Ornithine transcarbamylase

Depicted is CP situated in OTC's Binding Site with residues that play an important role in binding CP.[9]

Ser-Thr-Arg-Thr-Arg motif from one subunit and a His from the neighboring subunit both interact with the phosphate group of CP for binding. Binding the primary nitrogen of CP are residues Gln, Cys, and Arg. The carbonyl oxygen of CP is bound by residues Thr, Arg, and His.[10]

 Plant OTCs have the largest difference from other OTCs. There are 50 to 70% less Leu residues, while there are twice as many Arg residues. The number of subunits in OTCs vary from 322 to 340 residues. Animals have the highest density of Leu. This residue breakdown causes a pI for the animal enzyme of 6.8 while the plant enzyme has a pI of 7.6.[11] Rat, bovine, and human OTC have the same C terminal residue of phenylalanine. Their N-terminal residues on the other hand differ. Rat ends with Ser, bovine with aspartate, and human with glycine.[12][13]

341 mutations in human OTC have been reported. At least 259 of these mutations are considered to be disease-causing mutations.[15] 149 of these mutations are known to cause onset of hyperammonemia during the first weeks of life. 70 manifest as hyperammonemia in male patients later in life. Most of the mutations occur in known functional motifs, such as the SMG loop or CP binding domains.[16]

Early onset is seen in newborns. The symptoms of a urea cycle disorder are often not seen until the child is at home and may not be recognized in a timely manner by the family and primary care physician. Symptoms in young children with hyperammonemia are non-specific: not willing to eat, problems with breathing, body temperature, seizures, unusual body movements (twitches) and somnolence.[17] As ammonia build up continues, symptoms progress from somnolence to lethargy potentially ending in a coma. Abnormal posturing (uncontrolled movement) and encephalopathy (brain damage) are often related to the degree of central nervous system swelling and pressure upon the brainstem. About 50% of neonates with severe hyperammonemia have seizures.

In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma ammonia concentration [Bourrier et al. 1988]. Patients with partial enzyme deficiencies may have a delay of symptoms for months or years. Indicators that you maybe suffering from OTC deficiency or a urea cycle disorder include "episodes of delirium, erratic behavior, or reduced consciousness, headaches, vomiting, aversion to foods high in protein, and seizures."[18]

A potential treatment for the high ammonia levels is to give sodium benzoate, which combines with glycine to produce hippurate, at the same time removing an ammonium group. Biotin also plays an important role in the functioning of the OTC enzyme[19] and has been shown to reduce ammonia intoxication in animal experiments. Additionally, the use of whole-body therapeutic hypothermia (TH) has been proposed and studied as a treatment. TH is thought to increase the effectiveness of dialysis to extract ammonia from the body.[20][21]