Chapter 18: Pages 638-655
Benzoate and phenylacetate are given as dietary supplements for patients with urea cycle defects. Benzoate forms an adduct with glycine and phenyl acetate forms an adduct with glutamine. Both of these adducts are non toxic and are excreted in the kidneys. The other treatment is to severely restrict the protein intake of the patient so as to ensure that there is no dietary excess of amino acids. What are the ten essential dietary amino acids?
Back on page 634, the terms ammonotelic, ureotelic adn uricotelic were defined. Then, on page 638, the rationale for each type of elimination system is described.
Skip pages 640-645. Folate is needed for proper brain and spine development as deficiencies have been linked to an increase in spina bifida, tetrahydrofolate is also a target of the anticancer drug, methotrexate--but that is related to its role in the synthesis of dTMP from dUMP, page 864.
Figure 18-14 on page 647 shows how the carbons of all 20 amino acids end up in the Kreb's cycle. Don't worry about where each carbon ends up. We are only going to study some of the amino acid catabolism pathways. You will need to know the diseases listed in box 18-2, and the amino acid metabolism defect that is associated with each disease.
Diseases due to defects in the urea cycle include: Argininemia, Argininosuccinc acidemia, Carbamoyl phosphate synthetase I deficiency.
In order to understand Albinism, Alkaptonuria and Phenylketonuria, we need to know the pathway for the metabolism of phenylalanine and tyrosine. What enzyme is defective in PKU? What cofactor is required for this enzyme? After phenylalanine is hydroxylated, it is the precursor for norepinephrine, epinephrine, dopamine and melanin. What does each of those molecules do? One of the reasons that elevated levels of phenylalanine in the blood is toxic is because all of the aromatic amino acids use the same transporters to cross the blood brain barrier. Too much phenylalanine will keep tryptophan from getting into the brain. Tryptophan is needed to make some very important molecules, the last paragraph on page 644 discusses this. If the normal pathway for phenylalanine hydroxylation is defective, how is phenylalanine metabolized? What molecule gives the urine of PKU patients its characteristic odor. These patients are treated by giving them a diet that is very limited in phenylalanine and supplemented with tyrosine. (Tyrosine is not normally an essential amino acid because the normal body makes it from phenylalanine.) Why is this dietary restriction essential during childhood and not critical after puberty?
PKU can also be caused by a defect in dihydrobiopterin reductase. Explain why this defect causes PKU. How will the treatment of these patients differ from the patients with the first type of PKU?
Why should PKU patients avoid diet Coke. Some folks complain of headaches and other neurological symptoms after ingesting artificially sweetened foods. Could this be related to phenylalanine metabolism? (The www is full of informatio on this.)
What is the enzyme deficiency in patients with alkaptonuria? What is characteristic of these patients' urine? This disease is of historical importance because it was the first connection between a defective gene and a heritable trait.
Methylmalonic acidemia results from defects in the catabolism of branched chain amino acids and methionine. What are the branched chain amino acids? Page 650 discusses and shows the reactions for the metabolism for these amino acids. The court case that was discussed in class when we were studying the metabolism of fatty acids with an odd number of carbons is explained in box 18-2. You should know the reactions involved in converting propionyl CoA to succinyl CoA.
Muscle, kidney, adipose and brain tissues can use branched chain amino acids for fuels because they have an aminotransferase that will use either valine, threonine or leucine as a substrate. (This amino transferase is not present in the liver.) The resulting a keto acids are then substrates for branched chain a keto acid dehydrogenase complex. This enzyme complex has essentially the same mechanism and cofactors and the "cereal" enzyme that metabolizes a ketoglutarate. What are the products for each of these amino acids? How is this enzyme complex regulated? How was pyruvate dehydrogenase regulated. A defect in this enzyme will cause the branched chain amino acids to build up in the blood and spill out into the urine, the resulting urine has the smell of maple syrup. What are the other effects of a defect in this enzyme?
So far, we have incountered two enzymes that are present in extrahepatic tissues: branched chain aminotransferase and one other for the metabolism of ketones (what was it?). Why would the liver be short changed and not get these enzymes? What is one major function of the liver?
Ketones and Glucose come from amino acid carbons
Be aware that the carbons from some amino acids end up as glucose. The same amino acids carbons also end up as ketones. Some amino acids are both glucogenic and ketogenic. Only leucine and lysine are exclusively ketogenic. Why is this important under starvation conditions? Why is this important for the diabetic patient?
Why does uncontrolled diabetes cause weight loss? How does the alanine cycle exacerbate hyperglycemia for the diabetic patient?