Question

A. Individuals with urea cycle disorders have glucose intravenously injected into their blood stream. How could maintaining high levels of glucose in the blood stream partially reduce the accumulation of ammonia in individuals with a urea cycle disorder?

B. Please explain why individuals with defects in the malate-aspartate shuttle would exhibit increased levels of ammonia in their bloodstream based upon the reactions of the urea cycle?

Answer 1

Urea cycle disorders (UCDs) are inborn errors of nitrogen detoxification/arginine synthesis due to defects in the urea cycle enzymes, carbamoylphosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase 1 (ARG1), leading to respective deficiencies. the treatment of UCDs has as common elements the reduction of protein in the diet, removal of excess ammonia and replacement of intermediates missing from the urea cycle. Administration of lactulose (a nonabsorbable disaccharide) results in reduced ammonia production in the gut and, therefore, less ammonium ion is delivered to the portal circulation from the intestines. Bacteria metabolize lactulose to acidic byproducts which then promotes excretion of ammonia in the feces as ammonium ion, NH4+ and interferes with the production of ammonia through reduced catabolism of other nitrogenous compounds.

2. malate aspartate shuttle operates in liver and heart. this complex shuttle is bidirectional an requires the cooperation in a cyclic manner of cytoplasmic and mitochondrial isozymes of malate dehydrogenase and aspartate glutamate transaminase as well as mitochondrial membrane transport system.The activity of mitochondria shuttles is essential for cells to metabolize glucose and lactate as energy sources. GDH and GS assimilate ammonia, generating glutamate and glutamine. Glutamate contributes to the urea cycle through conversion to aspartate by GOT2 and mitochondrial export via AGC1/2. GDH is a bidirectional enzyme, and high ammonia levels reverse the direction of GDH, favoring the reductive activity