Calcium binding protein synthesis

Calcium is absorbed from the intestine by facilitated diffusion and active transport. In the former, Ca " moves from the mucosal to the serosal compartments along a concentration gradient. The active transport system requires a cation pump. In both processes, a calcium-binding protein (CaBP) is thought to be required for the transport. Synthesis of CaBP is activated by 1,25-DHCC. In the active transport, release of Ca " from the mucosal cell into... 

Vitamin K Is Also Important in the Synthesis of Bone Calcium-Binding Proteins... 

Calmodulin, a calcium binding protein, is involved in Ca2+-dependent regulation of several synaptic functions of the brain synthesis, uptake and release of neurotransmitters, protein phosphorylation and Ca+2 transport. It reacts with TET, TMT and TBT which then inactivates enzymes like Ca+2-ATPase and phosphodiesterase. In vitro studies indicated TBT was greater at inhibiting calmodulin activity than TET and TMT, whereas in vivo the order was TET > TMT > TBT. This may be due to the greater detoxification of TBT (66%) in the liver before moving to other organs30,31. 

Once formed, 1,25-DHCC acts on duodenal epithelial cells as a lipid-soluble hormone. Its intracellular receptor (a Zn-finger protein) binds to response elements in enhancer regions of DNA to induce the synthesis of calcium-binding proteins thought to play a role in stimulating calcium uptake from the GI tract. 

Much discussion of vitamin D focuses on bone health, though this is by no means the only focus on vitamin D action. One result of l,25(OH)2D action is the upregulation of the synthesis of a calcium-binding protein whose function is to transport dietary calcium across the intestinal mucosa and into the systemic circulation. Phosphate accompanies the calcium. This has the effect of increasing the fraction of dietary calcium that is actually absorbed and is, therefore, potentially useful for bone formation. In addition, l,25(OH2)D has the effect of mobilizing calcium from bone. Both actions tend to raise the extracellular level of calcium. 

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

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 is typical of steroid hormones (see p. 238). 

The next stage involves the synthesis of specific calcium-binding proteins, typified by the intestinal CaBP253 discussed in Section 62.1.3.4.5, which probably stimulates the transport of calcium. The role of the protein in vitamin D-dependent absorption of calcium is supported by the good correlation between the concentration of CaBP and the rate of calcium absorption. Under conditions of low calcium or phosphorus diets, chicks and other animals produce more intestinal CaBP to increase the efficiency of uptake of calcium. In general, adaptation to a low calcium diet involves increased synthesis of l,25-(OH)2D3 and the intestinal CaBP. Lowered requirements for calcium in old age are manifested by lower levels of both factors.449,450... 

Q -Lactalbumin (a-LA) is a component of mammalian milk. It complexes with jS-galactosyl transferase to form lactose synthetase that catalyzes the synthesis of lactose. Unlike most of the other known calcium-binding proteins that have clusters of calcium ions or cooperative calcium binding, only one calcium-binding site with very high calcium-binding... 

H)2D3 also appears to mobilize calcium from bone, although the presence of parathyroid hormone is necessary. The rise in plasma calcium produced by l,25-(OH)2D3 also seems to involve protein and RNA synthesis, and it has been suggested that a calcium-binding protein is synthesized in response to the vitamin 0. High affinity binding proteins for vitamin D metabolites have been found in bone cytosols. 

PTH also increases intestinal calcium absorption by increasing 1,25 (OH) 2D. PTH is a major trophic factor for renal 25(OH)t>-la-hydroxylase. It increases the conversion of 25(0H)D to the active vitamin D metabolite, l,25(OH)2D. Calcium is absorbed principally in the duodenum, although it can also be absorbed by the distal small bowel and colon. About 30% of a daily calcium intake of 1 g (25 mmo ) is absorbed. Approximately 100 mg (2.5 mmol) of calcium is secreted into gut lumen by intestinal secretion therefore net calcium absorption is 200 mg (5.0 mmol)/day. Calcium is absorbed by passive diffusion and by an active transport system. It is estimated that passive diffusion accounts for absorption of about 10% of ingested calcium per day. Active calcium absorption in the duodenum is under the control of l,25(OH)2D. This vitamin D metabolite increases the intestinal cell synthesis of a calcium-binding protein (CaBP), which enhances the net absorption of ingested calcium. 

Intracellular ionized calcium acts as a second messenger, coupling the action of a hormone or electrical impulse (the first messenger) on the outside of the cell to intracellular events, such as hormone or protein secretion, protein kinase activity, or muscle contraction. The effect of Ca on intracellular processes is often mediated by a small calcium-binding protein, such as troponin C in muscle (Chapter 21) or calmodulin in many other cells (Chapters 15 and 30). Synthesis of these calciumbinding proteins is not directly affected by vitamin D or any of its metabolites. Many stimuli that affect permeability to calcium also activate membrane-bound adenylate cyclase and increase the intracellular concentration of cAMP (Chapter 30). 

PTH increases serum calcium levels by two other mechanisms. PTH increases the synthesis of the active form of vitamin D, 1,25-dihyroxycholecalciferol, in the kidney, which in turn stimulates production of calcium binding protein. Calcium binding protein enhances calcium phosphate absorption from the gut lumen. PTH also inhibits renal calcium excretion, while promoting phosphate excretion, causing a small increase in serum calcium levels. 

Induces synthesis of calcium-binding protein which increases absorption of calcium... 

Calcitriol increases the intestinal absorption of calcium and phosphate by stimulating the active system for transport of calcium. It also stimulates the synthesis of the calcium-binding protein in the mucosa cells. Calcitriol is more than five times as active as 25(OH)D3 with respect to its effect on the intestinal calcium absorption and more than 100 times as effective as an absorber of Ca ftom the skeleton. The concentration of calcitriol in plasma is about 70 pmol/liter, which is about 1000 times lower than the concentration of 25(OH)D3. 

Harmeyer, J., and H. F. DeLuca Calcium Binding Protein and Calcium Absorption after Vitamin D Administration. Arch. Biochem. Biophys. 133, 247 (1969). Harrison, I. T., and B. Lythgoe Calciferol and its Relatives. Part III. Partial Synthesis of Calciferol and of Epicalciferol. J. Chem. Soc. (London) 1958, 837. Harrison, R. G., B. Lythgoe, and P. W. Wright Calciferol and its Relatives. Part XVIII. Total Synthesis of la-Hydroxyvitamin D3. J. Chem. Soc. Perkin I 1974, 2654. 

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