturally occurring inorganic elements in biology. By weight, > 50% of living matter is inorganic. Metal ions at the core of biomolecules control many key life processes. Use metals as probes and drugs Examples: Cisplatin, auranofin as pharmaceuticals Cardiolyte ( 99m Tc) and Gd, imaging agents MoS 4 2-, Wilson’s disease; cancer??

3. Respiration - Three O 2 Carriers in Biology oxyHb, MbdeoxyHb, Mb deoxyHc oxyHc oxyHr deoxyHr

4. The Heme Group; the Defining Example of a Bioinorganic Chip Peripheral carboxylates and axial ligands matter!

5. The Major Metal Units in ET Proteins Iron-Sulfur clusters, electron transfer relay stations

7. Structure of the Streptomyces lividans (KcsA) Potassium Channel (MacKinnon, et al., 1998) Extracellular Cytoplasm Top view

8. Cobalamin structures

9. Three Inorganic Compounds Used in Modern Medicine

10. Course Organization What metals? How taken up? How assemble? How do cells regulate metal ion concentrations? Homeostasis. How do metal ions fold biopolymers? How is the correct metal ion inserted into its site? What physical methods are used and how do they work? Electron transfer metalloproteins. Substrate binding and activation, non-redox. Bioorganometallic chemistry is now established. Atom and group transfer (mainly oxygen chemistry). Protein tuning of active sites.

11. Choice, Uptake and Assembly of Metal Ions in Cells PRINCIPLES: Relatively abundant metal ions used (geosphere/biosphere) Labile metals used (nature works at a kilohertz) Low abundance metals concentrated by ATP driven processes Entry to the cell controlled by specific channels and pumps Co-factors employed: bioinorganic chips (porphyrins) Self-assembling units form - from geosphere Metallochaperones assure that metal ions find their proteins ILLUSTRATIONS: The selectivity filter of the potassium channel Uptake of iron

12. Relative abundance of metal ions in the earth’s crust and seawater Kinetics of H 2 O exchange:  10 8 sec -1, labile  10 -3 -10 -6 sec -1, inert

13. Iron Uptake in the Cell Iron is the second most abundant metal after aluminum Its Fe(II) and Fe(III) redox states render it functionally useful At pH 7, iron is insoluble (10 -18 M) The challenge: How to mobilize iron in the biosphere? The Solutions: In bacteria, siderophores In humans, transferrin The Challenge:

14. Synthesis and Structure of Dinuclear Ferric Citrate Complexes Shweky et. al. Inorg. Chem. 1994, 33, 5161- 5162. “It will be interesting to determine whether solutions of 1 or 2 are taken up by living cells.”

15. Ferric Citrate-Binding Site of Outer Membrane Transporter FecA Ferguson et. al. Science, 2002, 295, 1715-1719.

16. 1.98 Å 2.01 Å 1.96 Å2.00 Å 2.02 Å 2.05 Å 2.00 Å 2.02 Å Diiron Core of the Outer Membrane Transporter FecA Fe

17. Enterobactin: a Bacterial Siderophore

18. Enterobactin, a Cyclic Triserine Lactone A specific cell membrane receptor exists for ferric enterobactin. Release in the cell can occur by hydrolysis of the lactone, reduction to Fe(II), and/or lowering the pH.

19. Structure of Vanadium(IV) Enterobactin

20. Scheme showing the ATP-driven uptake of ferric enterobactin into E. coli cells through a specific receptor in the cell membrane. See Raymond, Dertz, and Kim, PNAS, 100, 3584. outer membrane cytoplasmic membrane intracellular esterase; hydrolyzes Ent, releases iron Does not distinguish  from 