The Oxidation of Glycine and Propionic Acid in Propionic Acidemia with Ketotic Hyperglycinemia

Ando, Toshiyuki; Nyhan, William L.; Connor, James D.; Rasmussen, Karsten; Donnell, George N.; Barnes, N. D.; Cottom, Dennis; Hull, D

doi:10.1203/00006450-197206000-00006

Cited by 32 publications

(20 citation statements)

References 14 publications

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“…The coexistence of a defective activity of propionyl-CoA carboxylase (or MMA-CoA mutase, respectively) and of the glycine cleavage reaction to CO,, NH,, and a C , unit has been demonstrated both in vivo and in vitro in some other patients with propionic acidemia and methylmalonic acidemia (1,27,33). Keating et al (19) described recently a patient in whom a ketotic hyperglycinemia syndrome was associated with a defect in the isoleucine degradation pathway (presumably at the /I-ketothiolase site).…”

Section: Resultsmentioning

confidence: 99%

Acute Neonatal Nonketotic Hyperglycinemia: Normal Propionate and Methylmalonate Metabolism

et al. 1975

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ExtractPropionyl-CoA carboxylase and combined methylmalonyl-CoA (MMA-CoA) racemase and -mutase activities were studied in liver and fibroblasts of two patients with the acute neonatal form of nonketotic hyperglycemia. In all experiments, these enzyme activities studied in tissues of the patients were within the range of healthy control subjects, whereas no propionyl-CoA carboxylase activity was measurable in the fibroblasts of a patient with propionic acidemia. Subcellular fractionation of liver and fibroblasts indicated that the normal amounts of MMA-CoA found after incubation of whole tissue homogenate were formed by propionyl-CoA carboxylase, a mitochondria1 enzyme, and not by acetyl-CoA carboxylase, which theoretically could also be involved in the carboxylation of propionyl-CoA.From the above data as well as from clinical and biochemical observations in three patients, it was concluded that there exists a true nonketotic hyperglycinemia which is not related etiologically to the different disorders of the ketotic hyperglycinemia syndrome. True nonketotic hyperglycinemia is not associated with ketoacidosis even after loading with propionate-and M M A precursors. It must be distinguished by exclusion from mild forms of the ketotic hyperglycinemia syndrome which may present clinically as hyperglycinemia without ketosis. SpeculationThe metabolism of propionate, methylmalonate, and branched chain amino acids is normal in true nonketotic hyperglycinemia. Further investigations will have to show whether the observed block in the glycine cleavage reaction to CO,, NH,, and a single-carbon tetrahydrofolate derivative represents the primary enzymatic defect.

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Section: Resultsmentioning

confidence: 99%

Acute Neonatal Nonketotic Hyperglycinemia: Normal Propionate and Methylmalonate Metabolism

et al. 1975

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“…Ando et al (3) studied the in vivo conversion of intravenously ' injected (~-'~~)~l~c i n e t o respiratory C 0 2 in three patients Glycine cleavage reaction consisting in oxidative cleavage of with nonketotic hyperglycinemia and three patients with glycine into methylene tetrahydrofolate U H F ) , CO2, and propionic acidemia (ketotic hyperglycinemia), N H~ has been extensively studied by Kikuchi et al (7)(8)(9)(10) in They found that all patients of both nonketotic and ketotic rat liver. In in vitro systems, the glycine cleavage reaction is type revealed an extremely low conversion of (1-1 4clglycine usually accompanied by the concomitant synthesis of serine, t o co2 as compared with that in control subjects even when a as can b e explained by t h e following Sequences of reactions.…”

Section: Jmentioning

confidence: 99%

A Block in Glycine Cleavage Reaction as a Common Mechanism in Ketotic and Nonketotic Hyperglycinemia

Tada

1974

Pediatr Res

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Pediat. Extract showed constantly elevated levels of glycine (6.0-10.0Our previous study demonstrated a block in glycine cleavage reaction in the liver from two patients with hyperglycinernia of the nonketotic type. The present study extended this work t o two other patients with nonketotic hyperglycinernia and a patient with ketotic hyperglycinemia. The liver specimens obtained from these patients by autopsy or biopsy were studied for the activities of glycine cleavage reaction and of serine hydroxymethylase.A low activity of glycine cleavage reaction was found in all three patients with nonketotic or ketotic hyperglycinemia, whereas the activity of serine hydroxymethylase remained within normal limits. Speculation mg/100 ml) and normal levels of propionic acid, methylmalonic acid, and isovaleric acid in the blood. No ketoacidosis was present. The liver specimen was biopsied at the age of 5 years.Case LK, a girl (nonketotic hyperglycinemia), was born after a full term pregnancy and spontaneous delivery. The girl was normal up t o the 4th day of life, when she was found t o be comatose and hypotonic. Laboratory examinations revealed a high level of serum glycine (17 mg/100 ml) and normal levels of propionic acid, methylmalonic acid, and isovaleric acid in blood.No ketoacidosis was present. The patient died on the 5 t h day of life and the Liver specimen was obtained immediately after death.Case VA, a girl (ketotic hyperglycinemia), was born after a full term pregnancy and spontaneous delivery. She began t o The present suggests that a in the glycine vomit in the lst week of life. The was hospitalized at the cleavage reaction, either primarily or secondarily, plays a n important role in glycine accumulation in both types of age of 2.5 months, when she was comatose, dehydrated, and hyperglycinemias.grossly underweight. Laboratory examinations showed a high level of serum glycine (9.0 mg1100 ml) and a remarkable elevation of propionic acid (716 rng/lOO ml) and methylHyperglycinemia represents a group of disorders charac-malonic acid (12.1 mg/100 ml). Marked acidosis was present, terized by elevated concentrations of glycine in body fluids. indicating blood Ph 7.06, H e 0 3 9.5 mEq/liter, and acetonuria. The disorder is now divided into two forms, the ketotic and She died 4 8 hr after admission in spite of intravenous fluid the nonketotic. In nonketotic hyperglycinemia, a defect of the therapy and peritoneal dialysis. The liver specimen was glycine cleavage enzyme in the liver was found t o be obtainedimmediatel~ after death. responsible for the accumulation of glycin (5,12,13). On the Case OR ( t r i s o m~ 13) died a t 4 months of postnatal age; other hand, it has been demonstrated that ketotic hyper-the liver specimen was obtained immediately after death. glycinemia is virtually due t o propionic acidemia, methylCase MM (congenital heart disease) died at 3 days of malonic acidemia, isovaleric acidemia (2, 6, 11). However, the postnatal age; the liver specimen was obtained immediately mechanisms of abnormal accu...

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“…These enzymes are in the pathway by which four amino acids, L-valine, L-isoleucine, L-methionine, and L-threonine are catabolized. Patients with these abnormalities present clinically with the ketotic hyperglycinemia syndrome with elevated concentrations of propionate in the blood (1)(2)(3)(4)(5)(6)(7). Two other disorders, isovaleric acidemia (8) and a-methyl-,j-hydroxybutyric aciduria (9) may also present with the ketotic hyperglycinemia syndrome.…”

Section: Introductionmentioning

confidence: 99%

Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.

Coudé¹,

Sweetman²,

Nyhan³

1979

J. Clin. Invest.

200

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A B S T R A C T In the search for the mechanism by which hyperammonemia complicates propionic and methylmalonic acidemia the effects of a series of acylcoenzyme A (CoA) derivatives were studied on the activity of N-acetylglutamate synthetase in rat liver mitochondria using acetyl-CoA as substrate. PropionylCoA was found to be a competitive inhibitor. The inhibition constant of 0.71 mM is in the range of concentrations ofpropionate found in the serum ofpatients with propionic and methylmalonic acidemia. PropionylCoA was also found to be a substrate for N-acetylglutamate synthetase, forming N-propionylglutamate. This compound was a weak activator of rat liver carbamoylphosphate synthetase; the activation constant was 1

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The Oxidation of Glycine and Propionic Acid in Propionic Acidemia with Ketotic Hyperglycinemia

Cited by 32 publications

References 14 publications

Acute Neonatal Nonketotic Hyperglycinemia: Normal Propionate and Methylmalonate Metabolism

Acute Neonatal Nonketotic Hyperglycinemia: Normal Propionate and Methylmalonate Metabolism

A Block in Glycine Cleavage Reaction as a Common Mechanism in Ketotic and Nonketotic Hyperglycinemia

Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.

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