MINERAL METABOLISM

(ZINC, MAGNESIUM AND COPPER)

DATED: 6th Feb, 2023

BY
DR. HASSAN BIN ASIF
ASSISTANT PROFESSOR
DEPARTMENT OF BIOCHEMISTRY
ATMC
OBJECTIVES OF THE LECTURE:
• Describe source, distribution and absorption of Zn, Mg and Cu.
• Discuss functions and clinical significance of Zn, Mg and Cu.
Introduction:
• Organic components such as CHO, proteins, and lipids form about
90% of the solid matter and mainly consist of C, H, O and N.
• The elements of the body are divided in five major groups:
1. Gr. I: C, H, O, N. Components of macromolecules such as CHO,
proteins, lipids, etc.
2. Gr. II: Nutritionally important minerals or principal elements.
• The daily requirement of these is >100mg.
• The deficiency of these can prove fatal.
• These include Na, K, Cl, Ca, P, Mg and S. They are also called
macroelements.
3. Gr. III: “Trace elements” which are essential.
• The requirement is <100mg.
• Deficiency can lead to serious disorders.
• They include Cr, Co, Cu, I, Fe, Mn, Mo, Se, Zn.
4. Gr. IV: These are additional trace elements which may be possibly
essential.
• They include Cd, Ni, Si, Sn, Vn.
5. Gr. V: These are not essential elements and may be toxic.
• They have no known function in the body and may enter the body
through polluted air, water, soil or food substances, e.g. As, CN–, Hg,
etc.
 COPPER
Adult humans contain 100-150mg of copper, out of which
• 65 mg is found in muscles
• 23 mg in bones
• 18 mg in liver.
Foetal liver contains ten times more copper than adult liver.
It occurs as:
1. Erythrocuprein (in red blood cells): Erythrocuprein is a colourless
protein containing 2 atoms of Cu per molecule.
2. Hepatocuprein found in liver
3. Cerebrocuprein found in brain
Sources of Copper:
Average diet provides 2 to 4 mg/day in the form of
• Meat
• Shellfish
• Legumes
• Nuts
• Cereals.
• Milk and milk-products are poor sources.
Requirements:
Infants and children: 0.05 mg Cu/kg body wt. per day.
Adult requirement: 2.5 mg/day.
Ordinary diets consumed daily contain about 2.5 to 5.0 mg Cu.
Absorption:
Primarily absorbed from the duodenum.
About 32% of the dietary Cu can be absorbed.
Phytates (stored form of Phosphorus), Zinc, Mo, Cd, Ag (argentum),
Hg and high amount of Vit. C inhibit Cu absorption.
Cu++ ions are highly insoluble.
Cu binds with low molecular weight metal binding protein called
metallothionein in intestinal mucosal cells.
Plasma:
In plasma, Cu binds to amino acids, particularly histidine and to
serum albumin.
Absorbed Cu is removed from the circulation by liver.
Role of Liver in Copper Absorption:
Liver processes absorbed Cu through two routes:
1. Cu is excreted in the bile from which it is not reabsorbed (major
route for excretion).
Normally, human urine contains only traces of Cu.
2. Incorporation as an integral part of Ceruloplasmin, a glycoprotein
synthesised exclusively by liver.
Serum Copper:
Serum Cu is present in two distinct forms:
1. Direct reacting Cu:
Loosely bound to albumin.
Approximately 4% present in this form.

2. Bound form:
Bound to α-globulin (Caeruloplasmin).
FUNCTIONS:
1. Role in Enzyme Action:
Cu forms integral part of certain enzymes, e.g. some of cytochromes,
cytochrome oxidase, tyrosinase, Monoamine oxidase (MAO), Lysyl oxidase,
Catalase, Ascorbic acid oxidase, uricase and superoxide dismutase.
Superoxide dismutase: Present in cytosol of mammalian liver, nerve and red
cells and contain 2 Cu++ and 2 Zn++ per molecule.
Function:
Changes superoxide radicals, formed by univalent reduction of O2 in
tissues, to H2O2.
“Mitochondrial” superoxide dismutase contain Mn++ instead of Cu++ and
Zn++ as its prosthetic group.
2. Role of Cu++ in Fe Metabolism:
Cu helps in the utilisation of Fe for Hb synthesis in the body.
Caeruloplasmin functions as serum Ferro-oxidase, catalyses the oxidation of Fe++
to Fe+++.
A yellow copper-protein called serum Ferro-oxidaseII or non-caeruloplasmin
ferro-oxidase participate in the oxidation of Fe++ in human plasma.
3. Copper helps to form insoluble elastin fibres.
4. Copper helps in the formation of bones and maintenance of myelin sheaths of
nerve-fibres.
5. Copper protein “haemocyanin” found in blood of certain invertebrates functions
as Hb in the storage and transport of O2.
Copper Deficiency Manifestations:
1. Loss of weight
2. Bone disorder
3. Microcytic hypochromic anaemia, due to impairment of erythropoiesis and
decreases in erythrocyte survival time.
4. Hair turns grey.
5. Atrophy of myocardium.
6. Non-coordinated movements and demyelination of the nerves in the animals..
CLINICAL ASPECT:
INHERITED DISORDERS
1. WILSON’S DISEASE (hepatolenticular degeneration):
It is inherited as autosomal recessive.
Mainly two defects:
1. Defect in incorporation of Cu into newly synthesised “apocaeruloplasmin”
to form caeruloplasmin.
2. The patients have impaired ability of the liver to excrete Cu into bile.
Variety of mutations copper binding P type ATPase was responsible for
Wilson’s disease.
A non-functional ATPase also causes the accumulation of copper in liver,
brain, kidney and RB cells.
It can be regarded as inability to maintain a near-zero copper balance,
resulting in copper toxicity.
Clinical features:
Total body retention of Cu is increased in liver, brain, kidney and cornea.
Hepatic cirrhosis.
Dysfunction of lenticular region of the brain, necrosis and sclerosis occurs.
Defects in renal tubular reabsorption producing aminoaciduria.
Kayser-Fleischer ring around the cornea due to Cu deposition.
The serum Cu is low, as caeruloplasmin in patient’s plasma contains no Cu.
Urinary excretion of Cu is markedly increased.
Treatment: Improvement can be achieved by removing the excess of tissue Cu by
administering Cu-chelating agent like Penicillamine.
2. MENKE’S DISEASE (Kinky or Steel hair syndrome):
It is an X-linked disorder of intestinal copper absorption.
Transport across the serosal aspect of the mucosal cell membrane is
defective.
Due to mutations in the gene for a “copper binding P type ATPase”.
Clinical Features: Mental retardation, temperature instability,
abnormal bone formation and susceptibility to infection.
3. ACAERULOPLASMINAEMIA:
In this genetic disorder, levels of ceruloplasmin is very low and hence
its ferroxidase activity is markedly deficient.
This leads to failure of release of iron from cells and iron accumulates
in certain brain cells, hepatocytes, and pancreatic islet cells.
Affected individuals exhibit severe neurologic disorders.
Use of a chelating agent or administration of plasma/or
caeruloplasmin concentrate may be beneficial.
 MAGNESIUM
Fourth most abundant and important cation in humans.
Sources:
Found in porphyrin group of chlorophyll of vegetable cells.
All animal tissues.
Cereals, beans, green vegetables, potatoes, almonds and dairy products, e.g.
cheese.
Distribution:
Total body magnesium is 2400 mEq.
Plasma level is 1.5 to 1.8 mEq/L, which is rigorously maintained within normal
limits.
Hyperthyroidism: Increases the amount of exchangeable Mg.
Mg exists in blood partly bound to proteins.
CS Fluid: Concentration of Mg in CS fluid is ½ as high as in plasma.
ABSORPTION:
Average daily intake in humans is 250–300 mg.
Roughly 1/3 of dietary Mg is absorbed; the remainder is passively
excreted in faeces.
Absorption takes place primarily in small bowel.
FACTORS AFFECTING ABSORPTION:
Increased absorption in calcium deficient diets.
In hurried bowel and damage mucosal state, absorption is decreased.
Vit. D helps in increased absorption.
Parathormone and growth hormone increases absorption.
High protein intake and neomycin therapy increases absorption.
Fatty acids, phytates and phosphates decrease absorption.
Excretion:
Magnesium is lost from the body in faeces, sweat and urine.
Factors Affecting Renal Excretion:
Increased dietary calcium.
Parathormone diminishes excretion.
ADH, GH and aldosterone increases Mg excretion.
80% greater excretion in hyperthyroidism.
Alcohol ingestion.
FUNCTIONS:
1. Role in Enzyme Action:
Mg is involved as a cofactor and as an activator to wide spectrum of enzyme
actions.
It is essential for peptidases, ribonucleases, glycolytic enzymes and co-
carboxylation reactions.
2. Neuromuscular Irritability:
Mg exerts an effect on neuromuscular irritability similar to that of Ca ++, high levels
depress nerve conduction and low levels may produce tetany (hypomagnesaemic
tetany; involuntary contraction of muscles).
 CLINICAL ASPECT

Hypermagnesaemia:
Uncontrolled Diabetes mellitus
Adrenocortical insufficiency
Hypothyroidism
Advanced renal failure
Acute renal failure.
. Renal diseases
Hypomagnesaemia:
Malabsorption syndrome and Kwashiorkor
Prolonged gastric suction
Hyperthyroidism
Portal cirrhosis
Prolonged use of diuretics
Chronic alcoholism
Delirium tremens (rapid onset of confusion)
Primary aldosteronism.
 Zinc
Sources:
(a) Animal sources: Liver, milk and dairy products, eggs.
(b) Vegetable sources: Unmilled cereals, legumes, pulses, oil seeds, yeast cells,
spinach and lettuce.
Distribution:
It is distributed in different parts of the body as follows:
70 to 86 mg/100 gm in skin and prostate.
15 to 25 mg/100 gm in bones and teeth
2.3 to 5.5 mg/100 gm in kidneys, muscles, heart, pancreas and spleen.
1.4 to 1.5 mg/100 gm in brain and lungs.
Absorption and Excretion:
 Occurs mainly from duodenum and ileum.
 Dietary calcium, phosphates and phytic acid interfere with zinc absorption.
Loss:
 9.0mg > faeces; 0.5mg > urine; 0.5mg > retained in the body.
 Whole blood contains zinc mainly in carbonic anhydrase enzyme.
 Plasma contains approximately 120 to 140 μg/100ml.
 10% of zinc in plasma is transported by α2-macroglobulin and the remainder being
transported by albumin.
Requirements: 0.3 mg zinc/per kg body wt.
Adult men and women require about 15 to 20 mg.
For pregnant and lactating women, the requirement is 25 mg
Infants and children requires 3 to 15 mg
FUNCTIONS:
1. Role in Enzyme Action:
Zinc forms an integral part of metallo-enzymes like
1. Superoxide dismutase: Present in cytosol of brain, liver and blood cells. It is a
Cu-Zn protein complex with two Zn++ per molecule of the enzyme.
2. Carbonic anhydrase: Present in RBCs, parietal cells and renal tubular epithelial
cells and contains one Zn++ per molecule of the enzyme.
3. Leucine amino peptidase (LAP): Intestinal juice.
4. Carboxy peptidase ‘A’: Pancreatic juice.
Examples of other zinc containing enzymes are:
Alcohol dehydrogenase; Retinine reductase; Alkaline phosphatase; Glutamate
dehydrogenase; Lactate dehydrogenase; DNA and RNA polymerase; δ-ALA
dehydratase
2. Role in Vitamin A Metabolism:
Zn++ stimulate the release of vitamin A
Zn++ containing metallo-enzyme “retinine reductase” participates in the
regeneration of rhodopsin in the eye during dark adaptation after
illumination with light.
3. Zinc participates in storage and secretion of Insulin.
4. Zinc deficiency may lead to ‘dwarfism’ and ‘hypogonadism’.
5. Zinc deficiency also lowers spermatogenesis in males and menstrual
cycles are disturbed in females.
6. Zinc is necessary for wound healing.
7. The biosynthesis of mononucleotides and their incorporation into the
nucleic acids require zinc.
CLINICAL SIGNIFICANCE:
1. Deficiency of zinc may interfere with storage and secretion of insulin leading to
DM.
2. In Leukaemias, zinc content is almost reduced to 10 per cent of the normal
amount.
3. Liver zinc concentration is significantly higher in subjects dying due to malignant
diseases than in subjects who are non-malignant.
4. Zinc therapy has been found to be useful in some cases of atherosclerosis.
5. Serum zinc level decreases in cirrhosis liver. Low plasma level of zinc has been
noted in acute viral hepatitis which returns to normal with recovery.
6. Decreased plasma zinc level has been observed in acute myocardial infarction.
7. In sickle cell anaemia, decreased zinc level (hypozincaemia) with hyperzincuria
have been noted.
8. Zinc deficiency produces skin lesions, scaly parakeratotic plaques with acanthosis.
Role of Zinc in binding of regulatory proteins to DNA:
The specificity involved in the control of transcription requires that regulatory
proteins bind with high affinity to the correct region of DNA.
Three Unique Motifs:
1. Helix-turn helix
2. Zinc finger motif
3. Leucine-Zipper