Principles of Bioinorganic Chemistry - 2003

The grade for this course will be determined by a term exam (35%), a written research paper with oral presentation (45%), problem sets (12%) and classroom participation (8%). The oral presentations will be held in research conference style at MIT's Endicott House estate in Dedham, MA, on Saturday, October 18. Please reserve the date for there are no excused absences. Papers will be due

approximately one week earlier.WEB SITE: web.mit.edu/5.062/www/

Lecture Date Lecture Topic Reading Problems1 9/4 (Th) Intro; Choice, Uptake, Assembly of Mn+ Ions Ch. 5 Ch. 12 9/9 (Tu) Metalloregulation of Gene Expression Ch. 6 Ch. 23 9/11 (Th) Metallochaperones; Metal Folding, X-linking Ch. 7 Ch. 34 9/16 (Tu) Metals in Medicine; Cisplatin Ch. 8 Ch. 45 9/18 (Th) Electron Transfer; Fundamentals Ch. 9 Ch. 56 9/23 (Tu) Long-Distance Electron Transfer Ch. 9 Ch. 67 9/25 (Th) Hydrolytic Enzymes, Zinc, Ni, Co Ch. 10 Ch. 78 9/30 (MU) Model Complexes for Metallohydrolases Ch. 109 10/2 (MU) Dioxygen Carriers: Hb, Mb, Hc, Hr Ch. 1110 10/7 (Tu) O2 Activation, Hydroxylation: MMO, P-450, R2 Ch. 11 Ch. 811 10/9 (Th) Model Chemistry for O2 Carriers/Activators Ch. 11 Ch. 912 10/16 (Th) Complex Systems: cyt. oxidase; nitrogenase Ch. 12 Ch. 1013 10/21 (Tu) Metalloneurochemistry/Medicinal Inorg. Chem. Ch. 12 Ch. 1114 10/23 (Th) Term Examination Ch. 12 Ch. 12

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 drugsExamples: Cisplatin, auranofin as pharmaceuticals Cardiolyte (99mTc) and Gd, imaging agents

MoS42-, Wilson’s disease; cancer??

Respiration - Three O2 Carriers in Biology

oxyHb, MbdeoxyHb, Mb

deoxyHc oxyHc

oxyHrdeoxyHr

The Heme Group; the Defining Example of a Bioinorganic Chip

Peripheral carboxylates and axial ligands matter!

The Major Metal Units in ET Proteins

Iron-Sulfurclusters, electron transfer relay stations

Structure of the Streptomyces lividans (KcsA) Potassium Channel(MacKinnon, et al., 1998)

Extracellular

Cytoplasm

Top view

Cobalaminstructures

Three Inorganic CompoundsUsed in Modern Medicine

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?•Electron transfer metalloproteins.•Substrate binding and activation, non-redox.•Atom and group transfer (main oxygen chemistry).•Protein tuning of active sites.

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

Relative abundance of metal ions in the earth’s crust and seawater

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, siderophoresIn humans, transferrin

The Challenge:

Synthesis and Structure of Dinuclear Ferric Citrate Complexes

Fe(NO3)3.2H2O

Na3citrate

pyridine, H2O(Hpy)2[Fe2(cit)2(H2O)2]

.2H2O

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.”

Neocuproine hydrate[Fe3O(OAc)6(H2O)3](NO3)Citric acid, H2O

(Hneo)3[Fe2(Hcit)3].nH2O

Ferric Citrate-Binding Site of Outer Membrane Transporter FecA

Ferguson et. al. Science, 2002, 295, 1715-1719.

1.98 Å

2.01 Å

2.01 Å

1.96 Å2.00 Å

2.02 Å

2.05 Å

2.00 Å

2.00 Å

2.02 Å

Diiron Core of the Outer Membrane Transporter FecA

Fe Fe

Enterobactin: a Bacterial Siderophore

Enterobactin, a Cyclic Triserine Lactone

A specific cell membrane receptor exists for ferricenterobactin. Release in the cell can occur by hydrolysisof the lactone, reduction to Fe(II), and/or lowering the pH.

O

O

O

NHR

NHRRHN

O

O

O

Fe3+ + ent6- = [Fe(ent)]3-, Kf = 1049

At pH 7, Kd = 10-25 since the

6 catechol groups have to be

deprotonated. Only the Δ isomer

.is found in nature

Structure of Vanadium(IV) Enterobactin

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

cytoplasminmembrane

intracellular esterase; hydrolyzes Ent, releases iron

Does not distinguishΔ from