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Biochemistry_Lippincott_1383	Biochemistry_Lippinco	8.1. Bleeding 8.2. Diarrhea and dermatitis 8.3. Neural tube defects 8.4. Night blindness (nyctalopia) 8.5. Sore, spongy gums and loose teeth Correct answers = H, B, A, C, E. Vitamin K is required for formation of the γcarboxyglutamate residues in several proteins required for blood clotting. Consequently, a deficiency of vitamin K results in a tendency to bleed. Niacin deficiency is characterized by the three Ds: diarrhea, dermatitis, and dementia (and death, a fourth D, if untreated). Folic acid deficiency can result in neural tube defects in the developing fetus. Night blindness is one of the first signs of vitamin A deficiency. Rod cells in the retina detect white and black images and work best in low light, for example, at night. Rhodopsin, the visual pigment of the rod cells, consists of 11-cis retinal bound to the protein opsin. Vitamin C is required for the hydroxylation of proline and lysine during collagen synthesis.	Biochemistry_Lippinco. 8.1. Bleeding 8.2. Diarrhea and dermatitis 8.3. Neural tube defects 8.4. Night blindness (nyctalopia) 8.5. Sore, spongy gums and loose teeth Correct answers = H, B, A, C, E. Vitamin K is required for formation of the γcarboxyglutamate residues in several proteins required for blood clotting. Consequently, a deficiency of vitamin K results in a tendency to bleed. Niacin deficiency is characterized by the three Ds: diarrhea, dermatitis, and dementia (and death, a fourth D, if untreated). Folic acid deficiency can result in neural tube defects in the developing fetus. Night blindness is one of the first signs of vitamin A deficiency. Rod cells in the retina detect white and black images and work best in low light, for example, at night. Rhodopsin, the visual pigment of the rod cells, consists of 11-cis retinal bound to the protein opsin. Vitamin C is required for the hydroxylation of proline and lysine during collagen synthesis.
Biochemistry_Lippincott_1384	Biochemistry_Lippinco	Severe vitamin C deficiency (scurvy) results in defective connective tissue, characterized by sore and spongy gums, loose teeth, capillary fragility, anemia, and fatigue. 8.6. A 52-year-old woman presents with fatigue of several months’ duration. Blood studies reveal a macrocytic anemia, reduced levels of hemoglobin, elevated levels of homocysteine, and normal levels of methylmalonic acid. Which of the following is most likely deficient in this woman? A. Folic acid B. Folic acid and vitamin B12 C. Iron D. Vitamin C	Biochemistry_Lippinco. Severe vitamin C deficiency (scurvy) results in defective connective tissue, characterized by sore and spongy gums, loose teeth, capillary fragility, anemia, and fatigue. 8.6. A 52-year-old woman presents with fatigue of several months’ duration. Blood studies reveal a macrocytic anemia, reduced levels of hemoglobin, elevated levels of homocysteine, and normal levels of methylmalonic acid. Which of the following is most likely deficient in this woman? A. Folic acid B. Folic acid and vitamin B12 C. Iron D. Vitamin C
Biochemistry_Lippincott_1385	Biochemistry_Lippinco	A. Folic acid B. Folic acid and vitamin B12 C. Iron D. Vitamin C Correct answer = A. Macrocytic anemia is seen with deficiencies of folic acid, vitamin B12, or both. Vitamin B12 is utilized in only two reactions in the body: the remethylation of homocysteine (Hcy) to methionine, which also requires folic acid (as tetrahydrofolate [THF]), and the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A, which does not require THF. The elevated Hcy and normal methylmalonic acid levels in the patient’s blood reflect a deficiency of folic acid as the cause of the macrocytic anemia. Iron deficiency causes microcytic anemia, as can vitamin C deficiency.	Biochemistry_Lippinco. A. Folic acid B. Folic acid and vitamin B12 C. Iron D. Vitamin C Correct answer = A. Macrocytic anemia is seen with deficiencies of folic acid, vitamin B12, or both. Vitamin B12 is utilized in only two reactions in the body: the remethylation of homocysteine (Hcy) to methionine, which also requires folic acid (as tetrahydrofolate [THF]), and the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A, which does not require THF. The elevated Hcy and normal methylmalonic acid levels in the patient’s blood reflect a deficiency of folic acid as the cause of the macrocytic anemia. Iron deficiency causes microcytic anemia, as can vitamin C deficiency.
Biochemistry_Lippincott_1386	Biochemistry_Lippinco	8.7. A 10-month-old African American girl, whose family recently located from Maine to Virginia, is being evaluated for the bowed appearance of her legs. The parents report that the baby is still being breastfed and takes no supplements. Radiologic studies confirm the suspicion of rickets caused by vitamin D deficiency. Which one of the following statements concerning vitamin D is correct? A. A deficiency results in an increased secretion of calbindin. B. Chronic kidney disease results in overproduction of 1,25dihydroxycholecalciferol (calcitriol). C. 25-Hydroxycholecalciferol (calcidiol) is the active form of the vitamin. D. It is required in the diet of individuals with limited exposure to sunlight. E. Its actions are mediated through binding to G protein–coupled receptors. F. It opposes the effect of parathyroid hormone.	Biochemistry_Lippinco. 8.7. A 10-month-old African American girl, whose family recently located from Maine to Virginia, is being evaluated for the bowed appearance of her legs. The parents report that the baby is still being breastfed and takes no supplements. Radiologic studies confirm the suspicion of rickets caused by vitamin D deficiency. Which one of the following statements concerning vitamin D is correct? A. A deficiency results in an increased secretion of calbindin. B. Chronic kidney disease results in overproduction of 1,25dihydroxycholecalciferol (calcitriol). C. 25-Hydroxycholecalciferol (calcidiol) is the active form of the vitamin. D. It is required in the diet of individuals with limited exposure to sunlight. E. Its actions are mediated through binding to G protein–coupled receptors. F. It opposes the effect of parathyroid hormone.
Biochemistry_Lippincott_1387	Biochemistry_Lippinco	E. Its actions are mediated through binding to G protein–coupled receptors. F. It opposes the effect of parathyroid hormone. Correct answer = D. Vitamin D is required in the diet of individuals with limited exposure to sunlight, such as those living at northern latitudes like Maine and those with dark skin. Note that breast milk is low in vitamin D, and the lack of supplementation increases the risk of a deficiency. Vitamin D deficiency results in decreased synthesis of calbindin. Chronic kidney disease decreases production of calcitriol (1,25-dihydroxycholecalciferol), the active form of the vitamin. Vitamin D binds to nuclear receptors and alters gene transcription. Its effects are synergistic with parathyroid hormone. 8.8. Why might a deficiency of vitamin B6 result in a fasting hypoglycemia? Deficiency of what other vitamin could also result in hypoglycemia?	Biochemistry_Lippinco. E. Its actions are mediated through binding to G protein–coupled receptors. F. It opposes the effect of parathyroid hormone. Correct answer = D. Vitamin D is required in the diet of individuals with limited exposure to sunlight, such as those living at northern latitudes like Maine and those with dark skin. Note that breast milk is low in vitamin D, and the lack of supplementation increases the risk of a deficiency. Vitamin D deficiency results in decreased synthesis of calbindin. Chronic kidney disease decreases production of calcitriol (1,25-dihydroxycholecalciferol), the active form of the vitamin. Vitamin D binds to nuclear receptors and alters gene transcription. Its effects are synergistic with parathyroid hormone. 8.8. Why might a deficiency of vitamin B6 result in a fasting hypoglycemia? Deficiency of what other vitamin could also result in hypoglycemia?
Biochemistry_Lippincott_1388	Biochemistry_Lippinco	8.8. Why might a deficiency of vitamin B6 result in a fasting hypoglycemia? Deficiency of what other vitamin could also result in hypoglycemia? Vitamin B6 is required for glycogen degradation by glycogen phosphorylase. A deficiency would result in fasting hypoglycemia. Additionally, a deficiency of biotin (required by pyruvate carboxylase of gluconeogenesis) would also result in fasting hypoglycemia. Micronutrients: Minerals 29 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW	Biochemistry_Lippinco. 8.8. Why might a deficiency of vitamin B6 result in a fasting hypoglycemia? Deficiency of what other vitamin could also result in hypoglycemia? Vitamin B6 is required for glycogen degradation by glycogen phosphorylase. A deficiency would result in fasting hypoglycemia. Additionally, a deficiency of biotin (required by pyruvate carboxylase of gluconeogenesis) would also result in fasting hypoglycemia. Micronutrients: Minerals 29 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW
Biochemistry_Lippincott_1389	Biochemistry_Lippinco	Micronutrients: Minerals 29 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW Minerals are inorganic substances (elements) required in small amounts by the body. They function in a number of processes including formation of bones and teeth, fluid balance, nerve conduction, muscle contraction, signaling, and catalysis. [Note: Several minerals are essential enzyme cofactors.] Like the organic vitamins (see Chapter 28), minerals are micronutrients required in mg or µg amounts. Those required by adults in the largest amounts (>100 mg/day) are referred to as the macrominerals. Minerals required in amounts between 1 and 100 mg/day are the microminerals (trace minerals). Ultratrace minerals are required in amounts <1 mg/day (Fig. 29.1). [Note: The classification of specific minerals into these categories can vary among sources.] Mineral concentrations in the body are influenced by their rates of absorption and excretion. II. MACROMINERALS	Biochemistry_Lippinco. Micronutrients: Minerals 29 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW Minerals are inorganic substances (elements) required in small amounts by the body. They function in a number of processes including formation of bones and teeth, fluid balance, nerve conduction, muscle contraction, signaling, and catalysis. [Note: Several minerals are essential enzyme cofactors.] Like the organic vitamins (see Chapter 28), minerals are micronutrients required in mg or µg amounts. Those required by adults in the largest amounts (>100 mg/day) are referred to as the macrominerals. Minerals required in amounts between 1 and 100 mg/day are the microminerals (trace minerals). Ultratrace minerals are required in amounts <1 mg/day (Fig. 29.1). [Note: The classification of specific minerals into these categories can vary among sources.] Mineral concentrations in the body are influenced by their rates of absorption and excretion. II. MACROMINERALS
Biochemistry_Lippincott_1390	Biochemistry_Lippinco	II. MACROMINERALS The macrominerals include calcium (Ca2+), phosphorus ([P] as inorganic phosphate [Pi, or PO43−]), magnesium (Mg2+), sodium (Na+), chloride (Cl−), and potassium (K+). [Note: The free ionic forms are electrolytes.] A. Calcium and phosphorus These macrominerals are considered together because they are components of hydroxylapatite (Ca5[PO4]3OH), which makes up bones and teeth.	Biochemistry_Lippinco. II. MACROMINERALS The macrominerals include calcium (Ca2+), phosphorus ([P] as inorganic phosphate [Pi, or PO43−]), magnesium (Mg2+), sodium (Na+), chloride (Cl−), and potassium (K+). [Note: The free ionic forms are electrolytes.] A. Calcium and phosphorus These macrominerals are considered together because they are components of hydroxylapatite (Ca5[PO4]3OH), which makes up bones and teeth.
Biochemistry_Lippincott_1391	Biochemistry_Lippinco	1. Calcium: Ca2+ is the most abundant mineral in the body, with ~98% being found in bones. The remainder is involved in a number of processes such as signaling, muscle contraction, and blood clotting. Ca2+ binds to a variety of proteins including calmodulin (see p. 133), phospholipase A2 (see p. 213), and protein kinase C (see p. 205) and alters their activity. [Note: Calbindin is a vitamin D–induced intracellular Ca2+-binding protein involved in Ca2+ absorption in the intestine (see p. 392).] Dairy products, many green vegetables (for example, broccoli, but not spinach), and fortified orange juice are good dietary sources. Although dietary deficiency syndromes are unknown, average Ca2+ intake in the United States is insufficient for optimal bone health. Toxicity is seen only with supplements (tolerable upper limit [UL] = 2,500 mg/day for adults). Hypercalcemia (elevated serum Ca2+) can result from overproduction of parathyroid hormone (PTH). This may cause constipation and kidney	Biochemistry_Lippinco. 1. Calcium: Ca2+ is the most abundant mineral in the body, with ~98% being found in bones. The remainder is involved in a number of processes such as signaling, muscle contraction, and blood clotting. Ca2+ binds to a variety of proteins including calmodulin (see p. 133), phospholipase A2 (see p. 213), and protein kinase C (see p. 205) and alters their activity. [Note: Calbindin is a vitamin D–induced intracellular Ca2+-binding protein involved in Ca2+ absorption in the intestine (see p. 392).] Dairy products, many green vegetables (for example, broccoli, but not spinach), and fortified orange juice are good dietary sources. Although dietary deficiency syndromes are unknown, average Ca2+ intake in the United States is insufficient for optimal bone health. Toxicity is seen only with supplements (tolerable upper limit [UL] = 2,500 mg/day for adults). Hypercalcemia (elevated serum Ca2+) can result from overproduction of parathyroid hormone (PTH). This may cause constipation and kidney
Biochemistry_Lippincott_1392	Biochemistry_Lippinco	(tolerable upper limit [UL] = 2,500 mg/day for adults). Hypercalcemia (elevated serum Ca2+) can result from overproduction of parathyroid hormone (PTH). This may cause constipation and kidney stones. Hypocalcemia (low serum Ca2+) can result from a deficiency of PTH or vitamin D. It can lead to bone demineralization (resorption). [Note: The hormonal regulation of serum Ca2+ levels was presented in the vitamin D section of Chapter 28 and is reviewed in 3. below.]	Biochemistry_Lippinco. (tolerable upper limit [UL] = 2,500 mg/day for adults). Hypercalcemia (elevated serum Ca2+) can result from overproduction of parathyroid hormone (PTH). This may cause constipation and kidney stones. Hypocalcemia (low serum Ca2+) can result from a deficiency of PTH or vitamin D. It can lead to bone demineralization (resorption). [Note: The hormonal regulation of serum Ca2+ levels was presented in the vitamin D section of Chapter 28 and is reviewed in 3. below.]
Biochemistry_Lippincott_1393	Biochemistry_Lippinco	Bone mass increases from infancy through the early reproductive years and then shows an age-related loss in both men and women that increases the risk for fracture. This loss is greatest in postmenopausal Caucasian women. Some studies have shown that supplementation with Ca2+ and vitamin D decreases this risk.	Biochemistry_Lippinco. Bone mass increases from infancy through the early reproductive years and then shows an age-related loss in both men and women that increases the risk for fracture. This loss is greatest in postmenopausal Caucasian women. Some studies have shown that supplementation with Ca2+ and vitamin D decreases this risk.
Biochemistry_Lippincott_1394	Biochemistry_Lippinco	2. Phosphorus: Free phosphate (Pi) is the most abundant intracellular anion. However, 85% of the body’s phosphorus is in the form of inorganic hydroxylapatite, with most of the remainder in intracellular organic compounds such as phospholipids, nucleic acids, ATP, and creatine phosphate. Phosphate is supplied as ATP for kinases and as Pi for phosphorylases (for example, glycogen phosphorylase, see p. 128). [Note: Its addition (by kinases) or removal (by phosphatases) is an important means of covalent regulation of enzymes (see Chapter 24).] Phosphorus is widely distributed in food (milk is a good source), and dietary deficiency is rare. Hypophosphatemia can be caused by refeeding carbohydrates to malnourished patients (refeeding syndrome, see p. 369), overuse of aluminum-containing antacids (aluminum chelates Pi), and increased urinary loss in response to increased production of PTH (see below). Muscle weakness is a common symptom. Hyperphosphatemia is caused primarily by decreased	Biochemistry_Lippinco. 2. Phosphorus: Free phosphate (Pi) is the most abundant intracellular anion. However, 85% of the body’s phosphorus is in the form of inorganic hydroxylapatite, with most of the remainder in intracellular organic compounds such as phospholipids, nucleic acids, ATP, and creatine phosphate. Phosphate is supplied as ATP for kinases and as Pi for phosphorylases (for example, glycogen phosphorylase, see p. 128). [Note: Its addition (by kinases) or removal (by phosphatases) is an important means of covalent regulation of enzymes (see Chapter 24).] Phosphorus is widely distributed in food (milk is a good source), and dietary deficiency is rare. Hypophosphatemia can be caused by refeeding carbohydrates to malnourished patients (refeeding syndrome, see p. 369), overuse of aluminum-containing antacids (aluminum chelates Pi), and increased urinary loss in response to increased production of PTH (see below). Muscle weakness is a common symptom. Hyperphosphatemia is caused primarily by decreased
Biochemistry_Lippincott_1395	Biochemistry_Lippinco	(aluminum chelates Pi), and increased urinary loss in response to increased production of PTH (see below). Muscle weakness is a common symptom. Hyperphosphatemia is caused primarily by decreased PTH levels. The excess Pi can combine with Ca2+ and form crystals that deposit in soft tissue (metastatic calcification). [Note: The Ca2+/Pi ratio is important for bone formation (the ratio is ~2/1 in bone), and some experts are concerned that replacement of Ca2+-rich milk by Ca2+-poor, Pi-rich soft drinks can affect bone health.] 3. Hormonal regulation: Serum levels of Ca2+ and Pi are primarily controlled by calcitriol (1,25-dihydroxycholecalciferol, the active form of vitamin D) and PTH, both of which respond to a decrease in serum Ca2+ . Calcitriol, produced by the kidneys, increases serum Ca2+ and Pi by increasing bone resorption and intestinal absorption and renal reabsorption of Ca2+ and Pi (Fig. 29.2). PTH (from the parathyroid glands) increases serum Ca2+ by increasing bone resorption,	Biochemistry_Lippinco. (aluminum chelates Pi), and increased urinary loss in response to increased production of PTH (see below). Muscle weakness is a common symptom. Hyperphosphatemia is caused primarily by decreased PTH levels. The excess Pi can combine with Ca2+ and form crystals that deposit in soft tissue (metastatic calcification). [Note: The Ca2+/Pi ratio is important for bone formation (the ratio is ~2/1 in bone), and some experts are concerned that replacement of Ca2+-rich milk by Ca2+-poor, Pi-rich soft drinks can affect bone health.] 3. Hormonal regulation: Serum levels of Ca2+ and Pi are primarily controlled by calcitriol (1,25-dihydroxycholecalciferol, the active form of vitamin D) and PTH, both of which respond to a decrease in serum Ca2+ . Calcitriol, produced by the kidneys, increases serum Ca2+ and Pi by increasing bone resorption and intestinal absorption and renal reabsorption of Ca2+ and Pi (Fig. 29.2). PTH (from the parathyroid glands) increases serum Ca2+ by increasing bone resorption,
Biochemistry_Lippincott_1396	Biochemistry_Lippinco	and Pi by increasing bone resorption and intestinal absorption and renal reabsorption of Ca2+ and Pi (Fig. 29.2). PTH (from the parathyroid glands) increases serum Ca2+ by increasing bone resorption, increasing renal reabsorption of Ca2+ , and activating the renal 1-hydroxylase that produces calcitriol from calcidiol (see p. 390) (Fig. 29.3). In contrast to calcitriol, PTH decreases Pi reabsorption in the kidneys, lowering serum Pi. [Note: High serum Pi increases PTH and decreases calcitriol.] A third hormone, calcitonin (from the C cells of the thyroid gland), responds to elevated serum Ca2+ levels by promoting bone mineralization and increasing renal excretion of Ca2+ (and Pi).	Biochemistry_Lippinco. and Pi by increasing bone resorption and intestinal absorption and renal reabsorption of Ca2+ and Pi (Fig. 29.2). PTH (from the parathyroid glands) increases serum Ca2+ by increasing bone resorption, increasing renal reabsorption of Ca2+ , and activating the renal 1-hydroxylase that produces calcitriol from calcidiol (see p. 390) (Fig. 29.3). In contrast to calcitriol, PTH decreases Pi reabsorption in the kidneys, lowering serum Pi. [Note: High serum Pi increases PTH and decreases calcitriol.] A third hormone, calcitonin (from the C cells of the thyroid gland), responds to elevated serum Ca2+ levels by promoting bone mineralization and increasing renal excretion of Ca2+ (and Pi).
Biochemistry_Lippincott_1397	Biochemistry_Lippinco	B. Magnesium About 60% of the body’s Mg2+ is in bone, but it accounts for just 1% of the bone mass. The mineral is required by a variety of enzymatic reactions, including phosphorylation by kinases (Mg2+ binds the ATP cosubstrate) and phosphodiester bond formation by DNA and RNA polymerases. Mg2+ is widely distributed in foods, but the average intake in the United States is below the recommended level. Hypomagnesemia can result from decreased absorption or increased excretion of Mg2+ . Symptoms include hyperexcitability of skeletal muscles and nerves and cardiac arrhythmias. With hypermagnesemia, hypotension is seen. [Note: Magnesium sulfate is used in the treatment of preeclampsia, a hypertensive disorder of pregnancy.] C. Sodium, chloride, and potassium	Biochemistry_Lippinco. B. Magnesium About 60% of the body’s Mg2+ is in bone, but it accounts for just 1% of the bone mass. The mineral is required by a variety of enzymatic reactions, including phosphorylation by kinases (Mg2+ binds the ATP cosubstrate) and phosphodiester bond formation by DNA and RNA polymerases. Mg2+ is widely distributed in foods, but the average intake in the United States is below the recommended level. Hypomagnesemia can result from decreased absorption or increased excretion of Mg2+ . Symptoms include hyperexcitability of skeletal muscles and nerves and cardiac arrhythmias. With hypermagnesemia, hypotension is seen. [Note: Magnesium sulfate is used in the treatment of preeclampsia, a hypertensive disorder of pregnancy.] C. Sodium, chloride, and potassium
Biochemistry_Lippincott_1398	Biochemistry_Lippinco	These macrominerals are considered together because they play important roles in several physiologic processes. For example, they maintain water balance, osmotic equilibrium, acid–base balance (pH), and the electrical gradients across cell membranes (membrane potential) that are essential for the functioning of neurons and myocytes. [Note: These processes are discussed in Lippincott’s Illustrated Reviews: Physiology.] 1. Sodium and chloride: Na+ and Cl− are primarily extracellular electrolytes. They are readily absorbed from foods containing salt (NaCl), much of which comes from processed foods. [Note: Na+ is required for the intestinal absorption (and renal reabsorption) of glucose and galactose (see p. 87) and free amino acids (see p. 249) by Na+-linked transporters. Cl− is used to form hydrochloric acid required for digestion (see p. 248).] In the United States, the average daily consumption of NaCl is 1.5–3 times the adequate intake (AI) of 3.8 mg/day (UL = 5.8 g/day). Dietary	Biochemistry_Lippinco. These macrominerals are considered together because they play important roles in several physiologic processes. For example, they maintain water balance, osmotic equilibrium, acid–base balance (pH), and the electrical gradients across cell membranes (membrane potential) that are essential for the functioning of neurons and myocytes. [Note: These processes are discussed in Lippincott’s Illustrated Reviews: Physiology.] 1. Sodium and chloride: Na+ and Cl− are primarily extracellular electrolytes. They are readily absorbed from foods containing salt (NaCl), much of which comes from processed foods. [Note: Na+ is required for the intestinal absorption (and renal reabsorption) of glucose and galactose (see p. 87) and free amino acids (see p. 249) by Na+-linked transporters. Cl− is used to form hydrochloric acid required for digestion (see p. 248).] In the United States, the average daily consumption of NaCl is 1.5–3 times the adequate intake (AI) of 3.8 mg/day (UL = 5.8 g/day). Dietary
Biochemistry_Lippincott_1399	Biochemistry_Lippinco	hydrochloric acid required for digestion (see p. 248).] In the United States, the average daily consumption of NaCl is 1.5–3 times the adequate intake (AI) of 3.8 mg/day (UL = 5.8 g/day). Dietary deficiency is rare.	Biochemistry_Lippinco. hydrochloric acid required for digestion (see p. 248).] In the United States, the average daily consumption of NaCl is 1.5–3 times the adequate intake (AI) of 3.8 mg/day (UL = 5.8 g/day). Dietary deficiency is rare.
Biochemistry_Lippincott_1400	Biochemistry_Lippinco	a. Hypertension: Na+ intake is related to blood pressure (BP). Ingestion of Na+ stimulates thirst centers in the brain and secretion of antidiuretic hormone from the pituitary, leading to water retention. This results in an increase in plasma volume and, consequently, an increase in BP. Chronic hypertension can damage the heart, kidneys, and blood vessels. Modest reductions in Na+ intake have been shown to result in modest reductions in BP. [Note: Some populations (for example, African Americans) are “salt sensitive” and have larger responses to Na+.] b.	Biochemistry_Lippinco. a. Hypertension: Na+ intake is related to blood pressure (BP). Ingestion of Na+ stimulates thirst centers in the brain and secretion of antidiuretic hormone from the pituitary, leading to water retention. This results in an increase in plasma volume and, consequently, an increase in BP. Chronic hypertension can damage the heart, kidneys, and blood vessels. Modest reductions in Na+ intake have been shown to result in modest reductions in BP. [Note: Some populations (for example, African Americans) are “salt sensitive” and have larger responses to Na+.] b.
Biochemistry_Lippincott_1401	Biochemistry_Lippinco	Hyper-and hyponatremia: Hypernatremia, typically caused by excess water loss, and hyponatremia, typically caused by decreased ability to excrete water, can result in severe brain damage. [Note: Chronic hyponatremia increases Ca2+ excretion and can result in osteoporosis (low bone mass).] 2. Potassium: In contrast to Na+, K+ is primarily an intracellular electrolyte. [Note: The concentration differential of Na+ and K+ across the cell membrane is maintained by the Na+/K+ ATPase (Fig. 29.4).] In contrast to Na+ and Cl−, K+ (like Mg2+) is underingested in Western diets because its primary sources, fruits and vegetables, are underingested. [Note: Increasing dietary K+ decreases BP by increasing Na+ excretion.] There is a narrow range for normal serum K+ levels, and even modest changes (up or down, resulting in hyper-or hypokalemia) can result in cardiac arrhythmias and skeletal muscle weakness. [Note: Hypokalemia can result from the inappropriate use of laxatives to lose weight.] No UL for	Biochemistry_Lippinco. Hyper-and hyponatremia: Hypernatremia, typically caused by excess water loss, and hyponatremia, typically caused by decreased ability to excrete water, can result in severe brain damage. [Note: Chronic hyponatremia increases Ca2+ excretion and can result in osteoporosis (low bone mass).] 2. Potassium: In contrast to Na+, K+ is primarily an intracellular electrolyte. [Note: The concentration differential of Na+ and K+ across the cell membrane is maintained by the Na+/K+ ATPase (Fig. 29.4).] In contrast to Na+ and Cl−, K+ (like Mg2+) is underingested in Western diets because its primary sources, fruits and vegetables, are underingested. [Note: Increasing dietary K+ decreases BP by increasing Na+ excretion.] There is a narrow range for normal serum K+ levels, and even modest changes (up or down, resulting in hyper-or hypokalemia) can result in cardiac arrhythmias and skeletal muscle weakness. [Note: Hypokalemia can result from the inappropriate use of laxatives to lose weight.] No UL for
Biochemistry_Lippincott_1402	Biochemistry_Lippinco	resulting in hyper-or hypokalemia) can result in cardiac arrhythmias and skeletal muscle weakness. [Note: Hypokalemia can result from the inappropriate use of laxatives to lose weight.] No UL for K+ has been established.	Biochemistry_Lippinco. resulting in hyper-or hypokalemia) can result in cardiac arrhythmias and skeletal muscle weakness. [Note: Hypokalemia can result from the inappropriate use of laxatives to lose weight.] No UL for K+ has been established.
Biochemistry_Lippincott_1403	Biochemistry_Lippinco	III. MICROMINERALS (TRACE MINERALS) The trace minerals include copper (Cu), iron (Fe), manganese (Mn), and zinc (Zn). They are required by adults in amounts between 1 and 100 mg/day. A. Copper Cu is a key component of several enzymes that play critical functions in the body (Fig. 29.5). These include ferroxidases such as the ceruloplasmin and hephaestin involved in the oxidation of ferrous iron (Fe2+) to the ferric form (Fe3+) that is required for its intracellular storage or transport through blood (see B.1. below). Meat, shellfish, nuts, and whole grains are good dietary sources of Cu. Dietary deficiency is uncommon. If a deficiency does develop, anemia may be seen because of the effect on Fe metabolism. Toxicity from dietary sources is rare (UL = 10 mg/day). Menkes syndrome and Wilson disease are genetic causes of Cu deficiency and Cu overload, respectively. 1.	Biochemistry_Lippinco. III. MICROMINERALS (TRACE MINERALS) The trace minerals include copper (Cu), iron (Fe), manganese (Mn), and zinc (Zn). They are required by adults in amounts between 1 and 100 mg/day. A. Copper Cu is a key component of several enzymes that play critical functions in the body (Fig. 29.5). These include ferroxidases such as the ceruloplasmin and hephaestin involved in the oxidation of ferrous iron (Fe2+) to the ferric form (Fe3+) that is required for its intracellular storage or transport through blood (see B.1. below). Meat, shellfish, nuts, and whole grains are good dietary sources of Cu. Dietary deficiency is uncommon. If a deficiency does develop, anemia may be seen because of the effect on Fe metabolism. Toxicity from dietary sources is rare (UL = 10 mg/day). Menkes syndrome and Wilson disease are genetic causes of Cu deficiency and Cu overload, respectively. 1.
Biochemistry_Lippincott_1404	Biochemistry_Lippinco	1. Menkes syndrome: In Menkes syndrome (“kinky hair” disease), a rare X-linked (1:140,000 males) disorder, efflux of dietary Cu out of intestinal enterocytes into the circulation by a Cu-transporting ATPase (ATP7A) is impaired. This results in systemic Cu deficiency. Consequently, urinary and serum free (unbound) Cu are low, as is the concentration of ceruloplasmin, which carries over 90% of the Cu in the circulation (Fig. 29.6). Progressive neurologic degeneration and connective tissue disorders are seen, as are changes to hair. Parenteral administration of Cu has been used as a treatment with varying success. [Note: The mildest form of Menkes syndrome is called occipital horn syndrome.] 2.	Biochemistry_Lippinco. 1. Menkes syndrome: In Menkes syndrome (“kinky hair” disease), a rare X-linked (1:140,000 males) disorder, efflux of dietary Cu out of intestinal enterocytes into the circulation by a Cu-transporting ATPase (ATP7A) is impaired. This results in systemic Cu deficiency. Consequently, urinary and serum free (unbound) Cu are low, as is the concentration of ceruloplasmin, which carries over 90% of the Cu in the circulation (Fig. 29.6). Progressive neurologic degeneration and connective tissue disorders are seen, as are changes to hair. Parenteral administration of Cu has been used as a treatment with varying success. [Note: The mildest form of Menkes syndrome is called occipital horn syndrome.] 2.
Biochemistry_Lippincott_1405	Biochemistry_Lippinco	Wilson disease: In Wilson disease, an autosomal-recessive (AR) disorder affecting 1:35,000 live births, efflux of excess Cu from the liver by ATP7B is impaired. Cu accumulates in the liver; leaks into the blood; and is deposited in the brain, eyes, kidneys, and skin. In contrast to Menkes syndrome, urinary and serum free Cu are high (see Fig. 29.6). Hepatic dysfunction and neurologic and psychiatric symptoms are seen. Kayser-Fleischer rings (corneal deposits of Cu) may be present (Fig. 29.7). Life-long use of Cu-chelating agents, such as penicillamine, is the treatment. The bioavailability (percent of the amount ingested that is able to be absorbed) of a mineral can be influenced by other minerals. For example, excess Zn decreases the absorption of Cu, and Cu is needed for the absorption of Fe. B. Iron	Biochemistry_Lippinco. Wilson disease: In Wilson disease, an autosomal-recessive (AR) disorder affecting 1:35,000 live births, efflux of excess Cu from the liver by ATP7B is impaired. Cu accumulates in the liver; leaks into the blood; and is deposited in the brain, eyes, kidneys, and skin. In contrast to Menkes syndrome, urinary and serum free Cu are high (see Fig. 29.6). Hepatic dysfunction and neurologic and psychiatric symptoms are seen. Kayser-Fleischer rings (corneal deposits of Cu) may be present (Fig. 29.7). Life-long use of Cu-chelating agents, such as penicillamine, is the treatment. The bioavailability (percent of the amount ingested that is able to be absorbed) of a mineral can be influenced by other minerals. For example, excess Zn decreases the absorption of Cu, and Cu is needed for the absorption of Fe. B. Iron
Biochemistry_Lippincott_1406	Biochemistry_Lippinco	B. Iron The adult body typically contains 3–4 g of Fe. It is a component of many proteins, both catalytic (for example, hydroxylases such as prolyl hydroxylase, see p. 47) and noncatalytic. Iron can be linked to sulfur (S) as seen in the Fe–S proteins of the electron transport chain (see p. 75), or it can be part of the heme prosthetic group (see p. 25) in proteins such as hemoglobin (~70% of all Fe), myoglobin, and the cytochromes. [Note: Free ionic Fe is toxic because it can cause production of the hydroxyl radical, a reactive oxygen species (ROS).] Dietary Fe is available as Fe2+ in heme (animal sources) and Fe3+ in nonheme sources (plants). Heme iron is less abundant, but it is better absorbed. Meat, poultry, some shellfish, ready-toeat cereals, lentils, and molasses are good dietary sources of Fe. About 10% of ingested Fe is absorbed. This amount, ~1−2 mg/day, is sufficient to replace Fe lost from the body primarily by the sloughing of cells. 1.	Biochemistry_Lippinco. B. Iron The adult body typically contains 3–4 g of Fe. It is a component of many proteins, both catalytic (for example, hydroxylases such as prolyl hydroxylase, see p. 47) and noncatalytic. Iron can be linked to sulfur (S) as seen in the Fe–S proteins of the electron transport chain (see p. 75), or it can be part of the heme prosthetic group (see p. 25) in proteins such as hemoglobin (~70% of all Fe), myoglobin, and the cytochromes. [Note: Free ionic Fe is toxic because it can cause production of the hydroxyl radical, a reactive oxygen species (ROS).] Dietary Fe is available as Fe2+ in heme (animal sources) and Fe3+ in nonheme sources (plants). Heme iron is less abundant, but it is better absorbed. Meat, poultry, some shellfish, ready-toeat cereals, lentils, and molasses are good dietary sources of Fe. About 10% of ingested Fe is absorbed. This amount, ~1−2 mg/day, is sufficient to replace Fe lost from the body primarily by the sloughing of cells. 1.
Biochemistry_Lippincott_1407	Biochemistry_Lippinco	Absorption, storage, and transport: Intestinal uptake of heme is by a heme carrier protein (Fig. 29.8). Within the enterocytes, heme oxygenase releases Fe2+ from heme (see p. 282). Nonheme Fe is taken up via the apical membrane protein divalent metal ion transporter-1 (DMT-1). [Note: Vitamin C enhances absorption of nonheme Fe because it is the coenzyme for duodenal cytochrome b (Dcytb), a ferrireductase that reduces Fe3+ to Fe2+.] Absorbed Fe2+ from heme and nonheme sources has two possible fates: It can be 1) oxidized to Fe3+ and stored by the intracellular protein ferritin (up to 4,500 Fe3+/ferritin) or 2) transported out of the enterocyte by the basolateral membrane protein ferroportin, oxidized by the Cu-containing membrane protein hephaestin, and taken up by the plasma transport protein transferrin (2 Fe3+/transferrin), as shown in Figure 29.8. [Note: Cells other than enterocytes use the Cu-containing plasma protein ceruloplasmin in place of hephaestin.] In normal individuals,	Biochemistry_Lippinco. Absorption, storage, and transport: Intestinal uptake of heme is by a heme carrier protein (Fig. 29.8). Within the enterocytes, heme oxygenase releases Fe2+ from heme (see p. 282). Nonheme Fe is taken up via the apical membrane protein divalent metal ion transporter-1 (DMT-1). [Note: Vitamin C enhances absorption of nonheme Fe because it is the coenzyme for duodenal cytochrome b (Dcytb), a ferrireductase that reduces Fe3+ to Fe2+.] Absorbed Fe2+ from heme and nonheme sources has two possible fates: It can be 1) oxidized to Fe3+ and stored by the intracellular protein ferritin (up to 4,500 Fe3+/ferritin) or 2) transported out of the enterocyte by the basolateral membrane protein ferroportin, oxidized by the Cu-containing membrane protein hephaestin, and taken up by the plasma transport protein transferrin (2 Fe3+/transferrin), as shown in Figure 29.8. [Note: Cells other than enterocytes use the Cu-containing plasma protein ceruloplasmin in place of hephaestin.] In normal individuals,
Biochemistry_Lippincott_1408	Biochemistry_Lippinco	transferrin (2 Fe3+/transferrin), as shown in Figure 29.8. [Note: Cells other than enterocytes use the Cu-containing plasma protein ceruloplasmin in place of hephaestin.] In normal individuals, transferrin (Tf) is about one third saturated with Fe3+ . Ferroportin, the only known exporter of Fe from cells to the blood in humans, is regulated by the hepatic peptide hepcidin that induces internalization and lysosomal degradation of ferroportin. Therefore, hepcidin is the central molecule in Fe homeostasis. [Note: Transcription of hepcidin is suppressed when Fe is deficient.] 2.	Biochemistry_Lippinco. transferrin (2 Fe3+/transferrin), as shown in Figure 29.8. [Note: Cells other than enterocytes use the Cu-containing plasma protein ceruloplasmin in place of hephaestin.] In normal individuals, transferrin (Tf) is about one third saturated with Fe3+ . Ferroportin, the only known exporter of Fe from cells to the blood in humans, is regulated by the hepatic peptide hepcidin that induces internalization and lysosomal degradation of ferroportin. Therefore, hepcidin is the central molecule in Fe homeostasis. [Note: Transcription of hepcidin is suppressed when Fe is deficient.] 2.
Biochemistry_Lippincott_1409	Biochemistry_Lippinco	Recycling: Macrophages phagocytose old and/or damaged red blood cells (RBC), freeing heme Fe that is sent out of the cells via ferroportin, oxidized by ceruloplasmin, and transported by Tf as described above. This recycled Fe meets ~90% of our daily need, which is predominantly for erythropoiesis. 3. Uptake: Tf-bound Fe3+ from enterocytes and macrophages binds to receptors (TfR) on erythroblasts and other Fe-requiring cells and is taken up by receptor-mediated endocytosis. The Fe3+ is released from Tf for use (or stored on ferritin), and the TfR (and Tf) is recycled in a process similar to the receptor-mediated endocytosis seen with low-density lipoprotein particles (see p. 231). [Note: Regulation of the translation of the messenger RNA for ferritin and the TfR by iron regulatory proteins and iron-responsive elements is discussed on p. 474.] 4.	Biochemistry_Lippinco. Recycling: Macrophages phagocytose old and/or damaged red blood cells (RBC), freeing heme Fe that is sent out of the cells via ferroportin, oxidized by ceruloplasmin, and transported by Tf as described above. This recycled Fe meets ~90% of our daily need, which is predominantly for erythropoiesis. 3. Uptake: Tf-bound Fe3+ from enterocytes and macrophages binds to receptors (TfR) on erythroblasts and other Fe-requiring cells and is taken up by receptor-mediated endocytosis. The Fe3+ is released from Tf for use (or stored on ferritin), and the TfR (and Tf) is recycled in a process similar to the receptor-mediated endocytosis seen with low-density lipoprotein particles (see p. 231). [Note: Regulation of the translation of the messenger RNA for ferritin and the TfR by iron regulatory proteins and iron-responsive elements is discussed on p. 474.] 4.
Biochemistry_Lippincott_1410	Biochemistry_Lippinco	Deficiency: Fe deficiency can result in a microcytic, hypochromic anemia (Fig. 29.9), the most common anemia in the United States, as a result of decreased hemoglobin synthesis and, consequently, decreased RBC size. Treatment is the administration of Fe.	Biochemistry_Lippinco. Deficiency: Fe deficiency can result in a microcytic, hypochromic anemia (Fig. 29.9), the most common anemia in the United States, as a result of decreased hemoglobin synthesis and, consequently, decreased RBC size. Treatment is the administration of Fe.
Biochemistry_Lippincott_1411	Biochemistry_Lippinco	5. Excess: Fe overload can occur with accidental ingestion. [Note: Acute Fe poisoning is the most common cause of poisoning deaths of children age <6 years (UL = 40 mg/day for children, 45 mg/day for adults).] Treatment is use of an Fe chelator. Overload can also occur with genetic defects. An example is hereditary hemochromatosis (HH), an AR disorder of Fe overload found primarily in those of Northern European ancestry. It is most commonly caused by mutations to the HFE (high iron) gene. Hyperpigmentation with hyperglycemia (“bronze diabetes”) and damage to the liver (a major storage site for Fe), pancreas, and heart may be seen. In HH, serum Fe and Tf saturation are elevated. Treatment is phlebotomy or use of Fe chelators. [Note: Fe overload is seen with mutations to proteins of Fe metabolism that result in inappropriately low levels of hepcidin. It can result in hemosiderosis (the deposition of hemosiderin, an intracellular, insoluble storage form of Fe).] C. Manganese	Biochemistry_Lippinco. 5. Excess: Fe overload can occur with accidental ingestion. [Note: Acute Fe poisoning is the most common cause of poisoning deaths of children age <6 years (UL = 40 mg/day for children, 45 mg/day for adults).] Treatment is use of an Fe chelator. Overload can also occur with genetic defects. An example is hereditary hemochromatosis (HH), an AR disorder of Fe overload found primarily in those of Northern European ancestry. It is most commonly caused by mutations to the HFE (high iron) gene. Hyperpigmentation with hyperglycemia (“bronze diabetes”) and damage to the liver (a major storage site for Fe), pancreas, and heart may be seen. In HH, serum Fe and Tf saturation are elevated. Treatment is phlebotomy or use of Fe chelators. [Note: Fe overload is seen with mutations to proteins of Fe metabolism that result in inappropriately low levels of hepcidin. It can result in hemosiderosis (the deposition of hemosiderin, an intracellular, insoluble storage form of Fe).] C. Manganese
Biochemistry_Lippincott_1412	Biochemistry_Lippinco	C. Manganese Mn is important for the function of several enzymes (Fig. 29.10). Whole grains, legumes (for example, beans and peas), nuts, and tea (especially green tea) are good sources of the mineral. Consequently, Mn deficiency in humans is rare. Toxicity from foods and/or supplements is also rare (UL = 11 mg/day for adults). D. Zinc	Biochemistry_Lippinco. C. Manganese Mn is important for the function of several enzymes (Fig. 29.10). Whole grains, legumes (for example, beans and peas), nuts, and tea (especially green tea) are good sources of the mineral. Consequently, Mn deficiency in humans is rare. Toxicity from foods and/or supplements is also rare (UL = 11 mg/day for adults). D. Zinc
Biochemistry_Lippincott_1413	Biochemistry_Lippinco	Zn plays important structural and catalytic functions in the body. Zinc fingers are supersecondary structures (motifs, see p. 18) in proteins (for example, transcription factors) that bind to DNA and regulate gene expression (Fig. 29.11). Hundreds of enzymes require Zn for activity. Examples include alcohol dehydrogenase, which oxidizes ethanol to acetaldehyde (see p. 317); carbonic anhydrase, which is important in the bicarbonate buffer system (see p. 30); porphobilinogen synthase of heme synthesis, which is inhibited by lead (lead replaces the zinc; see p. 279); and the nonmitochondrial isoform of superoxide dismutase (SOD), which also requires Cu (see Fig. 29.5). Dietary sources of Zn include meat, fish, eggs, and dairy products. Phytates (phosphate storage molecules in some plant products) irreversibly bind Zn in the intestine, decreasing its absorption, and can result in a deficiency. [Note: Phytates may also bind Ca2+ and nonheme Fe.] Several drugs (for example, penicillamine)	Biochemistry_Lippinco. Zn plays important structural and catalytic functions in the body. Zinc fingers are supersecondary structures (motifs, see p. 18) in proteins (for example, transcription factors) that bind to DNA and regulate gene expression (Fig. 29.11). Hundreds of enzymes require Zn for activity. Examples include alcohol dehydrogenase, which oxidizes ethanol to acetaldehyde (see p. 317); carbonic anhydrase, which is important in the bicarbonate buffer system (see p. 30); porphobilinogen synthase of heme synthesis, which is inhibited by lead (lead replaces the zinc; see p. 279); and the nonmitochondrial isoform of superoxide dismutase (SOD), which also requires Cu (see Fig. 29.5). Dietary sources of Zn include meat, fish, eggs, and dairy products. Phytates (phosphate storage molecules in some plant products) irreversibly bind Zn in the intestine, decreasing its absorption, and can result in a deficiency. [Note: Phytates may also bind Ca2+ and nonheme Fe.] Several drugs (for example, penicillamine)
Biochemistry_Lippincott_1414	Biochemistry_Lippinco	irreversibly bind Zn in the intestine, decreasing its absorption, and can result in a deficiency. [Note: Phytates may also bind Ca2+ and nonheme Fe.] Several drugs (for example, penicillamine) chelate metals, and their use may cause Zn deficiency. [Note: Severe deficiency is seen with a defect in the intestinal transporter for Zn that results in the malabsorption disorder acrodermatitis enteropathica. Symptoms include rashes, slowed growth and development, diarrhea, and immune deficiencies. Vision problems may also occur because Zn is needed in the metabolism of vitamin A.]	Biochemistry_Lippinco. irreversibly bind Zn in the intestine, decreasing its absorption, and can result in a deficiency. [Note: Phytates may also bind Ca2+ and nonheme Fe.] Several drugs (for example, penicillamine) chelate metals, and their use may cause Zn deficiency. [Note: Severe deficiency is seen with a defect in the intestinal transporter for Zn that results in the malabsorption disorder acrodermatitis enteropathica. Symptoms include rashes, slowed growth and development, diarrhea, and immune deficiencies. Vision problems may also occur because Zn is needed in the metabolism of vitamin A.]
Biochemistry_Lippincott_1415	Biochemistry_Lippinco	Eukaryotic cells infected with bacteria can restrict availability of the essential micronutrients Fe, Mn, and Zn to the pathogens. This decreases the intracellular survival of the pathogen and is known as “nutritional immunity.” E. Other microminerals Chromium (Cr) and fluorine (F) also play roles in the body. Cr potentiates the action of insulin by an unknown mechanism. It is found in fruits, vegetables, dairy products, and meat. F (as fluoride [F−]) is added to water in many parts of the world to reduce the incidence of dental caries (Fig. 29.12). F− replaces the hydroxyl group of hydroxylapatite, forming fluoroapatite that is more resistant to the enamel-dissolving acid produced by mouth bacteria. IV. ULTRATRACE MINERALS The ultratrace minerals include iodine (I), selenium (Se), and molybdenum (Mo). They are required by adults in amounts <1 mg/day. A. Iodine	Biochemistry_Lippinco. Eukaryotic cells infected with bacteria can restrict availability of the essential micronutrients Fe, Mn, and Zn to the pathogens. This decreases the intracellular survival of the pathogen and is known as “nutritional immunity.” E. Other microminerals Chromium (Cr) and fluorine (F) also play roles in the body. Cr potentiates the action of insulin by an unknown mechanism. It is found in fruits, vegetables, dairy products, and meat. F (as fluoride [F−]) is added to water in many parts of the world to reduce the incidence of dental caries (Fig. 29.12). F− replaces the hydroxyl group of hydroxylapatite, forming fluoroapatite that is more resistant to the enamel-dissolving acid produced by mouth bacteria. IV. ULTRATRACE MINERALS The ultratrace minerals include iodine (I), selenium (Se), and molybdenum (Mo). They are required by adults in amounts <1 mg/day. A. Iodine
Biochemistry_Lippincott_1416	Biochemistry_Lippinco	A. Iodine I is utilized in the synthesis of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) that are required for development, growth, and metabolism. Circulating iodide (I−) is taken up (“trapped”) and concentrated in the epithelial follicular cells of the thyroid gland. It then is sent into the colloid of the follicular lumen where it is oxidized to iodine (I2) by thyroperoxidase (TPO), as shown in Figure 29.13. TPO then uses I2 to iodinate selected tyrosine residues in thyroglobulin (Tg), forming monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT), as shown in Figure 29.14. [Note: Tg is synthesized and secreted into colloid by follicular cells.] The coupling of two DIT on Tg gives T4, whereas coupling one MIT and one DIT gives T3. The iodinated Tg is endocytosed and stored in follicular cells until needed, at which time it is proteolytically digested to release T3 and T4, which are secreted into the circulation (see Fig. 29.13).	Biochemistry_Lippinco. A. Iodine I is utilized in the synthesis of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) that are required for development, growth, and metabolism. Circulating iodide (I−) is taken up (“trapped”) and concentrated in the epithelial follicular cells of the thyroid gland. It then is sent into the colloid of the follicular lumen where it is oxidized to iodine (I2) by thyroperoxidase (TPO), as shown in Figure 29.13. TPO then uses I2 to iodinate selected tyrosine residues in thyroglobulin (Tg), forming monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT), as shown in Figure 29.14. [Note: Tg is synthesized and secreted into colloid by follicular cells.] The coupling of two DIT on Tg gives T4, whereas coupling one MIT and one DIT gives T3. The iodinated Tg is endocytosed and stored in follicular cells until needed, at which time it is proteolytically digested to release T3 and T4, which are secreted into the circulation (see Fig. 29.13).
Biochemistry_Lippincott_1417	Biochemistry_Lippinco	Under normal conditions, ~90% of secreted thyroid hormone is T4 that is carried by transthyretin. In target tissues (for example, the liver and developing brain), T4 is converted to T3 (the more active form) by Se-containing deiodinases. T3 binds to a nuclear receptor that binds DNA at thyroid response elements and functions as a transcription factor. [Note: Thyroid hormone production is controlled by thyrotropin (thyroid-stimulating hormone ([TSH]) from the anterior pituitary. TSH secretion is itself controlled by thyrotropin-releasing hormone (TRH) from the hypothalamus.] 1.	Biochemistry_Lippinco. Under normal conditions, ~90% of secreted thyroid hormone is T4 that is carried by transthyretin. In target tissues (for example, the liver and developing brain), T4 is converted to T3 (the more active form) by Se-containing deiodinases. T3 binds to a nuclear receptor that binds DNA at thyroid response elements and functions as a transcription factor. [Note: Thyroid hormone production is controlled by thyrotropin (thyroid-stimulating hormone ([TSH]) from the anterior pituitary. TSH secretion is itself controlled by thyrotropin-releasing hormone (TRH) from the hypothalamus.] 1.
Biochemistry_Lippincott_1418	Biochemistry_Lippinco	Hypothyroidism: Underingestion of I can result in goiter (enlargement of the thyroid in response to excessive stimulation by TSH), as shown in Figure 29.15. More severe deficiency results in hypothyroidism that is characterized by fatigue, weight gain, decreased thermogenesis, and decreased metabolic rate (see p. 359). If hormone deficiency occurs during fetal and infant development (congenital hypothyroidism), irreversible intellectual disability (formerly called “cretinism”), hearing loss, spasticity, and short stature can result. In the United States, dairy products, seafood, and meat are the primary sources of I. The use of iodized salt has greatly reduced dietary I deficiency. [Note: Autoimmune destruction of TPO is a cause of Hashimoto thyroiditis (a primary hypothyroidism).] 2.	Biochemistry_Lippinco. Hypothyroidism: Underingestion of I can result in goiter (enlargement of the thyroid in response to excessive stimulation by TSH), as shown in Figure 29.15. More severe deficiency results in hypothyroidism that is characterized by fatigue, weight gain, decreased thermogenesis, and decreased metabolic rate (see p. 359). If hormone deficiency occurs during fetal and infant development (congenital hypothyroidism), irreversible intellectual disability (formerly called “cretinism”), hearing loss, spasticity, and short stature can result. In the United States, dairy products, seafood, and meat are the primary sources of I. The use of iodized salt has greatly reduced dietary I deficiency. [Note: Autoimmune destruction of TPO is a cause of Hashimoto thyroiditis (a primary hypothyroidism).] 2.
Biochemistry_Lippincott_1419	Biochemistry_Lippinco	Hyperthyroidism: This condition is the result of overproduction of thyroid hormone. Although it can be caused by overingestion of I-containing supplements (UL = 1.1 g/day for adults), the most common cause of hyperthyroidism is Graves disease, in which an antibody that mimics the effect of TSH is produced, resulting in dysregulated production of thyroid hormone. This can cause nervousness, weight loss, increased perspiration and heart rate, protruding eyes (exophthalmos, Fig. 29.16), and goiter. B. Selenium	Biochemistry_Lippinco. Hyperthyroidism: This condition is the result of overproduction of thyroid hormone. Although it can be caused by overingestion of I-containing supplements (UL = 1.1 g/day for adults), the most common cause of hyperthyroidism is Graves disease, in which an antibody that mimics the effect of TSH is produced, resulting in dysregulated production of thyroid hormone. This can cause nervousness, weight loss, increased perspiration and heart rate, protruding eyes (exophthalmos, Fig. 29.16), and goiter. B. Selenium
Biochemistry_Lippincott_1420	Biochemistry_Lippinco	B. Selenium Se is present in ~25 human proteins (selenoproteins) as a constituent of the amino acid selenocysteine, which is derived from serine (see p. 268). Selenoproteins include glutathione peroxidase that oxidizes glutathione in the reduction of hydrogen peroxide, a ROS, to water (see p. 148); thioredoxin reductase that reduces thioredoxin, a coenzyme of ribonucleotide reductase (see p. 297); and deiodinases that remove I from thyroid hormones. Meat, dairy products, and grains are important dietary sources. Keshan disease, first identified in China, is a cardiomyopathy caused by eating foods produced from Se-deficient soil. Toxicity (selenosis) caused by overingestion of supplements causes brittle nails and hair. Cutaneous and neurologic effects may also be seen (UL = 400 µg in adults). C. Molybdenum	Biochemistry_Lippinco. B. Selenium Se is present in ~25 human proteins (selenoproteins) as a constituent of the amino acid selenocysteine, which is derived from serine (see p. 268). Selenoproteins include glutathione peroxidase that oxidizes glutathione in the reduction of hydrogen peroxide, a ROS, to water (see p. 148); thioredoxin reductase that reduces thioredoxin, a coenzyme of ribonucleotide reductase (see p. 297); and deiodinases that remove I from thyroid hormones. Meat, dairy products, and grains are important dietary sources. Keshan disease, first identified in China, is a cardiomyopathy caused by eating foods produced from Se-deficient soil. Toxicity (selenosis) caused by overingestion of supplements causes brittle nails and hair. Cutaneous and neurologic effects may also be seen (UL = 400 µg in adults). C. Molybdenum
Biochemistry_Lippincott_1421	Biochemistry_Lippinco	C. Molybdenum Mo functions as a cofactor for a small number of mammalian oxidases (Fig. 29.17). Legumes are important dietary sources. No dietary deficiency syndromes are known. Mo has low toxicity in humans (UL = 2 mg/day in adults). Cobalt (Co), an ultratrace mineral, is a component of vitamin B12 (cobalamin, see p. 379), which is required as methylcobalamin in the remethylation of homocysteine to methionine (see p. 264) or adenosylcobalamin in the isomerization of methylmalonyl coenzyme A (CoA) to succinyl CoA (see p. 194). No Recommended Dietary Allowance or Daily Reference Intake (see p. 358) has been established for Co. V. CHAPTER SUMMARY The minerals are summarized in Figure 29.18 on p. 408. For Questions 29.1–29.7, match the mineral to the most appropriate description. A. Calcium B. Chloride C. Copper D. Iodine E. Iron F. Magnesium G. Manganese H. Molybdenum I. Phosphorus J. Potassium K. Selenium L. Sodium	Biochemistry_Lippinco. C. Molybdenum Mo functions as a cofactor for a small number of mammalian oxidases (Fig. 29.17). Legumes are important dietary sources. No dietary deficiency syndromes are known. Mo has low toxicity in humans (UL = 2 mg/day in adults). Cobalt (Co), an ultratrace mineral, is a component of vitamin B12 (cobalamin, see p. 379), which is required as methylcobalamin in the remethylation of homocysteine to methionine (see p. 264) or adenosylcobalamin in the isomerization of methylmalonyl coenzyme A (CoA) to succinyl CoA (see p. 194). No Recommended Dietary Allowance or Daily Reference Intake (see p. 358) has been established for Co. V. CHAPTER SUMMARY The minerals are summarized in Figure 29.18 on p. 408. For Questions 29.1–29.7, match the mineral to the most appropriate description. A. Calcium B. Chloride C. Copper D. Iodine E. Iron F. Magnesium G. Manganese H. Molybdenum I. Phosphorus J. Potassium K. Selenium L. Sodium
Biochemistry_Lippincott_1422	Biochemistry_Lippinco	A. Calcium B. Chloride C. Copper D. Iodine E. Iron F. Magnesium G. Manganese H. Molybdenum I. Phosphorus J. Potassium K. Selenium L. Sodium M. Zinc 9.1. Elevated levels of which mineral may result in hypertension in certain populations? 9.2. Which mineral is the major extracellular anion? 9.3. A decrease of which mineral is seen in refeeding syndrome and with overuse of aluminum-containing antacids? 9.4. Which mineral is a constituent of some amino acids found in proteins involved in antioxidant defense, thyroid hormone metabolism, and redox reactions? 9.5. Which mineral is required for the formation of a supersecondary protein structure that allows binding to DNA? (Its deficiency can result in a dermatitis.) 9.6. Deficiency of which mineral can cause bone pain, tetany (intermittent muscle spasms), paresthesia (a “pins and needles” sensation), and an increased tendency to bleed? 9.7. Deficiency of which mineral can result in goiter and a decreased metabolic rate?	Biochemistry_Lippinco. A. Calcium B. Chloride C. Copper D. Iodine E. Iron F. Magnesium G. Manganese H. Molybdenum I. Phosphorus J. Potassium K. Selenium L. Sodium M. Zinc 9.1. Elevated levels of which mineral may result in hypertension in certain populations? 9.2. Which mineral is the major extracellular anion? 9.3. A decrease of which mineral is seen in refeeding syndrome and with overuse of aluminum-containing antacids? 9.4. Which mineral is a constituent of some amino acids found in proteins involved in antioxidant defense, thyroid hormone metabolism, and redox reactions? 9.5. Which mineral is required for the formation of a supersecondary protein structure that allows binding to DNA? (Its deficiency can result in a dermatitis.) 9.6. Deficiency of which mineral can cause bone pain, tetany (intermittent muscle spasms), paresthesia (a “pins and needles” sensation), and an increased tendency to bleed? 9.7. Deficiency of which mineral can result in goiter and a decreased metabolic rate?