Flashcards in Clinical Correlates 7 Amino Acid Metabolism Deck (22):
___ involves the transfer of an amino group from one amino acid (which is converted to its corresponding a-ketoacid) to an a-ketoacid (which is converted to its corresponding a-amino acid). Thus, the nitrogen from one amino acid appears in another amino acid.
Hereditary deficiency of carbamoyl phosphate synthetase I (CPS I) results in an inability for nitrogenous waste (ammonia) to be metabolized via the urea cycle.
Ammonia levels in such patients rise, leading to ____ ___, without strict dietary control.
brain damage, coma, or death
Deficiency of ___ transcarbamoylase, an X-linked trait, results in similar neurologic sequelae as CPS I deficiency.
Citrullinemia results from a deficiency of the enzyme ___ synthetase, causing an elevation in serum levels of citrulline. Again, without dietary management, the manifestations of this disease include __ ___ ___, and behavioral changes.
lethargy, hypotonia, seizures, ataxia
Argininosuccinate aciduria results from a deficiency of the enzyme argininosuccinate lyase in the urea cycle, resulting in ___ with grave effects on the ___.
Unlike deficiencies of other enzymes in the urea cycle, arginase deficiency does not result in severe hyperammonemia. The reason is twofold. First, the formed arginine, containing two ‘‘waste’’ nitrogen molecules, can be ___ ___. Second, there are two isozymes, and in the event that the predominant liver enzyme is dysfunctional, the peripheral isozyme is ___, leading to adequate restoration of the pathway.
excreted in the urine
Type I primary ____ results from the absence of a transaminase, which converts glyoxylate to glycine, resulting in renal failure due to ___ __ in the kidney.
In the rare hereditary metabolic disorder of ___, histidase, which converts histidine to urocanate, is defective. Early cases were reported to be associated with ___ ___, but more recently, deleterious consequences have not been observed.
The hereditary deficiency of methylmalonyl CoA mutase results in __ __, vomiting, dehydration, developmental delay, and seizures. Consequences of this deficiency are compounded by accumulation of propionyl CoA, a substrate for the TCA cycle enzyme ___ synthase, leading to the condensation of propionyl CoA with oxaloacetate, which leads to the accumulation of the TCA toxin, __ __.
failure to thrive
____ is most often due to a defect in cystathionine b-synthase, leading to increased homocysteine and methionine. Patients present with dislocation of the lens, mental retardation, and skeletal and neurologic abnormalities.
In maple syrup urine disease, the enzyme complex that decarboxylates the transamination products of the branched-chain amino acids (the a-ketoacid dehydrogenase) is defective. __ ___ __ accumulate. Urine has the odor of maple syrup. Mental retardation and poor myelination of nerves occur. Dietary restrictions are difficult to implement because three essential amino acids are required.
Valine, isoleucine, and leucine
In phenylketonuria (PKU), the conversion of phenylalanine to tyrosine is defective owing to defects in _____. A variant, nonclassic PKU, is a result of a defective enzyme in ____ synthesis. Phenylalanine accumulates in both disorders and is converted to compounds such as the phenylketones, which give the urine a musty odor. Mental retardation occurs. PKU is treated by restriction of phenylalanine in the diet.
In ___, homogentisic acid, which is a product of phenylalanine and tyrosine metabolism, accumulates because homogentisate oxidase is defective. Homogentisic acid auto-oxidizes, and the products polymerize, forming ___ ___, which accumulate in various tissues and are sometimes associated with a degenerative arthritis.
Isovaleric acidemia results from a defect in isovaleryl CoA dehydrogenase, preventing the degradation of isovaleryl CoA during the degradation of ___. The defect results in ___ ___ and mental retardation. The patient has a distinctive odor of ‘‘sweaty feet.’’ Limiting the intake of leucine helps limit the progression of symptoms.
1. A 5-year-old mentally retarded child is seen by an ophthalmologist for ‘‘blurry vision.’’ Ocular examination demonstrates bilateral lens dislocations, and further workup is significant for osteoporosis and homocystinuria. Serum analysis would most likely show an elevation of which of the following substances?
E. The child has homocystinuria, a deficiency of cystathionine b-synthase, which manifests with mental retardation, osteoporosis, and lens dislocations. This enzyme is responsible for the metabolism of sulfur-containing amino acids and normally catalyzes the conversion of homocysteine to cystathionine. When the enzyme is defective, homocysteine can dimerize via disulfide bond formation, generating homocystine. Another fate of homocysteine is remethylation to methionine, which can also accumulate in this disorder. Because cystathionine cannot be formed under these conditions, it will not accumulate. Valine, phenylalanine, and tyrosine are not associated with the defective pathway, and their blood levels remain normal.
2. A 3-month-old child presents with vomiting and convulsions. Notable findings include hepatomegaly
and hyperammonemia. A deficiency in which of the following enzymes would most likely cause an elevation of blood ammonia levels?
(A) CPS II
(C) Argininosuccinate lyase
(D) Asparagine synthetase
C. There are two major types of hyperammonemia: acquired and hereditary. The hereditary type can result from deficiencies of any of the five enzymes of the urea cycle, which include CPS I, ornithine transcarbamoylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase. CPS II is involved in pyrimidine synthesis and utilizes glutamine as a substrate (not ammonia). Glutaminase will generate (not fix) ammonia, and therefore a loss of glutaminase activity will not increase ammonia levels. Asparagine synthetase requires glutamine as a substrate (not ammonia). Urease is a bacterial and plant enzyme that can degrade urea into ammonia; it is not present in humans.
3. A 55-year-old man suffers from cirrhosis of the liver. He has been admitted to the hospital several times for hepatic encephalopathy. His damaged liver has compromised his ability to detoxify ammonia. Which of the following amino acids can be used to fix ammonia and thus transport and store ammonia in a nontoxic
B. Three enzymes can fix ammonia into an organic molecule: glutamate dehydrogenase (a-ketoglutarate plus ammonia yield glutamate), CPS I (carbon dioxide, ammonia, and two ATP molecules yield carbamoyl phosphate), and glutamine synthetase (glutamate plus ammonia plus ATP yield glutamine). Thus, of the answer choices provided, glutamate is the correct answer. Aspartate is the precursor for asparagine synthesis, but glutamine is the nitrogen donor in that reaction, not ammonia. Serine, cysteine, and histidine are not utilized for nitrogen transport.
4. A 27-year-old, semiprofessional tennis player seeks advice from a hospital-based nutritionist concerning his diet supplements. His coach had given him amino acid supplements consisting of phenylalanine and tyrosine. The rationale was that these neurotransmitter precursors
would ‘‘help his brain focus’’ on his game. In reality, excess phenylalanine will be metabolized to provide energy. Phenylalanine will enter the TCA cycle as which one of the following TCA cycle intermediates?
(E) Succinyl CoA
D. Although it is true (see Chapter 13) that tyrosine and phenylalanine are precursors for neurotransmitter synthesis, excess amino acid intake will lead to their degradation. Phenylalanine is converted directly to tyrosine and, through homogentisic acid, enters the TCA cycle as fumarate. Aspartate and asparagine enter through oxaloacetate; glutamate directly feeds into a-ketoglutarate; and valine, threonine, isoleucine, and methionine enter via propionyl CoA to succinyl CoA.
5. A 2-year-old girl was seen in the emergency room for vomiting and tremors. Laboratory tests revealed a plasma ammonium ion concentration of 195 mM(normal, 11- to 50 mM) and serum elevation of arginine. Two days later, after stabilization, ammonia and arginine levels were normal. You conclude that this patient may have a defect in which of the following enzymes?
(A) CPS I
(B) CPS II
(C) Ornithine transcarbamoylase
(E) Argininosuccinate lyase
D. Arginase deficiency, the least common of the urea cycle defects, presents with episodic increases in serum ammonia and arginine, leading to the observed symptoms of vomiting and tremors. A defect in CPS I leads to constant hyperammonemia, without elevated arginine. A defect in CPS II would interfere with pyrimidine synthesis and does not alter blood ammonia levels. An ornithine transcarbamoylase deficiency leads to hyperammonemia and orotic aciduria. An argininosuccinate lyase deficiency leads to elevated argininosuccinate, not elevated arginine levels.
6. A 23-year-old Golden Gloves boxing contender presents with assorted metabolic disorders, most notably ketosis. During the history and physical examination, he describes his training regimen, which is modeled after the Rocky films and involves consuming a dozen raw eggs a day for protein. Raw eggs contain a 70-kD protein called avidin, with an extremely high affinity for a cofactor required by propionyl CoA carboxylase, pyruvate carboxylase, and acetyl CoA carboxylase. The patient is functionally deficient in which one of the following cofactors?
(E) Pyridoxal phosphate
C. The cofactor required for propionyl CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase is biotin. Avidin binds extremely tightly (hence the name avidin) to biotin, which can then no longer be used by these enzymes as a cofactor. Loss of pyruvate carboxylase activity reduces gluconeogenesis, so hypoglycemia and ketosis will result. Avidin does not bind to tetrahydrobiopterin, tetrahydrofolate, B12, or pyridoxal phosphate.
7. A new test is developed that can nonradioactively ‘‘label’’ compounds in the human body. As a physician with a background in the new field of metabolomics, you assess a 21-year-old with classic PKU. The patient is fed phenylalanine with a label in the phenyl ring, and a 24-hour urine sample is collected. Which of the following compounds would you expect to contain the greatest amount of label in this urine sample?
D. PKU results from a defect in phenylalanine hydroxylase, resulting in a block in the conversion of phenylalanine to tyrosine. Phenylalanine accumulates in cells and is converted to phenylketones, which enter the blood and urine. Tyrosine is the product whose formation is blocked, and epinephrine, a product of tyrosine, would not be synthesized, so it would not contain a ‘‘label.’’ Acetate and tryptophan are not derived from labeled phenylalanine in a patient with PKU, so those compounds would not contain the label.