Arg supplementation is helpful because the Arg will be hydrolyzed to urea + ornithine by arginase. The ornithine will be combined with CP to form citrulline (see figure above). With ASL (and ASS) deficiency, citrulline accumulates and is excreted, thereby carrying waste nitrogen out of the body. Answer = D. In individuals with milder (partial) deficiencies in the enzymes of the urea cycle, hyperammonemia may be triggered by physiologic stress (for example, an illness or prolonged fasting) that decreases the insulin/counterregulatory hormone ratio. [Note: The degree of the hyperammonemia is usually less severe than that seen in the neonatal onset forms.] The shift in the ratio results, in part, in skeletal muscle proteolysis, and the amino acids that are released get degraded. Degradation involves transamination by pyridoxal phosphate–requiring aminotransferases that generate the α-keto acid derivative of the amino acid + glutamate. The glutamate undergoes oxidative deamination to α-ketoglutarate and ammonia (NH3) by glutamate dehydrogenase (GDH; see figure at right). [Note: GDH is unusual in that it uses both nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) as coenzymes.]
The NH3, which is toxic, can be transported to the liver as glutamine (Gln) and alanine (Ala). The Gln is generated by the amination of glutamate by ATP-requiring glutamine synthetase. In the liver, the enzyme glutaminase removes the NH3, which can be converted to urea by the urea cycle or excreted as ammonium (NH4+) (see figure at right). Gln, then, is a nontoxic vehicle of NH3 transport in the blood. Ala is generated in skeletal muscle from the catabolism of the branched-chain amino acids (BCAA). In the liver, Ala is transaminated by alanine transaminase (ALT) to pyruvate (used in gluconeogenesis) and glutamate. Thus, Ala carries nitrogen to the liver for conversion to urea (see figure below). Therefore, defects in the urea cycle would result in an elevation in NH3, Gln, and Ala. The elevated NH3 drives respiration, and the hyperventilation causes a rise in pH (respiratory alkalosis). [Note: Hyperammonemia is toxic to the nervous system. Although the exact mechanisms are not completely understood, it is known that the metabolism of large amounts of NH3 to Gln (in the astrocytes of the brain) results in osmotic effects that cause the brain to swell. Additionally, the rise in Gln decreases the availability of glutamate, an excitatory neurotransmitter.]
Case 10: Swollen, Painful Calf with Deep Venous Thrombosis