Calcium

1. Calcium
• Calcium is the most abundant among the minerals
in the body. The total content of calcium in an adult
man is about 1 to 1 .5 kg.
• As much as 99% of it is present in the bones and
teeth.
• A small fraction (1%) of the calcium, found outside
the skeletal tissue, performs a wide variety of
functions

2. Biochemical functions
1. Development of bones and teeth :
Calcium, along with phosphate, is required for the
formation and physical strength of skeletal tissue.
Bone is regarded as a mineralized connective
tissue.
• Bones which are in a dynamic state serve as
reservoir of Ca. Osteoblasts are responsible for
bone formation whi le osteoclast rsesult in
demineral izat ion

3. 2. Muscle contraction : Ca2+ interacts with
troponin C to trigger muscle contraction. Calcium
also activates ATPase, increases the interaction
between actin and myosin.
3. Blood coagulation : Several reactions in the
cascade of blood clotting process are dependent
on Ca2+(factor IV ).
4. Nerve transmission: Ca2+ is necessary for the
transmission of nerve impulse.
5. Membrane integrity and permeability : Ca2+
influences the membrane structure and transport
of water and several ions across it.

4. 6. Activation of enzymes : Ca2+ is needed for the direct
activation of enzymes such as lipase (pancreatic), ATPase
and succinate dehydrogenase.
7. Calmodulin mediated action of Ca2+ : Calmodulin (mol.
wt. 17,000) is a calcium binding regulatory protein. Ca-
calmodulin complex activates certain enzymes e.g.
adenylate cyclase, Ca2+ dependent protein kinases.
8. Calcium as intracellular messenger
9. Release of hormones
10. Action on heart : Ca2+ acts on myocardium and
prolongs systole

5. Dietary Requirements
Sources

6. Factors Promoting Calcium Absorption
1.Vitamin D (through its active form calcitriol)
induces the synthesis of calcium binding protein in
the intestinal epithelial cells and promotes Ca
absorption.
2.Parathyroid hormone enhances Ca absorption
through the increased synthesis of calcitriol.
3.Acidity (low pH) is more favorable for Ca
absorption.
4.Lactose promotes calcium uptake by intestinal cells.
5.The amino acids lysine and arginine facilitate Ca
absorption.

7. Factors Inhibiting Calcium Absorption
• 1. Phytates and oxalates form insoluble salts and interfere with
Ca absorption.
• 2. High content of dietary phosphate results in the formation of
insoluble calcium phosphate and prevents Ca uptake. The
dietary ratio of Ca and Phosphate between 1 : 2 and 2 : 1-is
ideal for optimum Ca absorption by intestinal cells.
• 3. The free fatty acids react with Ca to form insoluble calcium
soaps. This is particularly observed when the fat absorption is
impaired.
• 4. Alkaline condition (high pH) is unfavorable for Ca
absorption.
• 5. High content of dietary fiber interferes with Ca absorption.

9. Plasma Calcium
• Most of the blood Ca is present in the plasma since the blood
cells contain very little of it.
• The normal concentration of plasma or serum Ca is 9-11 mg/dl
(4.5-5.5 mEq/l.
• About half of this (5 mg/dl) is in the ionized form which is
functionally the most active. At least 1 mg/dl serum Ca is
found in association with citrate and/or phosphate.
• About 40% of serum Ca (4-Smg/dl) is bound to proteins,
mostly albumin and to a lesser extent globulin. lonized and
citrate( or phosphate) bound Ca is diffusible from blood to the
tissues while protein bound Ca is non-diffusible.
• In the usual laboratory determination of serum Ca, all the three
fractions are measured together.

10. Different forms of circulating calcium

11. Phosphorus
• An adult body contains about 1 kg phosphate and it is
found in every cell of the body.
• Most of it (about 80%) occurs in combination with Ca
in the bones and teeth. About 1 0% of body P is found
in muscles and blood in association with proteins,
carbohydrates and lipids.
• The remaining10% is widely distributed in various
chemical compounds

12. Biochemical functions
1. Phosphorus is essential for the development of bones and teeth.
2. It plays a central role for the formation and utilization of high-energy
phosphate compounds e.g. ATP, GTP, creatine phosphate etc.
3. Phosphorus is required for the formation of phospholipids,
phosphoproteins and nucleic acids (DNA and RNA).
4. It is an essential component of several nucleotide coenzymes e.g.
NAD+, NADP+, pyridoxal phosphate,A DP, AMP.
5. Several proteins and enzymes are activated by phosphorylation.
6. Phosphate buffer system is important for the maintenance of pH in the
blood (around 7.4) as well as in the cells

13. Dietary requirements
• The recommended dietary allowance (RDA) of
phosphate is based on the intake of calcium.
• The ratio of Ca : P of 1:1 is recommended (i.e.800
mg/day) for an adult.
• For infants, however, the ratio is around 2:1, which is
based on the ratio found in human milk.
Sources
• Milk, cereals, leafy vegetables, meat, eggs

14. Serum phosphate
• The phosphate level of the whole blood is around 40 mg/dl
while serum contains about 3-4 mg/dl. This is because the
RBC and WBC have very high content of phosphate.
• The serum phosphate may exist as free ions (40%) or in a
complex form (50%) with cations such as Ca2+, Mg2+,
Na+, K+.
• About 10% of serum phosphate is bound to proteins.
• It is interesting to note that the fasting serum phosphate
levels are higher than the postprandial. This is attributed to
the fact that following the ingestion of carbohydrate
(glucose)the phosphate from the serum is drawn by the cells
for metabolism (phosphorylation reactions)

15. Excretion
• About 500 mg phosphate is excreted in urine per day.
The renal threshold is 2 mg/dl. The reabsorption of
phosphate by renal tubules is inhibited by PTH.

16. Calcium Regulating Hormones
• Parathyroid Hormone
• Vitamin D
• Calcitonin

17. Parathyroid hormone
• Parathyroid hormone (PTH) is produced in the parathyroid glands
through the two-step conversion of pre-pro-PTH (115-amino acids)
to pro-PTH (90-amino acids) to the 84-amino acid peptide (PTH1-
84). Its molecular wt. is 9500.

19. PTH and kideny
• In kideny, PTH causes decreased renal excretion of calcium
and increased excretion of phosphates. The action is mainly
through increase in reabsorption of calcium from kidney
tubules.
PTH and intestine
• PTH stimulates 1-hydroxylation of 25-hydroxycalciferol in
kidney to produce calcitriol. This indirectly increases calcium
absorption from intestine.
PTH and bones:
•In bone , PTH causes demineralization. It induces pyrophosphatase
in the osteoclasts. The number of osteoclasts are also increased.
Osteoclasts release lactate into surrounding medium which
solubilizes calcium. PTH also causes secretion of collagenase from
osteoclasts. As a consequence, mucopolysaccharides and
hydrooxyproline are excreated in urine.

20. Biochemical Function of PTH

21. • Regulation of Parathyroid Hormone Secretion
• Parathyroid hormone is released in response to low
extracellular concentrations of free calcium. Changes in blood
phosphate concentration can be associated with changes in
parathyroid hormone secretion, but this appears to be an
indirect effect and phosphate per se is not a significant
regulator of this hormone.
• PTH reduces the reabsorption of phosphate from the proximal
tubule of the kidney, which means more phosphate is excreted
through the urine. However, PTH enhances the uptake of
phosphate from the intestine and bones into the blood. In the
bone, slightly more calcium than phosphate is released from the
breakdown of bone. In the intestines, absorption of both Calcium
and Phosphate is mediated by an increase in activated vitamin D.

22. Vitamin D synthesis
• PTH increases the activity of 1-α-hydroxylase enzyme,
which converts 25- hydroxycholecalciferol to 1,25-
dihydroxycholecalciferol, the active form of vitamin D.

23. •Vitamin D is sometimes called the sunshine vitamin. It can be produced in the
body through the action of sunlight, which is ultraviolet radiation.
•Also known as calciferol due to its role in calcium absorption
•Main role is to maintain calcium and potassium levels
•It is the only fat soluble vitamin that we can make- in the presence of sunlight
Vitamin D
The term vitamin D refers to group of two compounds that exhibit vitamin D
activity.
Vitamin D2 (ergocalciferol)
Vitamin D3 (cholecalciferol)
The provitamin of vitamin D2 is ergosterol and the provitamin of vitamin
D3 is 7-dehydrocholesterol .

26. Vitamin D, as either D3 or D2, does not have
significant biological activity. Rather, it must be
metabolized within the body to the hormonally-
active form known as 1,25-
dihydroxycholecalciferol. This transformation
occurs in two steps, as depicted in the diagram to the
right:
Within the liver, cholecalciferal is hydroxylated to
25-hydroxycholecalciferol by the enzyme 25-
hydroxylase.
Within the kidney, 25-hydroxycholecalciferol
serves as a substrate for 1-alpha-hydroxylase,
yielding 1,25-dihydroxycholecalciferol, the
biologically active form.
Each of the forms of vitamin D is hydrophobic, and
is transported in blood bound to carrier proteins. The
major carrier is called, appropriately, vitamin D-
binding protein. The half life of 25-
hydroxycholecalciferol is several weeks, while that
of 1,25-dihydroxycholecalciferol is only a few
hours.

27. Dietary Sources
Vitamin D is found only in a few foods.
The richest natural sources of vitamin D are
fish liver oils and saltwater fish such as sardines,
herring, salmon and mackerel.
 Eggs, meat, milk and butter also contain small
amounts.
Plants are poor sources, with fruit and nuts
containing no vitamin D at all.
 The amount of vitamin D in human milk is
insufficient to cover infant needs.

30. Biochemical Function of vitamin D
The overall function of 1,25-diOH D3 is to maintain adequate
plasma levels of calcium.
It performs this function by: 1) increasing uptake of calcium by
the intestine, 2) minimizing loss of calcium by the kidney, and 3)
stimulating resorption of bone when necessary.
1. Effect of vitamin D on the intestine: 1,25-diOH D3 stimulates
intestinal absorption of calcium and phosphate. 1,25-diOH D3
enters the intestinal cell and binds to a cytosolic receptor. The
1,25-diOH D3-receptor complex then moves to the nucleus where
it selectively interacts with the cellular DNA. As a result, calcium
uptake is enhanced by an increased synthesis of a specific
calcium-binding protein. Thus, the mechanism of action of 1,25-
diOH D3-receptor is typical of steroid hormones.

31. 2. Effect of vitamin D on bone: 1,25-diOH D3-receptor
stimulates the mobilization of calcium and phosphate from
bone by a process that requires protein synthesis and the
presence of PTH. The result is an increase in plasma calcium
and phosphate. Thus, bone is an important reservoir of calcium
that can be mobilized to maintain plasma levels.
3. Action of calcitriol on the kidney
Calcitriol is also involved in minimizing the excretion of
calcium and phosphate through the kideny, by decreasing their
excretion and enhancing reabsorption.

32. Calcitonin
Calcitonin is calcium regulating hormone. It is proved that calcitonin
originates from special cells, called C-cells or parafollicular cells of
the thyroid gland.
Chemistry
Calcitonin is a single chain polypeptide, have a molecular wt. of 3600.
It contains 32 amino acids.
Mechanism of action
Calcitonin binds to specific calcitonin receptors on the plasma
membrane of bone osteoclasts and renal tubular epithelial cells
activates adenylate cyclase, which increases cAMP level and mediates
the cellular effects of the hormone.

33. Metabolic role
Calcitonin acts both on
1) Bone
2) Kidney
Action on Bones
• Calcitonin inhibit the resorption of bones by osteoclasts and
there by reduced mobilization of Ca++ and inoganic
phosphorus from bones into the blood.
• It also stimulates influx of phosphates in bones.
• There is decrease in activities of lysosomal hydrolases,
pyrophosphatase and alkaline phosphatase in bones.
• Whether or not calcitonin promotes bone formation is
uncertain and controversial. But it has been established that the
hormone in addition to causing a decrease in number of
osteoclasts, it increases osteoblasts cell.

34. Action on Kidney
• The hormone acts on the distal tubule and ascending
limb of loop of henle and decrease tubular
reabsorption of both calcium and phosphorus thus
following calciuria and phosphaturia.
• The hormone inhibits α-1-hydroxylase and inhibits
synthesis of Vitamin D thus decreasing the calcium
absorption from intestine.