Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways

Ginguay, Antonin; Cynober, Luc; Curis, Emmanuel; Nicolis, Ioannis

doi:10.3390/biology6010018

Cited by 103 publications

(85 citation statements)

References 222 publications

(264 reference statements)

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“…Thus, when intracellular Orn concentration is low, the pathway is favored toward Orn. Conversely, increased Orn concentration promotes production of P5C for Pro, Glu or Gln biosynthesis [40]. The production of proline from Orn mediates a transfer of reducing potential from cytosolic NADPH to mitochondrial NAD + .…”

Section: Sources Of Free Proline For Cellular Metabolismmentioning

confidence: 99%

Proline-dependent regulation of collagen metabolism

Karna

Szoka

Huynh

et al. 2019

Cell. Mol. Life Sci.

131

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This review is focused on recent data on the role of proline (Pro) in collagen biosynthesis and cellular metabolism. It seems obvious that one of the main substrates for collagen biosynthesis Pro is required to form collagen molecule. The question raised in this review is whether the Pro for collagen biosynthesis is synthesized "de novo", comes directly from degraded proteins or it is converted from other amino acids. Recent data provided evidence that extracellular Pro (added to culture medium) had significant, but relatively little impact on collagen biosynthesis in fibroblasts (the main collagen synthesized cells) cultured in the presence of glutamine (Gln). However, extracellular Pro drastically increased collagen biosynthesis in the cells cultured in Gln-free medium. It suggests that Pro availability determines the rate of collagen biosynthesis and demand for Pro in fibroblasts is predominantly met by conversion from Gln. The potential mechanism of this process as well as possible implication of this knowledge in pharmacotherapy of connective tissue diseases is discussed in this review.

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Section: Sources Of Free Proline For Cellular Metabolismmentioning

confidence: 99%

Proline-dependent regulation of collagen metabolism

Karna

Szoka

Huynh

et al. 2019

Cell. Mol. Life Sci.

131

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“…Except in the intestine, OAT promotes the synthesis of glutamate from ornithine (see reference [12] for details):…”

Section: Transamination Reactionmentioning

confidence: 99%

“…Ornithine + α-ketoglutarate ⇋ glutamyl 5-semialdehyde + glutamate Of note, glutamyl 5-semialdehyde (G5A) can be cyclized into Δ 1 -pyrroline-5-carboxylate (P5C) and this reaction is not enzymatically mediated (see reference [12] for a recent review on this topic). P5C opens the way to proline and related metabolic pathways [13,14] through the action of P5C reductase [15].…”

Section: Transamination Reactionmentioning

confidence: 99%

Metabolism of Dietary Glutamate in Adults

Cynober

2018

Ann Nutr Metab

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Background: Glutamate is a non-essential amino acid at the crossroads of nitrogen and energy metabolism. Glutamate metabolism is characterized by reactions that may be anabolic or catabolic in nature depending on the tissue (i.e., glutamate dehydrogenase, transaminases), and it can also be either the precursor or the metabolite of glutamine. Unlike glutamine, which is the form of interorgan ammonia transport, glutamate metabolism is mostly compartmentalized within the cells, its interorgan exchanges being limited to a flux from liver to muscle. Summary: Glutamate catabolism is extremely intense in the splanchnic area, such that after a meal (rich in proteins) almost no glutamate appears in the systemic circulation. However, this process is saturable as after glutamate loading at a high dose level, glutamate appears dose-dependently in the circulation. This systemic glutamate appearance is blunted if glutamate is co-ingested with a carbohydrate source. Key Messages: The underlying reason for this highly specific metabolism is that glutamate plays a key role in nitrogen homeostasis, and the organism does all it can to limit the bioavailability of glutamate, which can be neurotoxic in excess. As glutamate is never eaten alone, its bioavailability will be limited if not negligible, and no adverse effects are to be expected in adult humans.

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“…These symptoms are postulated to result from either creatine deficiency or toxicity of ornithine and its downstream metabolites spermine and spermidine, which induce retinal cell death and photoreceptor degeneration via oxidative stress. 75,76 Taken together, all inborn errors of glutamate metabolism leading to defects of the urea-cycle or ammonia metabolism show hyperammonemia. However, in GOT2 deficiency, P5CS deficiency and GDH hyperactivity hyperammonemia is mild and does not result in glutamine excess.…”

Section: Disorders Of Ammonia Detoxificationmentioning

confidence: 99%

Inborn errors of enzymes in glutamate metabolism

Rumping

Vringer

Houwen

et al. 2019

J of Inher Metab Disea

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Glutamate is involved in a variety of metabolic pathways. We reviewed the literature on genetic defects of enzymes that directly metabolise glutamate, leading to inborn errors of glutamate metabolism. Seventeen genetic defects of glutamate metabolising enzymes have been reported, of which three were only recently identified. These 17 defects affect the inter‐conversion of glutamine and glutamate, amino acid metabolism, ammonia detoxification, and glutathione metabolism. We provide an overview of the clinical and biochemical phenotypes of these rare defects in an effort to ease their recognition. By categorising these by biochemical pathway, we aim to create insight into the contributing role of deviant glutamate and glutamine levels to the pathophysiology. For those disorders involving the inter‐conversion of glutamine and glutamate, these deviant levels are postulated to play a pivotal pathophysiologic role. For the other IEM however—with the exception of urea cycle defects—abnormal glutamate and glutamine concentrations were rarely reported. To create insight into the clinical consequences of disturbed glutamate metabolism—rather than individual glutamate and glutamine levels—the prevalence of phenotypic abnormalities within the 17 IEM was compared to their prevalence within all Mendelian disorders and subsequently all disorders with metabolic abnormalities notated in the Human Phenotype Ontology (HPO) database. For this, a hierarchical database of all phenotypic abnormalities of the 17 defects in glutamate metabolism based on HPO was created. A neurologic phenotypic spectrum of developmental delay, ataxia, seizures, and hypotonia are common in the inborn errors of enzymes in glutamate metabolism. Additionally, ophthalmologic and skin abnormalities are often present, suggesting that disturbed glutamate homeostasis affects tissues of ectodermal origin: brain, eye, and skin. Reporting glutamate and glutamine concentrations in patients with inborn errors of glutamate metabolism would provide additional insight into the pathophysiology.

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Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways

Cited by 103 publications

References 222 publications

Proline-dependent regulation of collagen metabolism

Proline-dependent regulation of collagen metabolism

Metabolism of Dietary Glutamate in Adults

Inborn errors of enzymes in glutamate metabolism

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