Inhibition of Glycine-Serine Interconversion in Cultured Human Fibroblasts by Products of Isoleucine Catabolism

Hillman, Richard E.; Otto, Elaine F

doi:10.1203/00006450-197412000-00005

Cited by 13 publications

(3 citation statements)

References 9 publications

(19 reference statements)

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“…However, even when using F 10, the same medium as that of Hillman et al we were unable to detect significant activity. In a later publication (12), the same group studied the glycine/serine interconversion in a similar set-up and demonstrated that incubation with both isoleucine and tiglic acid inhibited this reaction, and they suggested that the inhibition of serine hydroxymethyl-transferase caused ketotic hyperglycinemia. However, this is in disagreement with several earlier publications (6,27,29), which all demonstrated that there are deficiencies of the glycine cleavage system and not of serine hydroxymethyltransferase in patients with ketotic hyperglycinemia.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Glycine Cleavage System by Branched-Chain Amino Acid Metabolites

Kølvraa

1979

Pediatr Res

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SummaryThe effects of 18 normally occurring and 11 patalogical metabolites of the branched-chain amino acids on the glycine cleavage system were investigated on intact rat liver mitochondria. It was demonstrated, that 2-0x0-isovaleric acid, 2-methyl-butyric acid, and isobutyric acid significantly inhibited the glycine cleavage system in intact mitochondria.Further studies on the solubilized glycine cleavage system demonstrated that the inhibitory effect was due to 2-methyl-butyrylCoA (linear noncompetitive inhibition, ki: 0.1-0.15 mM) and isobutyryl-CoA (S-hyperbolic, I-linear noncompetitive inhibition, ki: 0.2-0.3 mM). Both 2-methyl-butyric acid and isobutyric acid exhibited less inhibition (2-methyl-butyric acid: competitive inhibition, ki: 5.5 mM, isobutyric acid: competitive inhibition, ki: 16 mM), while 2-0x0-isovaleric acid was without inhibitory effect, and probably affects intact mitochondria through transformation to isobutyryl-CoA.It is suggested that the inhibitory action of 2-methyl-butyrylCoA and isobutyryl-CoA may explain the hyperglycinemia seen in propionyl-CoA carboxylase deficiency, methyl-malonyl-CoA mutase deficiency and P-ketothiolase deficiency. SpeculationIn patients not suffering from any known inborn error of metabolism, hyperglycinemia has been described in connection with two circumstances, namely, severe generalized illness and medication with dipropylacetic acid. Because both these conditions might cause some derangement of the branched-chain amino acid metabolism, it is speculated that this hyperglycinemia might be due to inhibition of the glycine cleavage system by 2-methyl-butyryl-CoA and isobutyryl-CoA, and that these conditions thus might serve as n~odels for ketotic hyperglycinemia.In 1961, Childs and Nyhan (4) described a syndrome, named the hyperglycinemia syndrome, presenting as a severe neonatal illness in a child with elevated glycine concentrations in both serum and urine. In a following paper (23), they showed that administration of branched-chain amino acids resulted in deterioration of the clinical symptoms and further elevation of the glycine concentrations.During the following years, several new cases of hyperglycinemia were reported, and it became obvious that symptoms and signs associated with this condition varied considerably. It was, therefore, proposed that the syndrome covered several ethiologic entities (9).It is now firmly documented that the condition exists in connection with at least five different enzymatic defects. Three are in the metabolism of branched-chain amino acids (propionyl-CoA carboxylase deficiency (2). methylmalonyl-CoA mutase deficiency (la), and P-ketothiolase deficiency (I I), and one in the metabolism of glycine itself, namely, deficiency of the glycine cleavage system (24). The fifth has recently been described in a child with deficient D-glycerate dehydrogenase activity (16).Whereas it is not surprising that a primary defect in the glycine cleavage system results in hyperglycinemia. it is still not clear why elevated glycine concentrat...

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Glycine Cleavage System by Branched-Chain Amino Acid Metabolites

Kølvraa

1979

Pediatr Res

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“…Biochemically, the phenotype of human patients was accurately emulated, as illustrated by the types of metabolites that were increased and the extent of their elevation. For example, MMA levels in the urine were detected in a range comparable with human mut Ϫ patients (35), whereas glycine, thought to be increased by inhibition of the intramitochondrial glycine cleavage enzyme caused by accumulated organic acids or their CoA esters (36), was found at high levels in our mice, similar to the description in the first MMAuria patients (37). Further, we found elevated levels of odd chain fatty acids, most likely as a consequence of increased C3, which is used as a primer in fatty acid synthesis (6,23,38,39).…”

Section: Novel Mouse Models Recapitulate Clinical and Biochemicalmentioning

confidence: 99%

Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect

Forny

Schumann

Mustedanagic³

et al. 2016

Journal of Biological Chemistry

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Methylmalonic aciduria (MMAuria), caused by deficiency of methylmalonyl-CoA mutase (MUT), usually presents in the newborn period with failure to thrive and metabolic crisis leading to coma or even death. Survivors remain at risk of metabolic decompensations and severe long term complications, notably renal failure and neurological impairment. We generated clinically relevant mouse models of MMAuria using a constitutive Mut knock-in (KI) allele based on the p.Met700Lys patient mutation, used homozygously (KI/KI) or combined with a knockout allele (KO/KI), to study biochemical and clinical MMAuria disease aspects. Transgenic Mut(ki/ki) and Mut(ko/ki) mice survive post-weaning, show failure to thrive, and show increased methylmalonic acid, propionylcarnitine, odd chain fatty acids, and sphingoid bases, a new potential biomarker of MMAuria. Consistent with genetic dosage, Mut(ko/ki) mice have lower Mut activity, are smaller, and show higher metabolite levels than Mut(ki/ki) mice. Further, Mut(ko/ki) mice exhibit manifestations of kidney and brain damage, including increased plasma urea, impaired diuresis, elevated biomarkers, and changes in brain weight. On a high protein diet, mutant mice display disease exacerbation, including elevated blood ammonia, and catastrophic weight loss, which, in Mut(ki/ki) mice, is rescued by hydroxocobalamin treatment. This study expands knowledge of MMAuria, introduces the discovery of new biomarkers, and constitutes the first in vivo proof of principle of cobalamin treatment in mut-type MMAuria.

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“…Various products which accumulate because of the primary metabolic defect have been shown to alter glycine metabolism (Hillman et aI., 1973;Hillman and Otto, 1974;Ho and Hillman, 1974). The defect in the nonketotic syndromes is thought to involve directly the metabolism of glycine.…”

Section: Cytoplasmic Poolmentioning

confidence: 99%

Biochemical Aspects of Transmission at Inhibitory Synapses: The Role of Glycine

Aprison

Daly

1978

Advances in Neurochemistry

126

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Inhibition of Glycine-Serine Interconversion in Cultured Human Fibroblasts by Products of Isoleucine Catabolism

Abstract: Pediat. Res. 8: 941-945 (1974) Glycine serine isoleucine tiglic acid

Cited by 13 publications

References 9 publications

Inhibition of the Glycine Cleavage System by Branched-Chain Amino Acid Metabolites

Inhibition of the Glycine Cleavage System by Branched-Chain Amino Acid Metabolites

Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect

Biochemical Aspects of Transmission at Inhibitory Synapses: The Role of Glycine

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