BIOINORGANIC CHEMISTRY

discipline at the interface between inorganic chemistry and biology

BIOINORGANIC CHEMISTRY

discipline at the interface between inorganic chemistry and biology

Resources

Biological Inorganic Chemistry: Structure and ReactivityH. B. Gray, E. I. Stiefel, J. Selverstone Valentine, I. Bertini, Eds., University Science Books, 2006

The long history of iron in the Universe and in health and diseaseBiochim. Biophys. Acta, 2012, 1820, 161-187

THE ELEMENTS OF LIFE

24 elements are essential to life

H through Zn – excluding He, Ne, Ar, Li, Be, Al, Sc, Ti

Se, Mo, I

7 additional elements are essential to certain organisms

Sr, Ba, W, As, Br, Cd, Sn

THE ELEMENTS OF LIFE

bulk elements

C, H, N, O, P, S

macrominerals and ions

Na, K, Mg, Ca, Cl, PO43-, SO4

2-

trace elements

Fe, Zn, Cu

ultratrace nonmetals and metals

F, I, Se, Si, As, B Mn, Mo, Co, Cr, V, Ni, Cd, Sn

ELEMENTAL FUNCTIONALITY

charge carriers – Na, K, Cl

structure and templating – Ca, Zn, Si, S

signaling – Ca, B, N, O, Zn

buffering – P, C

catalysis – Zn, Fe, Ni, Mn, V, Co, Cu, W, S, Se

electron transfer – Fe, Cu, Mo

energy storage – H, P, S, Na, K, Fe

biomineralization – Ca, Mg, Fe, Si, Sr, Cu, P

THE ELEMENTS OF LIFE

bulk elements

C, H, N, O, P, S

macrominerals and ions

Na, K, Mg, Ca, Cl, PO43-, SO4

2-

trace elements

Fe, Zn, Cu

ultratrace nonmetals and metals

F, I, Se, Si, As, B Mn, Mo, Co, Cr, V, Ni, Cd, Sn

ELEMENTAL MASS ABUNDANCE IN A 70 kg HUMAN

SYMPTOMS OF ELEMENTAL DEFICIENCY IN HUMANS

ELEMENTAL ABUNDANCE IN THE UNIVERSE

TERRESTRIAL ELEMENTAL ABUNDANCE

TERRESTRIAL ELEMENTAL ABUNDANCE

ELEMENTAL ABUNDANCE

TERRESTRIAL ELEMENTAL ABUNDANCE

TERRESTRIAL ELEMENTAL ABUNDANCE

ELEMENTAL MOLAR ABUNDANCE OF TRANSITION METALS

TRAPS FOR BIOLOGICAL ELEMENTS

CARRIERS IN BLOOD PLASMA

ELEMENTAL MOLAR ABUNDANCE OF TRANSITION METALS

ELEMENTAL ABUNDANCE IN THE UNIVERSE

EVOLUTIONARY TIMELINE

HYDROLYSIS REACTIONS OF Fe3+

ELEMENTAL MASS ABUNDANCE IN A 70 kg HUMAN

AVERAGE IRON DISTRIBUTION IN HUMANS

BINDING OF O2 BY MYOGLOBIN

HEME REDUCTION POTENTIALS

Fe3+/Fe2+

IRON REDUCTION POTENTIALS

PROTEINS – CLASSES AND FUNCTIONS

dynamic

catalysis enzymes

transport hemoglobin

protection antibodies

muscle contraction actin and myosin

metabolic control hormones

gene transcription histones

storage ferritin

structural

matrices for bone collagen and elastinand connective tissue

PROTEINS

proteins are polymers of 20 different -amino acids, known as the common amino acids, which have a specific codon in the DNA genetic code

properties of 20 genetically coded amino acids

-amino group – except proline, which has an imino

group

-carboxyl group

unique R side chain and a hydrogen bound at the

central carbon

possess at least one asymmetric carbon (L form)

except glycine

HOOC – C – NH2

H

R

PROTEINS

at neutral pH, the amino and carboxyl groups are ionized, and the amino acids thus exist as zwitterions

proteins are produced by enzymatic polymerization of the 20 common amino acids, connected by peptide bonds formed by dehydration

AMINO ACIDS – ALIPHATIC

AMINO ACIDS – POLAR

AMINO ACIDS – AROMATIC

AMINO ACIDS – SULFUR OR SELENIUM

H

AMINO ACIDS – SECONDARY AMINE

AMINO ACIDS – CHARGED

PROTEINSproteins are produced by enzymatic polymerization of the 20 common amino acids, connected by peptide bonds formed by dehydration

the specific sequence of amino acids in the polypeptide chain is called the primary structure of the protein and is determined from the genetic information

PROTEINS

apoprotein – amino acids only

cofactors – small organic (e.g., vitamins, ATP, NAD, FAD) or inorganic molecules (particularly metal ions) that are required for activity; can be loosely bound (coenzymes) or tightly bound (prosthetic groups)

prosthetic group – tightly bound group (e.g., heme) to apoprotein

holoprotein – active protein with cofactors and prosthetic groups attached

COFACTORS

may participate directly in catalytic processes or carry other small molecules; binding to proteins may be weak or strong

are required in small quantities, may have to be supplied in diet and are either water or fat soluble

functions

metal ions maintain protein conformation through electrostatic interactions

prosthetic groups like heme may bind to active site and change the conformation to control bonding

may accept a substrate during reaction

METAL LIGATION

metal ions are bound in mononuclear or polynuclear coordination units in which amino acid side chains function as endogenous multidentate chelating ligands (protein)

often protein ligation does not coordinately saturate metals – catalysis

common bridging ligands

O2-, OH-, -CH2S-, S2-, -CH2CO2-, imidazole

exogenous terminal ligands are also often bound to metals

H2O, OH-, O2-, HS-, S2-

ENDOGENOUS METAL LIGATION

Oxygen atoms of peptide carbonyls, nitrogen atoms of deprotonated backbone amides, and lysine side chains are also available for metal coordination.

Protein residues as ligands for metal ions

ENDOGENOUS METAL LIGATION

ENDOGENOUS METAL LIGATION

PROTEINS

apoprotein – amino acids only

cofactors – small organic (e.g., vitamins, ATP, NAD, FAD) or inorganic molecules (particularly metal ions) that are required for activity; can be loosely bound (coenzymes) or tightly bound (prosthetic groups)

prosthetic group – tightly bound group (e.g., heme) to apoprotein

holoprotein – active protein with cofactors and prosthetic groups attached

PROSTHETIC GROUPS

biosynthesized groups that may participate directly in catalytic processes or carry other small molecules; binding to proteins is strong

functions

bind metal cations tightly

may accept a substrate

may participate in electron transfer

may bind to active site and change the conformation to control bonding

MACROCYCLIC LIGANDS

tetrapyrroles most common, best known bioinorganic compounds

study of structure/function and organic synthesis of these complexes led to several Nobel prizes

1915 – Willstätter (extraction of pigments, relationship between

chlorophyll and heme)

1930 – Fischer (formula of heme and chlorophyll, first synthesis of

tetrapyrroles)

1962 – Kendrew & Perutz (X-ray structure of hemoglobin and

myoglobin)

1964 – Crowfoot Hodgkin (X-ray structure of vitamin B12)

1965 – Woodward (total synthesis of vitamin B12 and chlorophyll)

1988 – Deisenhofer, Huber, & Michel (X-ray structure of photosynthetic

reaction centers containing heme and chlorophyll in bacteria)

TETRAPYRROLESpartially unsaturated, tetradentate, macrocyclic ligands

stable, rigid, planar or nearly planar ring system

deprotonated forms bind metal ions tightly and size selectively

extensive conjugation leads to very intense colors (pigments of life) and potentially to redox activity

PORPHYRINS

PORPHYRINS

PORPHYRINS

CHLORINS – CHLOROPHYLL a

chlorophyll a

CORRINS – VITAMIN B12

SPECIAL COFACTOR LIGANDS – PTERINS FOR Mo AND W

M = Mo or WR = H or adenosine

M = Mo or WR = H, adenosine, cytosine, guanosine, hypoxanthine

SPECIAL COFACTOR LIGANDS FOR MoMo NITROGENASE

A few families of bacteria and archea are the only organisms that can produce nitrogen-containing compounds from atmospheric dinitrogen (N2 fixation). All other fixed-nitrogen derives from abiological processes.

Current nitrogen fixation :

-Abiological natural processes (lightning, volcanic eruptions): ≈10%-Haber-Bosch process: ≈30%-Biological nitrogen fixation: ≈60%

The most common nitrogen-fixing enzyme is Mo-nitrogenase

SPECIAL COFACTOR LIGANDS FOR Mo – NITROGENASE

His

homocitrate

In fact, recent evidence indicates that there is a carbon in the middle of the FeMo cofactor of nitrogenase:

Science 2011, 334, 940Science 2011, 334, 974

Typical textbook drawing:

SPECIAL COFACTOR LIGANDS – IRON SULFUR CLUSTERS

SPECIAL COFACTOR LIGANDS – IRON SULFUR CLUSTERS

SPECIAL COFACTOR LIGANDS – IRON SULFUR CLUSTERS

Dark gray: Fe(III)Light gray: Fe(II)Dual color circle: Fe centers with +2.5 oxidation state

Localized and delocalized charges possibleFerromagnetic and antiferromagnetic coupling possible

FERREDOXINS