Calcium

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 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 I V ). 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.

8. 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.

9. Different forms of circulating calcium

10. 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

11. 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

12. 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

13. 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)

14. 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.

15. Calcium Regulating Hormones Parathyroid Hormone Vitamin D Calcitonin

16. 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.

17. 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.

18. Biochemical Function of PTH

19. 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.

20. 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.

21. 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 .

22. Vitamin D, as either D 3 or D 2 , 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.

23. 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.

24. 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.

25. 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 .

26. 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.

27. 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.

28. 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.