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BIOKIMIA MINERAL Calsium Phosphor Iron Zinc Iodine Dr Nur Rahman, STP MP CALCIUM Jumlah mineral paling banyak dlm tubuh sekitar 1.5%-2% berat bb dan 39% of total minerals tubuh. 99% calcium ada di bone and teeth 1% of calcium is in the blood and extracellular fluids and within the cells of all tissues, yg berfungsi mengatur metabolisme. Calcium occurrence In nature Tidak ada yg bebas Occurs mostly in soil systems as limestone (CaCO3), gypsum (CaSO4*2H2O) & fluorite (CaF2) In the body The most abundant mineral Average adult body contains app. 1 kg 0,1 % in the extra cellular fluid 1 % in the cells The rest (app. 99 %) in the skeleton (Bones can serve as large reservoirs, releasing calcium when extracellular fluid concentration decreases and storing excess calcium) Calcium functions Elemen penyususn utama tulang dan gigi calcium phosphate (Ca10(PO4)6(OH)2 (hydroxyapatatite) Komponen struktur sel Kekuatan tulan tgt dari konsentrasi l calcium Hormone regulation of calcium-phosphorus metabolism Parathyroid hormone (PTH) Organ-target: bones, kidneys Function of PTH - increase of Ca concentration in plasma Mechanisms: 1. Releasing of Са by bones (activation of osteoclasts – resumption of bones) 2. Increase of Са reabsorbing in kidneys 3. Activation of vit. Dз synthesis and increase of absorption in the intestine Vitamin D Thyreocalcitonin Organ-target - bones Function - decrease of Ca concentration in plasma Pathways of Calsium Metabolism Pengaturan metabolism Calsium melibatkan : intestinal absorption (gut), blood calsium (Ca) and Phosphate (P) concentrations, bone, the kidneys-which produce the hormonal form of vit D-and parathyroid glands (PTG), mengeluarkan parathyroid hormone (PTH). Rendah serum calsium or high serum phosphate level stimulates pengeluaran PTH n (Step 1) through negative Calcium functions (Bone) - Osteoclasts (bone cells) remodel the bone by dissolving or resorbing bone Osteoblasts (bone forming cells) synthesize new bone to replace the resorbed bone Found on the outer surfaces of the bones and in the bone cavities Calcium functions Berperan penting dlm pengaturan tbuh . A passive role: - - As a cofactor beberapa enzymes (e.g. Lipase) and proteins As component dlm pembekuan blood An active role: as an intracellular signal - - In the relaxation and constriction of blood vessels In cell aggregation and movement In muscle protein degradation In secretion of hormones as insulin In cell division In nerve impulse transmission Absorption, Transport, Storage, and Excretion Calsium diabsorsi di semua bagian small intestine, paling cepat di bagian duodenum, dlm kondisi acidic medium (pH < 7) prevails Calsium is absorbed by two mechanisms : 1. Active Transport 2. Konsentrasi calcium di usus rendah Mainly in duodenum and proximal jejenum Has limited capacity, and it is controlled through the action of Vit D Passive transfer Konsentrasi calcium di usus rendah Independent of vit D Sepanjang usus halus Calcium dapat juga diabsorsi dicolon tapi dlm jumlah kecil . Calcium diabsorsi dlm bentuk ion Calcium tidak dapat diabsorsi jikan ada oxalate or if it forms soap with free fatty acids. Calsium yg tidak diabsorb di buang via feces as calcium oxalates and calcium soaps Konsentrasi serum ionized calcium di controlled primarily by PTH, hormone ini dikeluarkan oleh parathyroid glands. Dan hormon lainya calcitonin, Vit D, estrogens and other. REGULATION OF SERUM CALCIUM Calcium di tulang akan selalu menyeimbangkan dg calsium dlm darah. PTH mengatur ca serum selalu normal , yaitu 10 mg/100 ml of blood serum (2,5 mmol/L). Ketika ca serum darah rendah , PTH stimulates ca tulang ke darah. Dalam waktu yang sama PTH promotes renal tubular resorption of calcium, and it indirectly stimulates increased intestinal absorption of calcium via the hormonal form of vitamin D (1,25[OH]2D3) REGULATION OF SERUM CALCIUM (lanjutan) Hormon yang lain spt : glucocorticoids, thyroid hormones, and sex hormones juga berperanan dlm calcium homeostatis Glucocorticoids berfungsi calcium absorption secara active and passive mechanism Thyroid hormones (T4 and T3) stimulates resorption bone; conditions chronic hyperthyroid result in loss of compact and trabecular bone. REGULATION OF SERUM CALCIUM (lanjutan) In woman, normal bone balance memerlukan serum konsentrasi estrogen agar kondisi normal . Kecepatan penurunan serum estrogen concentration selama menopause merupakan faktor contributing to bone resorption. Treating postmenopausal women with estrogen slows the rate of bone resorption. Bone resorption dihambat by testosterone. Interactions Phosphate: ↓ calcium excretion in the urine Caffeine: ↑ urinary and fecal excretion of calcium Sodium: ↑ sodium intake, ↑ loss of calcium in urine Dietary constituents: Phytic acid can reduce absorption of calcium by forming an insoluble salt (calcium phytate) Iron: calcium might have inhibitory effect on iron absorption Absorption and excretion Usual intakes is 1000 mg/day About 35 % is absorbed (350 mg/day) by the intestines Calcium remaining in the intestine is excreted in the feces 250 mg/day enters intestine via secreted gastrointestinal juices and sloughed mucosal cells 90 % (900 mg/day) of the daily intake is excreted in the feces 10 % (100 mg/day) of the ingested calcium is excreted in the urine Calcium must be in a soluble and ionized form before it can be absorbed Absorption and excretion factors Absorption increased by: Excretion increased by: - - - Body need Vitamin D Protein Lactose Acid medium - Low parathyroid hormone (PTH) High extracellular fluid volume High blood pressure Low plasma phosphate Metabolic alkalosis Absorption decreased by: Excretion decreased by: - Vitamin D deficiency Calcium-phosphorus imbalance Oxalic acid Phosphorous Dietary fiber Excessive fat High alkalinity Also stresses and lack of exercise - High parathyroid hormone Low extracellular fluid volume Low blood pressure High plasma phosphate Metabolic acidosis Vitamin D3 - - - - - - Metabolism Factors involved in calcium metabolism Bone Growth and Calcium Metabolism Figure 23-19: Bone growth at the epiphyseal plate Calcium Metabolism: Figure 23-20: Calcium balance in the body Regulation Vitamin D, parathyroid hormone and calcitonin Vitamin D (in active form) - Berefek pada peningkatan absorbsi ca dan phospat pd intestine and kidneys ke dlm cairan extracellular. Sangat berefek pd bone deposition and bone absorption Parathyroid hormone (PTH) - Meningkatkan mechanism controlling extracellular calcium and phosphate concentrations dg cara mengatur reabsorbsi di intestinal , renal excretion and perubahan diantara cairan extracellular and bone dari dua ions Calcitonin (a peptide hormone secreted by the thyroid gland) - Cenderung decrease concentration plasma calcium In general, mempunyai efek yg berlawanan thd PTH. - - Regulation Activation of vitamin D3 - Cholecalciferol formed in the skin by sun - Converted in liver (feedback effect) - 1,25 DHCC formation in kidney Controlled by PTH Plasma calcium concentration inversely regulates 1,25 DHCC Regulation - Kondisi jika konsentrasi plasma ionized calcium menurun akan dimediasi oleh PTH & vitamin D PTH regulates through 3 main effects: By stimulating bone resorption By stimulating activation of vitamin D → ↑ intestinal Ca reabsorption By directly increasing renal tubular calcium reabsorption Calcium and the Cell Translocation across the plasma membrane Translocation across the ER and mitochondrion; Ca2+ ATPase in ER and plasma membrane Phosphor 700 g phosphorus ada pd jaringan, dan 85% ada pd skeleton and teeth dlm bentuk calcium phosphate crystals. The serum inorganic phosphorus diatur PTH at 3 to 4 mg/100 ml in adults Figure 5-3 Phosphorus Balance is maintained primarily by the amount of phosphate absorbed versus the amount excreted by the kidneys and intestine Absorption, Transport, Storage, and Excretion Semua Phosphates di absorbed dlm bentuk inorganic state Ikatan Organically phosphate dihidrolisis di lumen intestine dan selanjutnya di keluarkan sbg inorganic phosphate, primarily through the action of pancreatic or intestinal phosphatases Bioavailability tgt bentuk dan pH phosphate. Adanya senyawa pitat akan pengaruhi phosphorus . The efficiency of phosphate absorption is 60% to 70% in adults, almost twice as high as for calcium The primary route of phosphorus excretion is renal, which also the primary site of phosphate regulation Hal utama penyebab hilangnya phosphorus dalam urin : 1. An increased intake of phosphate 2. An increase in phosphate absorption 3. The plasma Phosphorus concentration 4. Hyperparathyroidism 5. Acute respiratory or metabolic acidosis 6. The intake of diuretics 7. The expansion of extracellular volume Jika PTH levels tinggi, pengeluaran pospat akan meningkat. Kekuranga gizi dapat menyebabkan hypophosphatemia dan renal losses of phosphate Penurunan eksresi pospat berhubungan dg : Pembatasan dietary phosphorus; Peningkatan plasma insulin, thyroid hormone, growth hormone, glucagon, or glucocorticoids; metabolic or respiratory alkalosis; and extracellular volume contraction Toxicity Konsentrasi PTH yg tinggi secara permanen akan disebabkan konsemsi low-calcium, highphosphorus diet “Nutritional Secondary Hyper-parathyroidism” Selain itu akan terjadi peningkatan bone turnover that potentially can result in a reduction of bone mass and density Adequate calcium intakes, yg berasal dari suplemen akan menurunkan serum PTH concentration and membantu menghambat bone loss MAGNESIUM Magnesium jumlah terbanyak kedua setelh Potassium) dlm intracellular cation. In adult : approx. 20-28 g of magnesium, of which approx 60% is found in bone, 26% in muscle, and the remainder in soft tissues and body fluids. Magnesium in bone is present in exchangeable and non-exchangeable pools Normal serum levels 1,5 to 2,1 mEq/L (0,75 to 1,1 mmol/L) ½ magnesium in plasma is free, approx 1/3 is bound to albumin, and lainnya complexed with citrate, phosphate, or other anions No hormone yang terkait dg serum magnesium, although PTH has a minor role Absorption, Transport, Storage, and Excretion Efficiency absorption magnesium : 35% 45% Mg diabsorbsi sepanjang small intestine, but lebih banyak di jejunum Mg masuk dari saluran usus melalui 2 mekanism : 1. 2. a carrier-facilitated process (at low intraluminal conc) simple diffusion (at high intraluminal conc) Absorption, Transport, Storage, and Excretion (lanjutan) efficiency absorption tgt dari : Mg status, jumlah Mg diets, composition diet . Vit D has little or no effect on Mg absorption No homeostatic system for serum Mg regulation has been identified, but the serum Mg concentration is remarkably constant Maintenance of these constant values depend on absorption, excretion, and transmembranous cation flux rather than on hormonal regulation Magnesium Balance Figure 5-5 Magnesium Balance is maintained largely by GI Absorption and Renal Excretion IRON Iron dalam tubuh ada dua pengepoolan: (1) functional iron in hemoglobin, myoglobin, and enzymes, and (2) storage iron in ferritin, hemosiderin, and transferrin ( a transport protein in blood) Iron is highly conserved by the body; approx 90% is recovered and reused every day. The rest is excreted, primarily in the bile. Dietary iron must be available to maintain iron balance to meet this 10% gap, or else iron defficiency results Absorption, Transport, Storage, and Excretion Dietary iron ada dua bentuk secara kimia : 1. 2. Heme iron, yg ditemukan dlm hemoglobin, myoglobin, and some enzymes Non-heme iron, yg ditemukan pd plant foods tetapi juga ada beberpa di animal foods, as are nonheme enzymes and ferritin Intestinal Absorption of Iron from heme and Non-heme sources by an intestinal absorbing cell, or enterocyte see next page Ada beberapa bentuk yg mengandung protein heme : Hemoglobin, myoglobin, enzim (Nitrite oxide synthase dan rpostaglandin sintase. Non heme : Besisulfur protein oxidative phosporilation, dan transpot dan penyimpanan protein misalnya transferin, ferritin, Fe dikonsumsi dlm bentuk fe bebes atau fe heme. Dlm usus direduksi dari frri menjadi ferro dlm enterocite. Dan ditransport dg bantuan DMT1 (divalent metal transporter. Sedangkan usus mengambil heme fe dg bantuan HCP1 heme carrier protein, heme akan dilepas lagi menjadi fe dg bantuan enzim heme oxygenase . Iron dapat disimpan dlm usus enterocite atau ditranport ke darah . Besi ditranspor ke sirkulasi darah dg bantuan IREG1 (iron regulated gene 1). Dg bantuan enzim hephastine akan mengoksidasi ferro menjadi ferri kembali. ZINC Banyak terdapat dlm bentuk zinc di animal flesh, particularly red meat and poultry. Milk is a good source of zinc, but high intakes of calcium from the milk mengganggu absorption iron and zinc Tubuh mengandung 2 to 3 g of zinc, with the highes concentrations in the liver, pancreas, kidney, bone, and muscles Absorption, Transport, Storage, and Excretion Zinc absorption and excretion are controlled dg mekenisme homeostatic yg blm jelas The mechanism of absorption involves two pathways similar to those of calcium The entry step of absorption across the brush border is followed by the binding of zinc ions to metallothionein and other proteins within the cytosol of the absorbing cell. Absorption, Transport, Storage, and Excretion Metallothionein carries the zinc (via transcellular movement) to the basolateral border for the exit step from the absorbing cell to the blood. The exit step occurs by active transport Zinc absortion is affected tidak hanya jumlah zinc dlm diet tetapi adanya adanya zat pengganggu spt phytates Absorption, Transport, Storage, and Excretion A protein –rich diet membantu zinc absorption dg membentuk ikatan zinc amino acid yg mempermudah zinc diabsorbsi Absorption is associated with a variety of intestinal deseases, such kekurangan pancreatic Copper and cadmium compete for the same carrier protein, so they reduce zinc absorption High intake of iron dpt menurunkan zinc absorbed High Ca intakes menurunkan zinc absorption and balance IODIUM Thyroid gland Thyroid Gland: Hormones and Iodine Metabolism Figure 23-7b: The thyroid gland Thyroid gland Thyroxine and its precursors: Structure & Synthesis Figure 23-8: Thyroid hormones are made from tyrosine and iodine Thyroxine and its precursors: Structure & Synthesis Figure 23-9: Thyroid hormone synthesis Thyroid Follicles Synthesis and Secretion of the Thyroid Metabolic Hormones • Physiologic Anatomy of the Thyroid Fig. 76.1 Synthesis and Secretion of the Thyroid Metabolic Hormones Iodine is Required for the Formation of • Thyroxine • a. Iodine dlm bentuk iodides ; 1.0 mg/wk b. iodide di absorbed dari intestine, 80% dg cepat disekresi dikidneys, and 20% ditranspotr ke thyroid gland Synthesis and Secretion of the Thyroid Metabolic Hormones • Iodide Pump-the Sodium-Iodide Symporter (Iodide Trapping) Fir. 76.2 Thyroid cellular mechanisms for iodine transport, thyroxine and triiodothyronine formation, and thyroxine and triiodithyronine release into the blood Synthesis and Secretion of the Thyroid Metabolic Hormones • Iodide Pump-the Sodium-Iodide Symporter (Iodide Trapping) a. Transport iodine dari darah b. Formation and secretion thyroglobulin oleh thyroid cells c. Oxidation of the iodide ion d. Iodination of tyrosine and formation of the thyroid hormone (organification of thyroid) Synthesis and Secretion of the Thyroid Metabolic Hormones Fig. 76.3 Chemistry of thyroxine and triiodothyronine formation Synthesis and Secretion of the Thyroid Metabolic Hormones e. Storage of thyroglobulin-enough is stored to last the body for 2-3 months f. Release of throxine and triiodithyronine-cleaved from the thyroglobulin kemudian di lepas ke blood g. Kecepatan secretion per hari; 93% is normally thyroxine 7% triiodothyronine. However, about ½ of the thyroxine is slowly deiodinated to form the T3 so the tissues get mainly T3 Synthesis and Secretion of the Thyroid Metabolic Hormones h. Thyroxine and triodothyronine are transported bound to plasma proteins i. Because of the high affinity to the plasma proteins, the hormone is released very slowly j. Thyroid hormones have slow onset and long duration of action Physiological Functions of the Thyroid Hormones • Thyroid Hormones Increase the Transcription of Large Numbers of Genes a. Most of the thyroxine secreted by the thyroid is converted to triiodothyronine (T3) b. Thyroid hormones activate nuclear receptors Physiological Functions of the Thyroid Hormones Fig. 76.5 Thyroid hormone activation of target cells Physiological Functions of the Thyroid Hormones Thyroid Hormones Increase Metabolic Activity(increase the BMR 60-100x) • a. Thyroid hormones meningkatkan jumlah and activity mitochondria b. Increase active transport ions yg melewati cell membrane (sodium and potassium) Physiological Functions of the Thyroid Hormones • Thyroid Hormones Effect on Growth a. Memacu growth and development brain selama kehamilan dan first years of postnatal life b. Deficiency will retard growth during growing years Physiological Functions of the Thyroid Hormones • Effect on Specific Bodily Mechanisms a. Stimulation kecepatan metabolism- uptake glucose, dengan meningkatkan: glycolysis, gluconeogenesis, absorption, insulin secretion b. Stimulation fat metabolism-lipids di mobilized secara cepat dg penurunan simpanan fat, peningkatan konsentrasi free fatty acid dlm plasma, and percepatan oxidation free fatty acids dlm cells Physiological Functions of the Thyroid Hormones • Effect on Specific Bodily Mechanisms c. Increased thyroid hormone menurunkan concentrations cholesterol, phospholipids, and triglycerides dlm plasma and vice versa; penurunan cholesterol secretion in bile • Increased Requirement for Vitamins • Increased Metabolic Rate • Decreased Body Weight Physiological Functions of the Thyroid Hormones • Effect on the Cardiovascular System a. b. c. d. • • • • Increased blood flow and cardiac output Increased heart rate Increased heart strength Normal arterial pressure Increased Respiration Increased Gastrointestinal Motility Excitatory Effects on the CNS Muscles React With Vigor Physiological Functions of the Thyroid Hormones • Muscle Tremors with Hyperthyroidism • Difficulty in Sleeping and Constant Tiredness With Hyperthyroidism • Increased Thyroid Hormone Increases the Secretion of Several Other Endocrine Glands • Needs to be Normal for Normal Sexual Function Regulation of Thyroid Hormone Secretion • TSH (Anterior Pituitary) Increases Thyroid Secretion a. b. c. d. Increased proteolysis of the thyroglobulin Increased activity of the iodide pump Increased iodination tyrosine Increased size and secretory activity of the thyroid cells e. Increased number of thyroid cells • Cyclic AMP Mediates the Stimulatory Effect of TSHacting as a second messenger system Regulation of Thyroid Hormone Secretion • Secretion of TSH is Regulated by ThyrotropinReleasing Hormone from the Hypothalamus • Feedback Effect of Thyroid Hormone to Decrease the Secretion of TSH Fig. 76.7 Regulation of thyroid secretion .Iodine dlm makanan dlm bentuk ion iodide ions atau inorganic iodine or bentuk iodine atoms Iodide ions di absorbsi secara cepat di small intestine kemdian di distributed ke extracellular fluid. Free iodine direducsi to iodide ions, and absorbed One-third of iodine absorbed is taken up by the thyroid gland. The remainder is removed as it passes through the kidneys to be excreted in urine. Iodine is also lost through perspiration and faeces. The excretion of iodide protects against the accumulation of toxic levels. The iodide that enters the thyroid gland is oxidised back to iodine, which combines with residues of the amino acid tyrosine within the iodinestorage protein thyroglobulin. If the hypothalamus detects a fall in the blood thyroxin level, it releases a substance known as thyroxine releasing factor into the plasma. . The TRF travels to the pituitary gland, where it stimulates, the release into plasma of a hormone called Thyroid Stimulating Hormone—TSH. The TSH is transported to the thyroid gland, where it stimulates the production of an enzyme that acts on thyroglobulin to release the iodine-containing tyrosine residues from the protein. These residues are then converted into the two thyroid hormones T3 and T4 which are released into blood plasma in a ratio of four T4 molecules for each T3 molecule. They travel to every cell in the body to regulate the processes of energy release, which determine the overall metabolic rate of the body. Figure 12a gives absorption and metabolism of iodine. Iodine intake in excess of requirement is excreted primarily through the urine; urinary iodine is a good measure of iodine status. The steps in this process are as follows: The Na+/I- symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I- against its concentration gradient. I- is moved across the apical membrane into the colloid of the follicle. Thyroperoxidase oxidises two I- to form I2. Iodide is non-reactive, and only the more reactive iodine is required for the next step. The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid. Iodinated Thyroglobulin binds megalin for endocytosis back into cell. Thyroid-stimulating hormone (TSH) released from the pituitary gland binds the TSH receptor ( a Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T4 from the iodinated thyroglobulin. These vesicles are then exocytosed, releasing the thyroid hormones. Effect of iodine deficiency on thyroid hormone synthesis If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormone. The lack of thyroid hormone will lead to decreased negative feedback on the pituitary, leading to increased production of thyroid-stimulating hormone, which causes the thyroid to enlarge (the resulting medical condition is called endemic colloid goiter; see goiter). This has the effect of increasing the thyroid's ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone.