Integrated Metabolism—Vitamins, Minerals, and Hormones

Answers

138. The answer is b. (Murray, pp 525-542. Scriver, pp 3127-3162.) Ferrous iron (Fe²⁺) is the form absorbed in the intestine by ferritin, transported in plasma by transferrin, and stored in the liver in combination with ferritin or as hemosiderin (incorrect answers a, d, e). There is no known excretory pathway for iron, either in the ferric or ferrous form (incorrect answer c). For this reason, excessive iron uptake over a period of many years may cause hemochromatosis (MIM*235200), the likely diagnosis for this male. This is a condition of extensive hemosiderin deposition in the liver, myocardium, pancreas, and adrenals. The resulting symptoms include liver cirrhosis, congestive heart failure, diabetes mellitus, and changes in skin pigmentation.

139. The answer is c. (Murray, pp 49-516. Scriver, pp 1623-1650) Certain amino acids and lipids are dietary necessities because humans cannot synthesize them. The energy usually obtained from carbohydrates can be obtained from lipids and the conversion of some amino acids to intermediates of the citric acid cycle (incorrect answers a, d). These alternative substrates can thus provide fuel for oxidation and energy plus reduce equivalents for biosynthesis. Iodine is important for thyroid hormone synthesis, whereas calcium is essential for muscle contraction and bone metabolism (incorrect answers b, e).

140. The answer is e. (Murray, pp 525-542. Scriver, pp 3897-3964.) Ascorbic acid (vitamin C) is found in fresh fruits (citrus, strawberries, and tomatoes) and vegetables (broccoli, potatoes, cabbage, and spinach). Pantothenic acid (vitamin B₅) is found in most foods including meat and whole grains (incorrect answer d), as are niacin (vitamin B₃—not strictly a vitamin since it can be synthesized—incorrect answer b), thiamine (vitamin B₁—incorrect answer a), and cobalamin (vitamin B₁₂—found in meat, milk, and eggs—incorrect answer c). Deficiency of ascorbic acid produces scurvy, the “sailor’s disease.” Ascorbic acid is necessary for the hydroxylation of proline to hydroxyproline in collagen, a process required in the formation and maintenance of connective tissue. The failure of mesenchymal cells to form collagen causes the skeletal, dental, and connective tissue deterioration seen in scurvy. Thiamine, niacin, cobalamin, and pantothenic acid can all be obtained from fish or meat products. The nomenclature of vitamins began by classifying fat-soluble vitamins as A (followed by subsequent letters of the alphabet such as D, E, and K) and water-soluble vitamins as B. Components of the B vitamin fraction were then given subscripts, eg, thiamine (B₁), riboflavin (B₂), niacin (nicotinic acid [B₃]), pantothenic acid (B₅), pyridoxine (B₆), and cobalamin (B₁₂). The water-soluble vitamins C, biotin, and folic acid do not follow the B nomenclature.

141. The answer is c. (Murray, pp 525-542. Scriver, pp 3897-3964.) The retinal pigment rhodopsin is composed of the 11-cis-retinal form of vitamin A coupled to opsin. Light isomerizes 11-cis-retinal to all-trans-retinal, which is hydrolyzed to free all-trans-retinal and opsin. In order for regeneration of rhodopsin to occur, 11-cis-retinal must be regenerated. This dark reaction involves the isomerization of all-trans-retinal to 11-cis-retinal, which combines with opsin to reform rhodopsin. A deficiency of vitamin A, which is often derived from the β-carotene of plants, results in night blindness. Excess of vitamin A (hypervitaminosis A) can cause cerebral edema and other problems postnatally and severe birth defects when retinoids are taken prenatally (eg, women taking Accutane for acne).

142. The answer is b. (Murray, pp 151-162. Scriver, pp 3897-3964) Hypoglycemia during fasting suggests a disorder of gluconeogenesis, which involves the enzymes pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase to reverse key reaction steps in glycolysis. Pyruvate carboxylase catalyzes the conversion of pyruvate to oxaloacetate (incorrect answers d, e) and requires biotin with allosteric activation by acetyl-CoA. Biotin is a cofactor in several carboxylation reactions, while niacin is a source for NAD and NADH reactions (incorrect answers a, e) and pyridoxine for pyridoxal phosphate that is important in amino acid transferase reactions and steroid hormone action (incorrect answer d). Thiamine is important for pyruvate dehydrogenase, a first step in oxidative phosphorylation (incorrect answer c). High levels of acetyl-CoA indicate a fed state with oxidative breakdown of foods and high energy (ATP) levels. When ATP levels are high, oxaloacetate is consumed in gluconeogenesis, and when ATP levels are low, oxaloacetate enters the citric acid cycle. Gluconeogenesis only occurs in the liver and kidneys.

143. The answer is b. (Murray, pp 525-542. Scriver, pp 121-138, 287320, 3897-3964.) Pantothenic acid combines with the amino acid cysteine to become the pantetheine sulfhydryl component of coenzyme A (CoA) and acyl carrier protein (important for fatty acid synthesis). Acetyl-CoA is the activated form of acetate employed in acetylation reactions, including the citric acid cycle and lipid metabolism. Loss of myelin in Hallervorden-Spatz disease correlates with a role for activated pantothenic acid as a cofactor for fatty acid synthesis and as a carrier of acyl chains (which must be added to glycerol to form triacylglycerols), alkylacylglycerols (ether lipids), and (by acyl addition to sphingosine) cerebrosides, sphingomyelin, and gangliosides.

Mutations with severe impact on pantothenic acid kinase (mediating activation by its phosphorylation) present with neurologic signs in infancy (eg, infantile neuroaxonal dystrophy—MIM*256600), while those with less impact present in the second or third decades with cognitive decline, dementia, and psychiatric symptoms (eg, Hallervorden-Spatz disease, MIM*234200). Nutritional deficiencies of pantothenic acid have not been described except in artificial studies, perhaps because they would limit CoA and have deadly consequences in mammals. However, because it is common in foodstuffs, there is little evidence of pantothenic acid deficiency in humans.

144. The answer is b. (Murray, pp 525-542. Scriver, pp 3897-3964.) Pantothenate is the precursor of CoA, which participates in numerous reactions throughout the metabolic scheme. CoA is a central molecule of metabolism involved in acetylation reactions. Thus, a deficiency of pantothenic acid would have severe consequences. There is no documented deficiency state for pantothenate, however, because this vitamin is common in foodstuffs. Other choices are vitamins concerned with several metabolic pathways including electron transport (riboflavin, thiamine), organic acid conversion (cobalamin), and sulfhydryl group transfer (pyridoxamine).

145. The answer is c. (Murray, pp 216-220, 525-542. Scriver, pp 2297-2356.) Pantothenic acid (vitamin B₅) is a component of coenzyme A (CoA) and acyl carrier protein (ACP). These proteins carry acyl groups with acetyl-CoA being important for fatty acid oxidation and many other metabolic reactions while ACP functions in fatty acid synthesis. Folic acid is made from glycine, serine, and choline, and is important for methyl (one carbon) reactions such as the conversion of deoxyuridine monophosphate to thymidine (incorrect answers a, b and d, e). Stable forms of folate (folinic acid, synthetic leucovorin) can be used as part of a supplement mixture (thiamine, riboflavin, coenzyme Q, and lipoic acid) for mitochondrial dysfunction. The reactive prosthetic group of both ACP and CoA is a phosphopantetheine sulfhydryl. In ACP, the phosphopantetheine group is attached to the 77-residue polypeptide chain via a serine hydroxyl. In CoA, the phosphopantetheine is linked to the 5′ phosphate of adenosine that is phosphorylated in its 3′ hydroxyl.

146. The answer is a. (Murray, pp 525-542. Scriver, pp 3897-3964.) Thiamine (vitamin B₁) activated as its pyrophosphate is a cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase of the citric acid cycle, branched chain ketoacid dehydrogenase that metabolizes leucine/isoleucine/valine, and transketolase of the pentose phosphate pathway. Deficiency of thiamine causes beriberi and exacerbates encephalopathy in alcoholics, having impact on the nervous system in both diseases. Since pyruvate dehydrogenase commits pyruvate from glycolysis to acetyl-CoA in the citric acid cycle, its impairment will increase lactate (lactic acidosis), deplete energy (by impacting the citric acid cycle and the first steps of oxidative phosphorylation), and impair glucose metabolism—all key to neural function. Impairment of transketolase and the pentose phosphate shunt would reduce NADPH production, key to glutathione maintenance and reduction of oxidants in brain. Certain mutations in transketolase may thus increase susceptibility to Wernicke-Korsakoff syndrome (MIM*277730), a nice example of a Mendelian enzyme alteration brought out by environment (alcohol dependency) to cause a multifactorial disease (encephalopathy).

Lipoamide is also a cofactor in pyruvate dehydrogenase, transferring the acetyl group in pyruvate to coenzyme A. Lipoamide becomes acetyllipoamide and then dihydrolipoamide as it first accepts and then transfers an acyl group. This reaction and the regeneration of lipoamide are catalyzed by different parts of the dehydrogenase enzyme complex. ATP transfers phosphoryl groups, thiamine pyrophosphate transfers aldehyde groups, and NADH and FADH transfer protons. Mutations in the multipeptide pyruvate dehydrogenase complex occur in Leigh disease (MIM*256000), an end phenotype of many mutations that simulate the lactic acidosis and encephalopathy accompanying acute forms of thiamine deficiency (beriberi).

147. The answer is d. (Murray, pp 216-228, 525-542. Scriver, pp 2297-2326.) The key enzymatic step of fatty acid synthesis is the carboxylation of acetyl-CoA to form malonyl-CoA; again there is the correlation of a carboxylation reaction and biotin (incorrect answers a-c, e). The carboxyl of biotin is covalently attached to an epsilon amino group of a lysine residue of acetyl-CoA carboxylase. The reaction occurs in two stages. In the first step, a carboxybiotin is formed:

HCO₃^– + biotin-enzyme + ATP → CO₂-biotin-enzyme + ADP + P_i

In the second step, the CO₂ is transferred to acetyl-CoA to produce malonyl-CoA:

CO₂-biotin-enzyme + acetyl-CoA → malonyl-CoA + biotin-enzyme None of the other cofactors listed are involved in this reaction.

148. The answer is c. (Murray, pp 525-542. Scriver, pp 3897-3964.) The vitamin riboflavin (vitamin B₂) is a precursor of two cofactors involved in electron transport systems, riboflavin 5′-phosphate, also known as flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD). Strictly speaking, these compounds are not nucleotides, as they contain the sugar alcohol ribitol, not ribose. The cofactors are strongly bound to their apoenzymes and function as dehydrogenation catalysts. Pyruvate dehydrogenase is a multienzyme complex and contains the enzyme dihydrolipoyl dehydrogenase, which has, as its prosthetic group, two molecules of FAD per molecule of enzyme. In the overall reaction, the reduced FAD is reoxidized by NAD⁺. Mutations at several loci encoding the components of pyruvate dehydrogenase cause the clinical phenotype of Leigh syndrome (MIM*256000) with seizures, low muscle tone, neurodegeneration, and lactic acidosis. Succinate dehydrogenase also contains tightly bound FAD, one molecule per molecule of enzyme. Glutamate, lactate, malate, and glyceraldehyde-3-phosphate dehydrogenases all use nicotinamide dinucleotide cofactors and do not contain FAD as a prosthetic group.

149. The answer is c. (Murray, pp 525-542. Scriver, pp 3897-3964.) Pyridoxine (vitamin B₆) deficiency usually occurs concurrently with deficiency of other B vitamins or in association with drug therapy in individuals who are slow metabolizers for the antituberculosis drug isoniazid and others such as penicillamine or sulfa antibiotics (MIM*243400). Pyridoxine is present in many foods, particularly vegetables, cereals, and fruits. Niacin (precursor to nicotinamide adenine dinucleotide) is abundant in liver, poultry, and eggs; tetrahydrofolate in human and cow (not goat) milk, uncooked fruits, and vegetables; riboflavin (vitamin B₂—precursor to flavin adenine mononucleotide) in milk, eggs, meats, and fruits; retinoic acid (vitamin A) in animal tissues such as egg yolks, fish oils with other carotenoids in leafy vegetables.

The coenzyme pyridoxal phosphate is a versatile compound that aids in amino acid transaminations, deaminations, decarboxylations, and transulfurations. It is also important for operation of glycogen phosphorylase. A common feature of these reactions is formation of a Schiff-base intermediate with a specific lysine group at the active site of the appropriate enzymes.

150. The answer is a. (Murray, pp 525-542. Scriver, pp 3897-3964.) Vitamin A is essential for the normal differentiation of epithelial tissue as well as normal reproduction. Yellow and dark green vegetables as well as fruits are good sources of carotenes, which serve as precursors of vitamin A. However, egg yolk, butter, cream, and liver and kidneys are good sources of preformed vitamin A. Vitamin A is necessary for vision, not hearing. The visual pigment rhodopsin is formed from the protein opsin and 11-cis-retinal. During the photobleaching of rhodopsin, all-trans-retinal plus opsin is formed from dissociated rhodopsin, causing an impulse that is transmitted by the optic nerve to the brain. Isomerized from trans-retinal, 11-cis-retinal combines with opsin to reform rhodospin, making it ready for another photochemical cycle. All-trans-retinoic acid (tretinoin) has been found to be effective for topical treatment of psoriasis. Another form of vitamin A is 13-cis-retinoic acid (Accutane), which has been found to be effective in the treatment of severe cases of acne. Accutane causes birth defects of the face and brain if taken during the first trimester of pregnancy. Vitamin A is not synthesized in the skin. Vitamin D (derivatives of calciferol) can be synthesized in the skin under the influence of sunlight from 7-dehydrocholesterol, an intermediate in cholesterol synthesis.

151. The answer is a. (Murray, pp 525-542. Scriver, pp 121-138, 287-320, 3897-3964

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