Biochemistry of Minerals Biological forms of minerals in living systems Na K Ca Mg P Cl C N H O S Fe Zn Cu Mn Se V Si As Mo I Co Br F
Biochemistry of Minerals
Biological forms of minerals in living systems
Na K Ca Mg
P
Cl
C NH O S
Fe Zn Cu Mn Se
V Si As Mo I
Co
Br F
Favored Oxidation state
+1 +2 +2 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+
Na+, K+ Mg2+,Ca2+ Zn2+, Ni2+ Fe, Cu, Co, Mo, Mn
Characteristics of Biochemical Ion Complexes
After Frausto de Silva and Williams
Glucose
intestine
Glucose
Na+
liver
Mg2+
Mn2+
K+
Ca2+
PO43-
mitochondria
Hemoglobin
O2
Fe2+
H2O
Fe2+
PO43-
Mg2+
Cu2+
Inorganic Enzyme Cofactors(one-third of all enzymes require a metal ion for catalytic function)
Inorganic Cofactor Function Enzyme Class
Magnesium substrate binding kinasesCalcium substrate activation hydrolasesPotassium structure stabilization pyruvate kinase
Iron oxygen binding, electron transport cytochromesZinc substrate binding, structure stability DNA bindingCopper dioxygen activation oxidasesManganese dioxygen activation oxidasesCobalt group transfer mutases (with B12)Selenium peroxidation peroxidases
Metalloenzymes vs Metal Activated Enzymes
Metal Activated
1. Metal in equilibrium
Metalloenzyme
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 metalsZn2+, Fe2+. Cu2+, Co2+
Zinc (over 300)
DehydrogenasesRNA, DNA polymeraseCarbonic anhydraseCarboxypeptidaseAmino peptidase
Copper
Superoxide dismutaseTyrosinaseCytochrome oxidase (with Fe)Lysyl oxidasePeptide amidating Dopamine beta hydroxylase
Iron
Ribonucleotide reductaseCytochrome oxidase (with Cu)
Manganese
ArginaseWater splitting enzymePyruvate carboxylase
Cobalt (with B12)
Methylmalonyl CoA mutaseHomocysteine transmethylase
Molybdenum
NitrogenaseXanthine oxidase
Calcium
Thermolysin
NickelUrease
Examples of Metalloenzymes
Na+, K+, Cl-
Osmotic controlElectrolyte equilibriaIon currentsGated channels
Mg2+
Phosphate metabolism
Ca2+
Muscle contractionCell signalingEnzyme cofactorBlood clottingMineralizationMorphogenesisGene regualtion
Zn2+
Lewis acidEnzyme cofactorProtein structureHormone activatorNeurotransmitterGenetic expression regulator
Fe2+, Fe3+
Heme ironElectron transportOxygen activatorOxygen carrier
Cu+, Cu2+
Enzyme cofactorOxygen carrierOxygen activatorIron metabolism
Quick Overview of Mineral Functions
Quick Overview (cont.)
Se
Redox reactionsAntioxidant
Mo2+
Enzyme cofactorNitrogen activator
HPO4=, Si
Acid-base non metalsBiomineralization
Co3+
Vitamin b12
Ni2+
CoenzymeRemnant of early life
Cr3+
Insulin mimeticGlucose metabolism
Mn2+
Enzyme cofactor (limited)
Examples of Metalloproteins
1. Metallothionein
Function
Cu, Zn, Cd storage, heavy metal buffer
2. Ferritin 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
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.
Cortical bone with Halversion system (a series of channels supplying nutrients). Black dots are osteocytes
Cross section through trebecular and cortical bone revealing the internal architecture surrounded by marrow tissue.
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 Catalysis- One third of all enzymes require a metal ion for catalysis
His –Zn2+
His
His
O
H
CO
O
H2O
Zn 2+Polarizes H2O, making it a better
nucleophile
Zn 2+Polarizes H2O, making it a better
nucleophile
His –Zn2+
His
His
O
H
..+ C
O
O
His –Zn2+
His
His
O
H
..+ H+ + H O C
O
O
Bicarbonate
Displaces HCO3-
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 hydroxylase-
enzymes 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
L-tyrptophan + BH4 + O2 5 OH L-tryptophan + BH2 + H2O
Fatty Acid desaturase
Aldehyde Oxidase
R-CHO + O2 RCOOH + H-O-O-H
Tryptophan 5-monooxygenase
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
NADH
NAD+
FMN
FMNH2 CoQ
CoQH2
Cyt b(Fe3+)
Cyt b(Fe2+)
Cyt c1
(Fe3+)
Cyt c1
(Fe2+)Cyt c(Fe3+)
Cyt c(Fe2+)
Cyt a+a3
(Fe3+)
Cyt a+a3
(Fe2+) O2
H2O
A bucket-brigade
Reduced Oxidized
..
..
..
..
..
..
..
..
-0.32 volts + 0.82 volts
M o
M o - H
M o - H
H
M o - H
H
H -
N = N
H 2H - M o = N = N
F d - e -
F d
R
R e -
A TP A D P
H - M o = N - N H 2
0 . 2 9
F d - e -
F d
R
R e -
A T P A D P
0 . 4 0
F d - e -
F d
R
R e -
A TP A D P
M o = N
N H 3
N H 3
M o
A c t iv a t e d
Electron Transfer “Pump” Dinitrogenase
Dinitrogenase Reductase
e + H+
e + H+
e + H+
Iron and Molybdenum in Nitrogenase
Fe
N2 + 3H2 2NH3