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Biochemistry of Minerals

Na

Ca

Mg

Cl

Biological forms of minerals in


living systems
Fe

Zn

Si

Cu
As

Mn
Mo

Se
I

Co
Br

Characteristics of Biochemical Ion Complexes


Na+, K+
Favored
Oxidation
state

+1

Mg2+,Ca2+

+2

Zn2+, Ni2+

+2

Fe, Cu, Co, Mo, Mn


Variable, more
than one state

Stability of
complex

Very low

Low to
medium

High

High (medium
for Mn2+ and
Fe2+)

Favored
donor atoms

Oxygen

Oxygen

Sulfur or
nitrogen

Sulfur or
nitrogen
(oxygen for Mn
and Fe)

Mobility in
biological
media

Very mobile

Semi mobile

Static

Static, semi
mobile for Mn2+
and Fe2+

After Frausto de Silva and Williams

Glucose

Hemoglobin
Fe2+

Na+
intestine

mitochondria

O2

Glucose
H2O

liver

Mg2+
Mn2+
K+
Ca2+
PO43-

PO43Fe2+
Mg2+
Cu2+

Inorganic Enzyme Cofactors


(one-third of all enzymes require a
metal ion for catalytic function)
Ino rganic C o facto r

Fu nct io n

E nz ym e C lass

M ag nesiu m
C a lc iu m
P otassiu m

substrate bind ing


substrate activatio n
structure stabilizat io n

k ina ses
hydro lase s
p yru vate kina se

Iro n
Z inc
C o pper
M a nga nese
C o ba lt
S e le niu m

o xyge n bind ing, e lectro n transpo rt


substrate bind ing, structure stabilit y
d io xyge n act ivat io n
d io xyge n act ivat io n
gro up transfer
pero xidat io n

c yto chro m es
D N A bind ing
o xida ses
o xida ses
m utases (w ith B 12)
pero xidases

Metalloenzymes vs Metal Activated Enzymes


Metal Activated

Metalloenzyme

1. Metal in equilibrium

Metal firmly affixed to protein

2. Activated by adding metal ion

Adding metal has minimal effect

3. Metal lost on isolation

Metal stays bound, removable by chelators

4. No stoichiometry with protein

Integral number per protein

5. Electrostatic bonding

Coordinate covalent bonding

6. Multiple metal binding sites

Limited number, generally one

7. Binding sites, angles irregular

Binding sites exhibit specific geometry

8. Mostly group IA and IIA metals


Na+, K+, Mg2+. Ca2+

Mostly 3d transition metals


Zn2+, Fe2+. Cu2+, Co2+

Examples of Metalloenzymes

Zinc (over 300)


Dehydrogenases
RNA, DNA polymerase
Carbonic anhydrase
Carboxypeptidase
Amino peptidase
Copper
Superoxide dismutase
Tyrosinase
Cytochrome oxidase (with Fe)
Lysyl oxidase
Peptide amidating
Dopamine beta hydroxylase

Manganese

Arginase
Water splitting enzyme
Pyruvate carboxylase
Cobalt (with B12)
Methylmalonyl CoA mutase
Homocysteine transmethylase
Molybdenum
Nitrogenase
Xanthine oxidase
Calcium

Iron

Thermolysin
Ribonucleotide reductase
Cytochrome oxidase (with Cu)

Nickel
Urease

Quick Overview of Mineral Functions


Zn2+

Na+, K+, ClOsmotic control


Electrolyte equilibria
Ion currents
Gated channels
Mg2+
Phosphate metabolism
Ca2+
Muscle contraction
Cell signaling
Enzyme cofactor
Blood clotting
Mineralization
Morphogenesis
Gene regualtion

Lewis acid
Enzyme cofactor
Protein structure
Hormone activator
Neurotransmitter
Genetic expression regulator
Fe2+, Fe3+
Heme iron
Electron transport
Oxygen activator
Oxygen carrier
Cu+, Cu2+
Enzyme cofactor
Oxygen carrier
Oxygen activator
Iron metabolism

Quick Overview (cont.)


Cr3+

Se
Redox reactions
Antioxidant

Insulin mimetic
Glucose metabolism

Mo2+
Enzyme cofactor
Nitrogen activator
HPO4=, Si
Acid-base non metals
Biomineralization
Co3+
Vitamin b12

Mn2+
Enzyme cofactor (limited)

Ni2+
Coenzyme
Remnant of early life

Examples of Metalloproteins
Function
1. Metallothionein

2. Ferritin

Cu, Zn, Cd storage, heavy metal buffer

Iron storage, iron buffer

3. Calmodulin

Ca binding, allosteric regulator

4. Transferrin

Iron transport

5. Selenoprotein W

Selenium transport

6. Calbindin

Calcium transport

Biomineralization
Calcium and phosphate
Bones and Teeth

Cross section through


trebecular and cortical
bone revealing the
internal architecture
surrounded by
marrow tissue.
Cortical bone with
Halversion system
(a series of
channels supplying
nutrients). Black
dots are osteocytes
Leg bone of a horse
showing the trebecular
(spongy) bone and the
cortical (solid) bone.
This bone is able to
withstand forces
generated by this
1,500 lb animal

Trebecular bone of
the lower spine.
Changes with
aging.

Demineralized bone: Shown is he organic matrix consisting mostly of


collagen upon which the bone crystals are laid.

Hydroxyapatite (crystal structure)


Ca10(PO4)6 OH2
Ca

Zinc Function
300 enzymes require zinc
DNA, RNA polymerases

numerous hormones require zinc


insulin
EGF

transcription factors (zinc finger


proteins)
membrane stability
myelination
skeletal development

Metal Ions in CatalysisOne third of all enzymes require a metal ion for catalysis

Zn 2+Polarizes H2O,
making it a better
nucleophile

His
His Zn2+
His

..

O
H

His

O
+ C

O
His Zn2+

His

C
O

H2 O
His

His Zn2+
His

Displaces HCO3-

..

O
H

+ H+

+ H O

O
Bicarbonate

Biochemical Iron

Hemoglobin- oxygen carrier in the blood


Myoglobin- O2 carrier in cells (mostly in muscle)
Cytochromes- electron carriers in membranes
Catalase- enzyme that destroys H2O2 (hydrogen
peroxide)
Cytochrome oxidase- electron transport, ATP
synthesis in mitochondria
Cytochrome P450- detoxifying enzyme
Nitrogenase- nitrogen fixation
Ferritin- iron storage in cells, plasma
Transferrin- iron transport in blood
Iron-sulfur electron proteins- electron carriers
Tyrosine and phenylalanine hydroxylaseenzymes that synthesizes L-DOPA and tyrosine,
respectively
Ribonucleotide reductase- enzyme that forms
deoxyribose from ribose

Function
Oxygen Transport & Storage
Hemoglobin
Myoglobin

Electron Transport & Energy Metabolism


Cytochromes
Fe-S proteins

Substrate Oxidation & Reduction


Iron dependent enzyme

Ribonucleotide reductase
Amino acid oxidases
Fatty acid desaturases
Nitric oxide synthetase
Peroxidases

All use O2 as a substrate

Examples of Iron-dependent Enzymes


Aldehyde Oxidase
R-CHO + O2 RCOOH + H-O-O-H
Tryptophan 5-monooxygenase
L-tyrptophan + BH4 + O2 5 OH L-tryptophan + BH2 + H2O
Fatty Acid desaturase
Stearoyl-CoA + NADH + H+ + O2 Oleoyl-CoA + NAD+ + 2H2O
Peroxidase
2H2O2 2H2O + O2
(O2 is either incorporated into the product or reduced by electrons)

Electron Transport Complexes


Membranes bound heme proteins or
cytochromes
Iron-Sulfur proteins..high reducing
potential
Mobile electron carriers
Coenzyme Q
Cytochrome c

Transport Mechanism
A bucket-brigade

..
NADH

NAD+

..
FMN CoQH2

..

..
Cyt b Cyt c1
(Fe3+) (Fe2+)

FMNH2 CoQ Cyt b


(Fe2+)
..

..
Reduced
-0.32 volts

Cyt c1
(Fe3+)

Cyt
Cyt c a+a3
(Fe3+) (Fe2+)

Cyt c Cyt
(Fe2+) a+a3
.. (Fe3+)

O2

H2O

..

Oxidized
+ 0.82 volts

Iron and Molybdenum in Nitrogenase


Electron Transfer Pump

Dinitrogenase

A c t iv a t e d

0 .4 0

Fe
F d

-e-

F d

M o
M o -H

R
R

M o -H
0 .2 9

e-

A TP

N=N

H
H - M o -H
H

A D P

H2

Dinitrogenase Reductase

H -M o = N = N
Fd-e-

M o

R
R e-

Fd

A TP

ADP

H -M o = N -N H 2
e + H+
e+

Fd-e-

H+

Fd

NH3

R eA TP

A DP

M o = N

NH3
e+

N2 + 3H2 2NH3

H+