Metabolic and Genetic Studies of a Family with Ornithine Transcarbamylase Deficiency

Goldstein, Arnold S.; Hoogenraad, Nicholas J.; Johnson, John D.; Fukanaga, Keiko; Swierczewski, Elizabeth; Cann, Howard M.; Sunshine, Philip

doi:10.1203/00006450-197401000-00002

Cited by 77 publications

(20 citation statements)

References 9 publications

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“…Glutamine (18), glutamate (4), alanine (30), and a-ketoglutarate (16) were measured by modifications of enzymatic fluorometric techniques, allowing capillary plasma to be used. Urinary orotate was measured by the method of Goldstein et al (11). A neurologic examination as described by Prechtl and Beintema (20) was performed on the low birthweight infants at 0-3 days of age.…”

Section: Speculationmentioning

confidence: 99%

Asymptomatic Hyperammonemia in Low Birthweight Infants

1978

Pediatr Res

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SummaryAt 0-3 days of age the plasma ammonium concentration in full term appropriate for gestational age (AGA) infants was (mean 2 SEM) 27.5 & 0.5 pM; a value similarlo that reported * in adults. Ammonium levels in low birthweight AGA and SGA groups were 47.0 + 2.0 p M and 45.1 r 3.3 p M respectively; significantly elevated (P < 0.001) as compared to the full term group. These increased ammonium levels persisted at 3-5 weeks of age. Associated with the hyperammonemia was a significant (P < 0.01) decrease in plasma a-ketoglutarate concentration:11.8 r 1.0 pM, in the low birthweight AGA as compared to 20.7 r 0.6 p M in the full term AGA infants. There was an inverse linear correlation between ~l a s m a concentrations of ammonium and a-ketoglutarate r = -0.86, P < 0.001. Urinary orotate excretion was significantly elevated (P < 0.05) in low birthweight AGA infants. There was no difference in the plasma concentrations of glutamine, glutamate, or alanine among the various groups. Hyperammonemia was not associated with neurologic dysfunction. SpeculationThere is a greater accumulation of ammonium in low birthweight as compared to full term infants. This may be a consequence of a developmental delay of one or more of the enzymes required for urea synthesis. Alternatively, the hyperammonemia may be related to arginine andlor ornithine diversion out of the cycle and incomplete repletion of ornithine from glutamate via the A'-pyrroline-5-carboxylate pathway.were measured once or twice a week on capillary blood during the first 2 months of life. Plasma a-ketoglutarate concentration and urinary orotate excretion were also measured at 0-3 days of age in 30 infants. Plasma ammonium determinations were performed within 30 min of blood drawing using a cation exchange resin, AS previobsly described (3). The normal adult range is 15-33 pM. Glutamine (18), glutamate (4), alanine (30), and a-ketoglutarate (16) were measured by modifications of enzymatic fluorometric techniques, allowing capillary plasma to be used. Urinary orotate was measured by the method of Goldstein et al. (11). A neurologic examination as described by Prechtl and Beintema (20) was performed on the low birthweight infants at 0-3 days of age. RESULTSThe full term group consisted of 25 males (22 were black) and 27 females (25 were black); the low birthweight groups consisted of 14 males (11 were black) and 22 females (20 were black).Birthweights of the groups were (mean + SEM): full term 3261 + 59 g, low birthweight SGA 1848 + 185 g, and low birthweight AGA 1963 + 79 g. Gestational age in the groups were (mean + SD): full term AGA 39 + 1.5 weeks, low birthweight SGA 37 + 3 weeks and low birthweight AGA 33 + 2.5 weeks. All infants received a proprietary milk formula (Similac) containing 1.5 g protein/100 ml, 18 parts bovine whey protein to 82 parts bovine caseins. Mean protein intake was similar in all groups at 3-5 weeks of age (3.0 g/kg/day) and was higher in the full term group during the first 3 days of life (1.7 compared to 1.2 &kg/ day). At 0-3 days of age,...

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Section: Speculationmentioning

confidence: 99%

Asymptomatic Hyperammonemia in Low Birthweight Infants

1978

Pediatr Res

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“…The excretion of these above-mentioned metabolites was not only observed in those disorders where carbamylphosphate accumu lates as in OCT deficiency (14) but also in the deficiencies of other urea cycle enzymes (3). In these latter disorders the high ammonia concen trations themselves may be responsible that ammonia is partially deviated for its detoxica tion into the pathway of pyrimidine synthesis via carbamylphosphate or aspartate.…”

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Enzymes of Ammonia Detoxication after Portacaval Shunt in the Rat

Berüter

Bachmann

et al. 1977

Enzyme

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At high systemic blood concentrations ammonia may be partially deviated into the pathway of pyrimidine synthesis, as has been observed in different genetic defects of the urea cycle. The portacaval shunt (PCS) rat presents an animal model to study ammonia detoxication without an underlying enzyme defect in the urea cycle. Since ammonia may induce a deviation into the pyrimidine pathway by influencing enzymatic reactions involved in this pathway, the activity of carbamylphosphate synthetase and aspartate transcarbamyiase in liver as well as the excretion of orotic acid in the urine were measured in rats 10, 20 and 30 days after PCS. The results suggest that in this experimental model ammonia may be channeled into the pyrimidine pathway leading to a stimulation of the first enzymatic step and to an increased excretion of orotic acid.

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“…The concentration of CP must be carefully regulated to produce adequate amounts of both pyrimidine and arginine, and a disturbance in one pathway may affect the synthesis of the other metabolite. In mammals, lesions in OTC result in overproduction and excretion of orotic acid (5).…”

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Regulation of Pyrimidine and Arginine Biosynthesis Investigated by the Use of Phaseolotoxin and 5-Fluorouracil

Jacques¹,

Sung²

1981

Plant Physiol.

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Purified phaseolotoxin inhibits the growth of carrot cells. Such inhibitions can be reversed completely by citrufline but not by arginine. This toxin inhibits ornithine transcarbamylase activity in vitro, which leads to an accumulation of ornithine and a decrease in argnine levels intracellularly. In carrot cells, 5-fluorouracil (5-FU) toxicity can be reduced by the addition of purified toxin and citrulline, or ornithine. The toxin also decreases the incorporation of I'4Cluracil and '4C15-FU into trichloroacetic acid precipitable material by 50%. Finally, a 5-FU-resistant line, F5 (Sung ZR, Jacques S 1980 Planta 148: 389-396), was found to be more sensitive to the toxin than were 5-FU-sensitive cells. One millimolar 5-FU roughly doubled the ability of F5 to tolerate phaseolotoxin. These results demonstrate a close regulation between the pyrimidine and arginine pathways in carrots.toxin, N8-(phosphosulfamyl)ornithylalanylhomoarginine (12), which inhibits OTC (18). Blockage of citrulline synthesis by phaseolotoxin may cause ornithine accumulation in carrots, as has been shown in bean (17). Ornithine is shown to increase in vitro CPS enzyme activity and to alleviate in vitro uridine monophosphate inhibition of CPS in Phaseolus aureus (16). The inhibition of OTC for citrulline synthesis, and the accumulation of ornithine, may allow more pyrimidine synthesis and, hence, increase resistance to 5-FU toxicity.Here, we use two inhibitors, one in each of the pyrimidine and arginine pathways, in studying the regulation of their biosynthesis. Purified phaseolotoxin is used to confirm previous results of culture filtrate's effect in reversing 5-FU toxicity on carrot culture. The 5-FU-resistant carrot variant F5 is used to study the effect of 5-FU in counteracting phaseolotoxin toxicity on carrots. We also compare the effect of phaseolotoxin on the growth of F5 and a 5-FU-sensitive carrot line, WOO IC.The pyrimidine and arginine biosynthetic pathways interact via their common precursor CP2 [see review by O'Donovan and Neuhard (14)1. In plants, the utilization of CP for pyrimidine nucleotide biosynthesis follows the orotic acid pathway (10), which begins with the conversion of CP and aspartate to carbamyl aspartate by aspartate transcarbamylase. OTC, on the other hand, converts ornithine and CP to citrulline, which eventually leads to arginine synthesis. The concentration of CP must be carefully regulated to produce adequate amounts of both pyrimidine and arginine, and a disturbance in one pathway may affect the synthesis of the other metabolite. In mammals, lesions in OTC result in overproduction and excretion of orotic acid (5).Metabolite analogs and enzyme inhibitors that interfere with a biosynthetic pathway or inhibit a specific enzyme are useful in studying metabolic consequences in related pathways. Hoogenraad et al. (7) showed that N-(phosphonacetyl)-L-ornithine, an inhibitor of OTC, not only inhibited the conversion of CP to citrulline, but also stimuilated the synthesis of orotate and uridine nucleotides i...

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Metabolic and Genetic Studies of a Family with Ornithine Transcarbamylase Deficiency

Cited by 77 publications

References 9 publications

Asymptomatic Hyperammonemia in Low Birthweight Infants

Asymptomatic Hyperammonemia in Low Birthweight Infants

Enzymes of Ammonia Detoxication after Portacaval Shunt in the Rat

Regulation of Pyrimidine and Arginine Biosynthesis Investigated by the Use of Phaseolotoxin and 5-Fluorouracil

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