Biochemistry of Minerals
C
H
Na
N
K
Ca
O
S
Mg
P
Cl
Biological forms of minerals in
living systems
Fe
Zn
V
Si
Cu
As
Mn
Mo
Se
I
Co
Br
F
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-
PO43-
Fe2+
Mg2+
Cu2+
Inorganic Enzyme Cofactors
(one-third of all enzymes require a
metal ion for catalytic function)
Inorganic Cofactor
Function
Enzyme Class
Magnesium
Calcium
Potassium
substrate binding
substrate activation
structure stabilization
kinases
hydrolases
pyruvate kinase
Iron
Zinc
Copper
Manganese
Cobalt
Selenium
oxygen binding, electron transport
substrate binding, structure stability
dioxygen activation
dioxygen activation
group transfer
peroxidation
cytochromes
DNA binding
oxidases
oxidases
mutases (with B12)
peroxidases
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
P
O
H
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
O
His –Zn2+
+ C
O
His
O
C
O
H
H2 O
His
His –Zn2+
His
Displaces HCO3-
..
O
H
+ H+
O
+
H O
C
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
R
NH3
R eA TP
A DP
M o = N
NH3
e+
N2 + 3H2  2NH3
H+