Metal Ions in Biochemical

processes
 1. Major components of body molecules
C, H, O, N, S
(obtained through intake of water fat, carbohydrates, proteins)

2. Nutritionally important minerals

Ca, P, Mg, Na K, Cl
(<100 mg/day)

3. Trace elements
Cr, Co, Cu, I, F, Fe, Mn, Mo, Se, Zn

4. Additional elements (non-essential for humans)

Ni, Si, Sn, V, B, Li
Transport and storage require
specific binding to carrier
proteins

Transferrin – Fe, Cr, Mn, Zn

Albumin – Cu, Zn
Amino acids – Cu, (Fe)
Trancobaltamin - Co
Globulins - Mn
Normal routes of excretion of trace
elements

Bile – Cu, Mn, Cr, Zn,

Urine – Co, Cr, Mo, Zn
Pancreatic juice – Zn
Sweat – Zn
Mucosal cell sloughing – Fe, Zn
 Sodium
• Na+ is the major cation of extracellular fluid.
• Plasma concentration - 135 -145 mmol/L
• ICT concentration - 3-10 mmol/L.
• Maintaining of total body fluid homeostasis and water
balance.
• Decrease in blood pressure and decreases in sodium
concentration result in the production of renin →
aldosteron production → decreases the excretion of
sodium in the urine
 Sodium
•Hypernatremia is associated with water depletion
(dehydratation).
• Low serum Na+ - hyponatremia, is associated with
excess of intravascular (and perhaps extravascular)
water.
• Maintaining electric potential in animal tissues
• Na+ are important in neuron (brain and nerve)
function – action potential
• Na+ are important in maintaining and influencing
osmotic balance between cells and the interstitial fluid
• Distribution is mediated by the Na+/K+-ATPase pump
 Potassium

• K+ is the principal cation of the intracellular fluid.

• Plasma concentration - 3,5 - 5,2 mmol/L.
• ICF concentration - 110 -160 mmol/L.
• Key role of K+ in skeletal and smooth muscle
contraction
• The main dietary source is the cellular material we
consume as foodstuffs.
 Potassium

• The concentration of K+ in plasma is influenced by the

pH of the blood (physiological pH 7,4 ± 0,04).
• Alkalosis (pH > 7.44) causes hypokalemia → transient
shifting of K+ into cells, presumably by stimulation of the
Na-K-ATPase.
• Acidosis (pH < 7,36) causes hyperkalemia → transient
shifting of K+ from cells at the expense of H+
• Hyperkalemia produces characteristic electrocardio-
graphic changes (life-threatening effect of K+ excess on
the heart).
 Calcium
• Total content of calcium in the body is more than 1200
mg.
• 99% of total content is deposit in bones and teeth,
• 1% in blood and body fluids
• Intracellular calcium:
- cytosol
- mitochondria
- other microsomes
- regulated by "pumps"
The serum level of calcium is closely regulated with a normal
total calcium of 2 -2.75 mmol/L (9-10.5 mg/dL) and a normal
ionized calcium of 1.1-1.4 mmol/L (4.5-5.6 mg/dL).
 Calcium metabolism

Multiple biological functions of calcium

Cell signaling
Neural transmission
Muscle function
Blood coagulation
Enzymatic co-factor
Membrane and cytoskeletal functions
Secretion
Biomineralization
 Calcium metabolism
• Absorption – duodenum and proximal jejunum.
• Active transport across cells.
• Calcium-binding proteins (calbindins) are synthesized
in response to the action of 1,25-
dihydroxycholecalciferol (vitamin D3).

• Parathyroid hormone – also increased intestinal

absorption of Ca.
 Calcium metabolism

Absorption is inhibited by:

oxalates (salts of oxalic acid),
phytates (salts of phytic acid - found in grain,
soyabeans),
phosphates (formation of insoluble salts),
sodium,
caffein
Recommended daily amount:
Children to age 11 – 1200 mg/day
From age 11 to 24 – 800 mg/day
From age 24 – 500 mg/day
In woman after menopase – 1500 mg/day (osteoporosis prevention).

Deficiency - hypocalcemia
tetany, increased neuromuscular excitability, neurological
disoders.
Result of vit. D deficiency, hypoparathyroidism, renal
insuficiency.
Symptoms are: rickets (children), osteomatacia (adults)

Toxicity – hypercalcemia (normally does not to occur)

Hyperparathyroidism, vitamin D intoxication, cancer.
 Phosphorus metabolism
Major role in structure and function of all living cells and as a
free ion
Integral part of:
nucleic acids
nucleotides
phospholipides
phosphoproteins
Enzymes that attach phosphates in ester or acid anhydride
linkages
Other enzymes (phosphatases, pyrophosphatases)
Blood phosphate: H2PO4- and HPO42-
Concentration measured as phosphorus: 2.5 - 4.5 mg/100 ml
Skeletal hydroxyapatite - Ca(PO4)2 or Ca(OH)2
 Phosphorus metabolism

Absorption in the jejunum.

Phosphate absorption is regulate by 1,25-
dihydroxycholecalciferol and parathyroid hormone.

PTH mediates mobilization and deposition of calcium and phosphate

from bone.

Deficiency
Rickets in children, osteomalacia in adults.
Abnormalities in erythrocytes, leucocytes, platelets, liver.
Depletion of phosphate occurs as a result of diminished absorption
from intestine or excessive wasting through kidney.

Hyperphosphatemia is associated with renal diseases.

 Magnesium
• Nearly 99% of the total body magnesium is located in bone or the
intracellular space.
• Second plentiful cation of the extracellular fluids.
• Mg is a cofactor of all enzymes involved in phosphate transfer
2+

reactions utilizing ATP and other nucleotide triphosphates as

substrate.
• Required for the structural integrity of numerous intracellular
proteins and nucleic acids.
• A substrate or cofactor for important enzymes such as adenosine
triphosphatase, guanosine triphosphatase, phospholipase C,
adenylate cyclase, and guanylate cyclase.
• A required cofactor for the activity of over 300 other enzymes.
• A regulator of ion channels; an important intracellular signaling
molecule.
• A modulator of oxidative phosphorylation.

Mg2+ is chelated between the beta and gamma

phosphates, diminishes the dense anionic
character of ATP
Magnesium metabolism

• Only 1% to 3% of total
intracellular Mg2+ exist as a free
ionized form (conc. 0.5 to 1.0
mmol/l).

• Total cellular concentration can

vary from 5 to 20 mmol/l.

• Intracellular Mg2+ is
predominantly complexed to organic
molecules.
 Magnesium metabolism
Effect on central nervous system:
• Certain effects of Mg2+ are similar to Ca2+.
• Increased concentration of Mg2+ cause depression of CNS
• Decreased concentration of Mg2+ cause irritability of CNS

Effect on neuromuscular system:

• Direct depressant effect on skeletal muscles – excess of Mg2+
cause decrease in acetylcholine release by motor nerve impulse.
• The action of increased Mg2+ on neuromuscular function are
antagonized by Ca2+.
• Abnormaly low concentration of Mg2+ in extracellular fluid result in
increased acetylcholine release and increased muscle excitability
(tetany).

Excess of Mg2+ cause vasodilatation.

 Magnesium metabolism

Hypomagnesemia cause:

• changes in skeletal and cardiac muscle

• changes in neuromuscular function,
• hyperirritability, psychotic behaviour
• tetany

Hypermagnesemia cause:

• muscle weakness
• hypotension
• ECG changes
• sedation and confusion

Hypermagnesemia is usual due to renal insuficiency.

 Copper
• Cu is an essential nutrient.
• Rapid growth increases Cu demands in infancy.
• The adult body contains approximately 100 mg of copper
– the highest concentrations are in liver, kidney, and hearth.

• The absorption in gastrointestinal tract requires a specific

mechanism - metal binding protein
metallothionein (Cu2+ ions are highly insoluble).

• Ceruloplasmin (CP) is a glycoprotein, copper-dependent

ferroxidase (95% of the total copper in human plasma),
oxidizes Fe2+ to Fe3+ in gastrointestinal iron absorption
mechanism.
 Copper metabolism
Model of Cu uptake and metabolism in hepatocytes:
Cu cross the plasma membrane through Ctrl1 (copper transporter1) or DMT1
(divalent metal transporter1) to the trans Golgi network (TGN) by chaperone
Hah1. Chaperone protein Ccs delivers Cu to cytosolic Cu/Zn SOD. Cox17
delivers Cu to mitochondria for cytochrome c oxidase.

Carrol et all, 2004)

 Copper metabolism
• Cu is an essential cofactor in a number of critical
enzymes in metabolism:
superoxide dismutase (Cu/Zn-SOD)
cytochrome c oxidase (COX)
tyrosinase
monoamino oxidase
lysyloxidase

• Cu metabolism is altered in inflammation, infection, an

cancer.
• In infection, Cu is essential for production of Ile-2 by
activated lymphocytes.
• In cancer, plasma CP is positively correlated with
disease stage.
 Molybdenum
Metal required for the function of the metalloenzymes:
xantine oxydase
aldehyde oxidase
sulfite oxidase

Some evidence that Mo can interfere with Co

metabolism by the diminishing the efficiency of copper
utilization.
(the foot content of Mo is highly dependent upon the
soil type in which the foodstuff are grown).
 Selenium
• an integral component of glutathion peroxidase
(intracellular antioxidant),
• a scavenger of peroxides,
• an essential element for immune function
(selenoproteins).

• Selenoproteins catalyse oxido-reduction reactions,

protective function from oxidative stress (macrophage-
or neutrophil-generated free-radical species, UV in
sunlight.

The foot content of Se is highly dependent upon the soil

type in which the foodstuff are grown.
 Manganese
• High concentration of Mn2+ is present in mitochondria
• Functions as a necessary factor for activation of
glycosyltransferases (enzymes responsible for the
synthesis of oligosaccharides, glycoproteins,
proteoglycans.
• Required for superoxid dismutase activity, for
activity of metalloenzymes:
hydrolases
kinases
decarboxylases
transferases.

Deficiency of Mn extensively reduce glycoprotein and

proteoglycan formation.
 Zinc

Component of zinc metalloenzymes :

carbonic anhydrase
lactate dehydrogenase
glutamate dehydrogenase
alkaline phosphatase
thimidine kinase
matrix metalloproteinases

Gustin – protein in saliva – major role in taste.

 Zinc

Deficiency of Zn has serious consequence :

• failure metabolism of nucleic acids (cell division, growth and

differentiation)
• multisystem disfunction as growth retardation,
hypogonadism, ophtalmologic, gastrointestinal,
neuropsychiatric symptoms.

Zink deficiency in children are marked by poor growth and

impairment of sexual development.
 Chromium
Regulation of glucose metabolism as a component of
glucose tolerance factor (GTF).
GTF increases effect of insulin (by facilitating its binding to
cell receptor site).
Chromium regulates plasma lipoprotein concentration.
Reduces serum cholesterol and serum triglycerides.

Iodine
Iodine is incorporated into thyroid hormones.
Iodine is absorbed in the form of inorganic iodine.
Thyreoperoxidase oxidizes inorganic iodine and oxidized I is
transported to phenyl group of tyrosin of thyroglobulin.
 Fluorine
Inorganic matrix of bone and teeth.
Deficiency – osteoporosis and teeth caries.

Boron
Influences of metabolism and use of Ca, Cu, Mn, N,
glucose, triglycerides.
Control of membranes function and their stabilization.
Negative influence on many metabolic processes –
inhibition of some key enzymes (inhibition of energetic
metabolism), immune system (respiratory burst).
 Vanadium
Control of sodium pump, inhibition of ATPase

Tin
Interaction with riboflavin

Lithium
Control of sodium pump, interference with the lipid metabolism

Silicon
Structural role in connective tissue, in metabolism of osteogenic cells

Nickel
Component of enzyme urease
 Iron
Major function of Fe – oxygen transport by hemoglobin.
Fe2+ and Fe3+ are highly insoluble – special transporter
systems are required.
Food Fe is predominantly in Fe3+, tightly bound to organic
molecules.

Apoferritin assimilates up to 4 300 Fe molecules to form

Fe storage protein – ferritin.

In the retikuloendothelial system ferritin provides an

available storage form for iron.

Apotransferrin (apoTf) – protein, that can bind 2 atoms

of Fe to form transferrin, Fe carrier in plasma.
Three properties of iron can account for its extensive use in terrestrial
biological reactions: (a) facile redox reactions of iron ions;
(b) an extensive repertoire of redox potentials available
by ligand substitution or modification;
(c) abundance and availability under conditions
apparently extant when terrestrial life began
The difference in the redox potentials of hydrated Fe3+ and
the electron-transport proteins in different iron-coordination
environments

The standard reduction potential for ferric ion in acid

solution is 0.77 volts; so here ferric ion is quite a good
oxidant. In contrast, cytochrome c has a redox potential of
0.25 volts. A wide range of redox potentials for iron is
achieved in biology by subtle differences in protein structure
The difference in the redox potentials of hydrated Fe3+ and
the electron-transport proteins in different iron-coordination
environments

Notice the large difference in the potential of cytochrome c

and rubredoxin,0.25voltsvs. -0.06volts,respectively. In
polynuclear ferredoxins, in which each iron is tetrahedrally
coordinated by sulfur, reduction potentials are near -
0.4volts. Thus, the entire range of redox potentials, as
illustrated in Table, is more than one volt.
Food iron is predominantly in the ferric state.
In the stomach, where the pH is less than 4, Fe3+
can dissociate and react with low-molecular weight
compounds such fructose, ascorbic acid, citric acid,
amino acids to form ferric complexes soluble in
neutral pH of intestine fluid.

A protein DMT1 (divalent metal transporter 1),

which transports all kinds of divalent metals, then
transports the iron across the cell membrane of
intestinal cells. These intestinal lining cells can
then store the iron as ferritin.

The transfer of iron from the storage ferritin (as

Fe3+ ) involves reduction to ferrous state – Fe2+ in
order for it to be released from ferritine.

The Fe2+ is subsequently again oxidized by

ferroxidase ceruloplasmin and transported bound to
plasma transferrin to storage sites in the bone
marrow, liver muscle, other tissues.
the ferritin protein, 24 peptide subunits are assembled into
a hollow spherical shell. The sphere that is formed is
approximately 80 Angstroms in diameter, and the walls are
approximately 10 Angstroms thick. The molecular weight
of ferritin (i.e., with all 24 subunits combined) is 474,000
g/mol
Iron is stored in ferritin as Fe(III) in the
mineral [FeO(OH)]8[FeO(H2PO4)]. This mineral can be
represented by ferrihydrite, FeO(OH) (shown above). Note: the
name "ferrihydrite" is used for both [FeO(OH)]8[FeO(H2PO4)] and
FeO(OH).
Figure (a) shows the unit cell (the repeating unit) for the
ferrihydrite mineral. Note: Iron (III) ions are shown in brown, and
oxygen (II) ions are shown in red. Hydrogen atoms are not shown
in this figure for simplicity.
Figure (b) shows the crystal-lattice structure of ferrihydrite. One
unit cell is shown in black and white so that it can be recognized
easily.
All of the 24 subunits are identical, but they have been
color coded to help illustrate the structure. Dark blue
subunits are closest to you, magenta subunits are farther
away, and light blue subunits are the farthest away from
you.
The four (4) subunits colored in dark blue form the walls of
a 4-fold channel. The 3-fold channels occur at the
intersections of the light blue, dark blue, and magenta-
colored subunits. The locations of 3-fold channels are
indicated on the figure, but the channels themselves are
obscured from this viewing angle.

This is a molecular
representation of the three-
fold (polar) channel in the
ferritin protein. Fe(II) can
leave the ferritin shell
through this channel.
aspartate (Asp) and
glutamate (Glu), the
polar amino acids that
line the three-fold
channels in ferritin. The
side chains are shown
in green.
 Metal ions in Biochemical processes

The protein coat of horse spleen A ribbon model of a subunits howing the
apoferritin deduced from x-ray packing of the four main alpha-
diffraction ofcrystalsofthe helices(A, B, C,and D), the connecting L-
protein loop and the E-helix