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PubMed2007

Requirement for, and patterns of, pyruvate and glutamine metabolism in the domestic dog oocyte in vitro.

Supplementation of energy substrates to culture medium is essential for resumption and completion of meiosis in vitro for many mammalian species. Objectives were to study the dog oocyte, specifically the influences of pyruvate and glutamine on maturation and the utilization of these two substrates at various developmental stages and incubation times. Ovarian oocytes (n=681) were obtained from spayed bitches and cultured for 48 hr in TCM 199 medium containing various concentrations of pyruvate (0-2.5 mM) and glutamine (0-4 mM) before being assessed for nuclear status. For analyzing metabolic activity, 259 dog oocytes were cultured for 0, 12, 24, 36, or 48 hr, assessed for pyruvate and glutamine metabolism using the hanging drop method and then evaluated for nuclear status. Neither pyruvate nor glutamine had influence (P > 0.05) on oocyte maturation in vitro (IVM). However, both culture interval and meiotic status influenced pyruvate uptake (P < 0.05). Specifically, pyruvate uptake declined as the oocyte progressed from the germinal vesicle (GV) to metaphase II (MII) stage. Glutamine oxidation decreased as culture duration progressed (P < 0.05). In summary, pyruvate or glutamine is not required to promote successful IVM of dog oocytes. But, both substrates are being metabolized, and in patterns different to the domestic cat, another carnivore species. Pyruvate played an important role earlier in the maturational process, and less glutamine was oxidized as the oocyte neared nuclear maturation. These variations emphasize the importance of defining species specificities in carnivores before expecting consistently successful IVM/IVF.

Animals↗
PubMed1988

Role of glucocorticoids in increased muscle glutamine production in starvation.

The influence of glucocorticoids on muscle glutamine production in starvation was studied by using cortisol-treated or non-cortisol-treated, starved, adrenalectomized rats. Administration of cortisol at physiological doses in vivo (1 mg/100 g body weight) to fasted, adrenalectomized rats increased the muscle ratio of glutamine/glutamate and the activity of glutamine synthetase after only 6 hours. Prior treatment of fasted, adrenalectomized animals with actinomycin D or proflavine abolished these increases by cortisol. Therefore, cortisol induces muscle glutamine synthetase, and this induction can be detected by changes in the fresh-muscle ratio of glutamine/glutamate. Using this ratio as a qualitative indicator of muscle glutamine synthesis, the role of glucocorticoids in modifying muscle glutamine production in starvation was studied. In fresh-frozen soleus, extensor digitorum longus, and diaphragm muscle, starvation led to greater ratios of glutamine/glutamate and higher levels of tyrosine, which are indicative of enhanced muscle protein turnover. These effects were not apparent in starved, adrenalectomized animals but were restored, at least partially, by administering a physiological dose of cortisol. Therefore, glucocorticoids seem essential for promoting muscle glutamine production in starvation probably by inducing the activity of glutamine synthetase.

Adrenal Glands↗
PubMed2001

Optical determination of glutamine using a genetically engineered protein.

We have developed a reagentless optical biosensor for glutamine based on the Escherichia coli glutamine binding protein (GlnBP). Site-directed mutagenesis was performed to engineer single cysteine mutants which were covalently modified with environmentally sensitive sulfhydryl-reactive probes. The fluorescence emission of acrylodan and 2-(4'-(iodoacetamido)anilino)naphthalene-6-sulfonic acid (IAANS) attached to GlnBP mutant S179C was shown to decrease 65 and 35%, respectively, upon titration with increasing amounts of glutamine (0 to 6.4 microM; K(Dapp) 160 nM). No significant changes in the fluorescence intensity were observed for the structurally similar amino acids glutamate, asparagine, and arginine. Time-resolved intensity decays showed a 2.4-fold decrease in mean lifetime for GlnBP S179C-acrylodan upon the addition of glutamine, indicating the possibility of a lifetime-based assay. Anisotropy decay measurements for GlnBPS179C-acrylodan showed a 13-ns rotational correlation time in the ligand-free state, whereas multiple correlation times were assigned in the glutamine-bound conformation. The decrease in fluorescence intensity of S179C-acrylodan was adapted to polarization sensing of glutamine. The engineered GlnBP is a first step toward the development of a nonenzymatic biosensor capable of determining glutamine concentrations in cell cultures.

Biosensing Techniques↗
PubMed1995

Effect of glutamine supplement and hepatectomy on DNA and protein synthesis in the remnant liver.

One of the physiological roles of glutamine is as a precursor for DNA synthesis. The aims of this study were to determine (1) whether glutamine-supplemented total parenteral nutrition (TPN) enhanced DNA and protein synthesis in the liver and (2) whether glutamine uptake was increased following partial hepatectomy in rats. Male Donryu rats (n = 59; body weight, 250-275 g) were randomized into four groups: (1) sham operation + standard TPN solution (C-STPN); (2) C + glutamine-supplemented TPN (C-GTPN); (3) 70% partial hepatectomy + STPN (H-STPN); (4) partial hepatectomy + GTPN (H-GTPN). On Day 0, rats underwent either a sham operation or 70% partial hepatectomy and concomitantly were catheterized in the jugular vein. TPN was begun immediately after the surgery. GTPN was isocaloric and isonitrogenous with STPN and 25% of total nitrogen was given as glutamine. On Day 2, the animals were sacrificed after either a continuous infusion of 1-14C-leucine or a bolus i.v. injection of bromodeoxyuridine. The rate of hepatic regeneration was enhanced with glutamine supplementation (H-STPN, 60.8 +/- 1.6% vs H-GTPN, 66.3 +/- 2.0, P < 0.05) due to an increase in protein synthesis in the liver (H-STPN, 134.0 +/- 10.3%/day vs H-GTPN, 160.9 +/- 6.9, P < 0.05) and DNA synthesis in hepatocytes (H-STPN, 23.1 +/- 2.5% vs H-GTPN, 31.4 +/- 2.9, P < 0.05). The uptake of glutamine by the liver was increased following hepatectomy with GTPN supplementation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Characterization of glutamine and glutamate transport in rat lung plasma membrane vesicles.

Insufficient glutamine for the lungs during sepsis may contribute to an impairment in lung function. Lung glutamine metabolism is supported by both blood glutamine uptake and de novo biosynthesis using circulating glutamate as a precursor. Information regarding the specific plasma membrane carriers involved in this uptake is lacking. Furthermore, the effect of sepsis on amino acid transport in whole lung has not been studied. We isolated lung plasma membrane vesicles (LPMVs) from control and LPS-treated rats and assayed glutamine and glutamate transport activity in LPMVs. Vesicle purity and functionality were confirmed by time-dependent concentrative amino acid uptake in the presence of Na+, impoverishment of microsomal enzymes, and a 25-fold enrichment in the plasma membrane marker 5'-nucleotidase. Eighty percent of glutamine uptake in lung vesicles was mediated via the high affinity Na(+)-dependent carrier System ASC (Vmax = 80 +/- 10 pmole/mg protein/15 sec; Km = 224 +/- 30 microM) while 19% occurred via the Na(+)-independent System ASC (Vmax = 11 +/- 2 pmole/mg/15 sec; Km = 141 +/- 23 microM). Ninety percent of glutamate transport was mediated by the Na(+)-independent System XAG-. Treatment of rats with LPS resulted in a decrease in both glutamine and glutamate transport in LPMVs. LPMVs offer a novel method for characterizing lung amino acid transport and studying the effects of catabolic states on this activity. The effects of endotoxin on System ASC and XAG- activity may contribute to reduced lung glutamine availability during septic states which may impair cellular metabolism and function.

5'-Nucleotidase↗
PubMed2000

The prophylactic and therapeutic effects of glutamine- and arginine-enriched diets on radiation-induced enteritis in rats.

BACKGROUND: Recent studies indicated that glutamine and arginine support the mucosal barrier in several ways. This experimental study hypothesized that administration of glutamine- and arginine-enriched diets before abdominal radiation therapy would provide a radioprotective effect on intestinal mucosa, and this would augment the therapeutic effectiveness provided by postirradiation administration. MATERIALS AND METHODS: A rat model of radiation enteritis was designed with a single dose of 1100 cGy to the abdomen. Thirty-five rats were randomized into five groups of seven. A 7-day glutamine-enriched diet for Group I and a 7-day arginine-enriched diet for Group II were administered both pre- and postradiation. For Groups III and IV, the same glutamine and arginine diets were given, respectively, postradiation only. Group V was fed a glutamine- and arginine-free diet and was the control group. The rats underwent laparotomy for culture of mesenteric lymph nodes and removal of segments of ileum, jejenum, and colon for microscopic examination. RESULTS: Bacterial translocation was significantly higher in Group V (P < 0.05), while intestinal villus count and villus height were significantly higher in all of the groups fed glutamine and arginine when compared with the control group (P < 0.0001 and P < 0.05, respectively). CONCLUSION: Both arginine- and glutamine-enriched diets have protective effects on gut mucosa in the postirradiation state; however, pre- and postirradiation administration together does not provide superior protection versus postradiation administration alone.

Animals↗
PubMed1981

The stimulus-secretion coupling of amino acid-induced insulin release. Biosynthetic and secretory responses of rat pancreatic islet to L-leucine and L-glutamine.

L-glutamine dramatically augments insulin release evoked by L-leucine. The dynamics, specificity and environmental modifications of the insulin secretory response to the combination of L-glutamine and L-leucine were investigated. L-glutamine alone failed to stimulate proinsulin biosynthesis or insulin release in rat pancreatic islets, but augmented synthesis and secretion evoked by L-leucine. In relation to the secretory response, L-glutamine could be replaced by L-asparagine but not L-glutamate; L-leucine could be replaced by L-norvaline or L-isoleucine but not by L-valine, L-norleucine, glycine, L-serine, L-lysine, L-phenylalanine or L-arginine. The secretory response to L-leucine was rapid and biphasic whereas the enhancing action of L-glutamine upon insulin release was progressive. The release of insulin evoked by the combination of L-leucine and L-glutamine was inhibited by antimycin A, menadione, ammonium ions, verapamil, adrenaline, and by the absence of extracellular Ca2+. It was increased at high carbon dioxide tension, and by glucose, theophylline and cytochalasin B. It is concluded that the enhancing action of L-glutamine upon insulin release evoked by certain amino acids represents a phenomenon dependent on the integrity of oxidative metabolism and involving essentially the same sequence of metabolic, ionic and motile events as that characterizing the process of glucose-induced insulin release.

Animals↗
PubMed1981

Glutamine auxotrophs with mutations in a nitrogen regulatory gene, ntrC, that is near glnA.

Some mutations to glutamine auxotrophy in the 86 unit region of the Salmonella chromosome lie within the nitrogen regulatory gene, ntrC, rather than the structural gene encoding glutamine synthetase, glnA, Assignment of mutations to ntrC is based on fine structure mapping by P22-mediated transduction and on complementation analysis. Strains with ntrC lesions that cause glutamine auxotrophy (NtrCrepressor) have very low levels of glutamine synthetase (lower than those of strains that completely lack ntrC function and comparable to those of strains that lack ntrA function). NtrCrep strains fail to increase synthesis of glutamine synthetase or several amino acid transport components under nitrogen limiting conditions. Thus, like ntrA strains, they appear to repress glnA transcription and fail to activate transcription of glnA or other nitrogen controlled genes. Mutations that suppress the glutamine requirement caused by NtrCrep lesions arise at high frequency; these mutations also suppress the glutamine requirement caused by ntrA lesions. Several suppressor mutations result in loss of function of ntrC.

Genes↗
PubMed1990

Genetic transformation of glutamine auxotrophy to prototrophy in the cyanobacterium Nostoc muscorum.

Glutamine auxotrophic (Gln-) and L-methionine D,L-sulfoximine (MSX) resistant (MSXr) mutants of N. muscorum were isolated and characterized for nitrogen nutrition, nitrogenase activity, glutamine synthetase (GS) activity and glutamine amide, alpha-keto-glutarate amido transferase (GOGAT) activity. The glutamine auxotroph was found to the GOGAT-containing GS-defective, incapable of growth with N2 or NH4+ but capable of growth with glutamine as nitrogen source, thus, suggesting GS to be the primary enzyme of both ammonia assimilation and glutamine formation in the cyanobacterium. The results of transformation and reversion studies suggests that glutamine auxotrophy is the result of a mutation in the gln A gene and that gln A gene can be transferred from one strain to another by transformation.

Ammonia↗
PubMed1987

L-glutamine: a major substrate for tumor cells in vivo?

From 65 human breast cancer xenografts investigated, a net glutamine uptake was found in 13 tumors (mean +/- SE: 15.7 +/- 4.5 nmol/g per min) whereas a net release (22.5 +/- 3.3 nmol/g per min) was observed in 40 tumors. In 12 tumors neither a significant net uptake nor a net release was obvious. There is experimental evidence that glutamine is taken up by cancer cells only at arterial concentrations greater than 0.5 mM. Another parameter determining glutamine utilization by tumor cells may be the tissue oxygenation. In hypoxic or anoxic tumor areas, glutamine oxidation is unlikely since oxygen is required for the reoxidation of coenzymes which are reduced in the course of this metabolic pathway. The pronounced net release could be due to proteolysis within the tumors investigated. In ascitic fluid (DS-carcinosarcoma), glutamine accumulated during growth, implicating a reduction in the glutamine consumption rate, proposedly also due to a worsening of the oxygen supply to the suspended tumor cells. Thus, the generally held opinion that L-glutamine is a (if not the) major substrate for the energy metabolism of rapidly growing tumor cells should be reconsidered since evidence for this hypothesis has been derived mainly from in vitro systems with abundant oxygen.

Animals↗
PubMed1980

Acid-base balance and plasma glutamine concentration in man.

Plasma glutamine concentrations were measured in chronic metabolic acidosis and alkalosis in healthy male volunteers. Metabolic acidosis resulted in a significant drop in glutamine concentration while metabolic alkalosis significantly elevated glutamine levels. These changes in glutamine concentration correlated with both the bicarbonate and PCO2 levels. To determine whether bicarbonate or PCO2 levels influence the glutamine concentrations, respectively acidosis was induced by respiring 5% CO2. This resulted in a significant elevation in both PCO2 and glutamine while bicarbonate levels remained unchanged. The results demonstrate an effect of acid-base alterations upon plasma glutamine concentration mediated by PCO2.

Acidosis↗
PubMed1991

GABA synthesis in brain slices is dependent on glutamine produced in astrocytes.

The rate of gamma-aminobutyric acid (GABA) synthesis in rat-brain slices was determined by inhibiting GABA transaminase with 20-microM gabaculine and measuring the increase of GABA. Added 500-microM glutamine increased the rate of GABA synthesis by 50%, indicating that glutamate decarboxylase is not saturated in brain slices. The stimulation of GABA synthesis with added glutamine in brain slices was much less than that reported for synaptosomes. The lower stimulation in slices was attributable to astrocytic glutamine production, as the rate of GABA synthesis decreased by 44% when glutamine production was inhibited with methionine sulfoximine. Added glutamine restored the rate to the maximal value observed in brain slices. The rate of GABA synthesis was decreased by 65% in slices pretreated with an inhibitor of glutaminase, and added glutamine did not reverse this effect. These results suggest that glutamine produced by astrocytes is a quantitatively important precursor of GABA synthesis in cortical slices.

4-Aminobutyrate Transaminase↗
PubMed1987

Uptake and release for glutamine and glutamate in a crude synaptosomal fraction from rat brain.

[14C]Glutamine uptake in a crude synaptosomal (P2) fraction, (representing the sum of [14C]glutamine accumulated and [14C]glutamate formed by hydrolysis), is distinct from glutamate uptake. Glutamine uptake is Na+-independent and unaffected by the Na+-K+-ATPase inhibitor ouabain, whereas glutamate uptake is Na+-dependent and inhibited by ouabain. The uptake of both glutamine and glutamate is unaffected by the gamma-glutamyltransferase inhibitor, Acivicin. This indicates that glutamine uptake is not mediated by a carrier, as distinct from that of glutamate, and also not linked to gamma-glutamyl-transferase. Na+ affects the distribution of glutamine-derived glutamate by increasing the synaptosomal content and reducing that of the medium. When glutamate release from synaptosomes preloaded with [14C]glutamate is measured by superfusion technique in order to prevent reuptake, Na+ has been found to inhibit release in a non-depolarizing medium (Ringer buffer with no Ca2+) of the [14C]glutamate as well as of endogenous glutamate. The specific activity of the [14C]glutamine-derived glutamate in the incubation medium is much higher than that in the synaptosomes, indicating that there exists a readily releasable pool of newly formed glutamate in addition to another pool. The latter glutamate pool is partially reduced by Na+.

Animals↗
PubMed1999

L-glutamine enemas attenuate mucosal injury in experimental colitis.

PURPOSE: The aim of this study was to investigate the role of 1-glutamine, short chain fatty acid, prednisolone, and mesalazine (5-aminosalicylic acid) enemas on mucosal damage and inflammation in experimental colitis. METHODS: Colitis was induced in rats with trinitrobenzene sulfonic acid in ethanol. Saline (n = 14), prednisolone (n = 13), 5-aminosalicylic acid (n = 14), 1-glutamine (n = 14), and short chain fatty acid (n = 13) enemas were applied twice daily to the rats for seven days after the induction of colitis. The sham group (n = 9) received only saline enemas. Rats were killed at the seventh day and their colonic macroscopic inflammatory scores were determined. Colonic mucosal gamma glutamyl transpeptidase activity and colonic mucosal malondialdehyde levels were measured. The same measurements but no enemas were done in the control group (n = 7). RESULTS: There were significant differences in macroscopic inflammatory scores between sham and colitis groups (P < 0.001). The macroscopic inflammatory scores of the colitis group were higher than the short chain fatty acid and glutamine groups (P < 0.05). Whereas the mucosal gamma glutamyl transpeptidase activity was diminished in prednisolone, 5-aminosalicylic acid, and short chain fatty acid groups when compared with the control group; in the colitis, sham, and glutamine groups the activity of this enzyme did not change. The mucosal malondialdehyde levels were significantly lower in the prednisolone and glutamine groups than in the colitis group. CONCLUSION: Only one of four agents tested, namely, 1-glutamine enemas, could decrease the severity of colitis both morphologically and biochemically. Moreover, L-glutamine prevented the colitis-induced oxidant injury in the colonic mucosa. On the other hand, prednisolone and short chain fatty acids seemed to improve only the physiologic changes of colitis.

Animals↗
PubMed2003

13C NMR analysis reveals a link between L-glutamine metabolism, D-glucose metabolism and gamma-glutamyl cycle activity in a clonal pancreatic beta-cell line.

AIMS/HYPOTHESIS: Pancreatic islet cells and clonal beta-cell lines can metabolise L-glutamine at high rates. The pathway of L-glutamine metabolism has traditionally been described as L-glutamine-->L-glutamate-->2-oxoglutarate-->oxidation in TCA cycle following conversion to pyruvate. Controversially, the metabolism of D-glucose to L-glutamate in beta cells is not widely accepted. However, L-glutamate has been proposed to be a stimulation-secretion coupling factor in glucose-induced insulin secretion. We aimed to investigate the metabolism of glutamine and glucose by using (13)C NMR analysis. METHODS: BRIN-BD11 cells were incubated in the presence of 16.7 mmol/l [1-(13)C]glucose, 2 mmol/l [2-(13)C]L-glycine or 2 mmol/l [1,2-(13)C]glutamine in the presence or absence of other amino acids or inhibitors. After an incubation period the cellular metabolites were extracted using a PCA extract procedure. After neutralisation, the extracts were prepared for analysis using (13)C-NMR spectroscopy. RESULTS: Using (13)C NMR analysis we have shown that L-glutamine could be metabolised in BRIN-BD11 cells via reactions constituting part of the gamma-glutamyl cycle producing glutathione. Moderate or high activities of the enzymes required for these pathways of metabolism including glutaminase, gamma-glutamyltransferase and gamma-glutamylcysteine synthetase were observed. We additionally report significant D-glucose metabolism to L-glutamate. Addition of the aminotransferase inhibitor, aminooxyacetate, attenuated L-glutamate production from D-glucose. CONCLUSION/INTERPRETATION: We propose that L-glutamine metabolism is important in the beta cell for generation of stimulus-secretion coupling factors, precursors of glutathione synthesis and for supplying carbon for oxidation in the TCA cycle. D-glucose, under appropriate conditions, can be converted to L-glutamate via an aminotransferase catalysed step.

Animals↗
PubMed2005

Identification of novel targets of cephaloridine in rabbit renal proximal tubules synthesizing glutamine from alanine.

Cephaloridine, which accumulates in the renal proximal tubule, is a model compound used for studying the toxicity of antibiotics towards this nephron segment. Several studies have demonstrated that cephaloridine alters renal intermediary and energy metabolism, but the mechanism by which this compound interferes with renal metabolic pathways remains incompletely understood. In an attempt to improve our knowledge in this field, we have studied the influence of cephaloridine on the synthesis of glutamine, which represents a key metabolic process involving several important enzymatic steps in the rabbit kidney. For this, suspensions of rabbit renal proximal tubules were incubated for 90 and 180 min in the presence of 5 mM alanine, an important glutamine precursor, both in the absence and the presence of 10 mM cephaloridine. Glutamate accumulation and glutamine synthesis were found to be inhibited by cephaloridine after 90 and 180 min of incubation, and cephaloridine accumulation in the renal proximal cells occurred in a time-dependent manner. The renal proximal tubule activities of alanine aminotransferase and glutamate dehydrogenase, which initiates alanine removal and releases the ammonia needed for glutamine synthesis, respectively, were inhibited to a significant degree and in a concentration-dependent manner by cephaloridine concentrations in the range found to accumulate in the renal proximal cells. Citrate synthase and glutamine synthetase activities were also inhibited by cephaloridine, but to a much lesser extent. The above enzymatic activities were not found to be inhibited when they were measured after successive dilutions of renal proximal tubules incubated for 180 min in the presence of 5 mM alanine and 10 mM cephaloridine. When microdissected segments (S1-S3) of rabbit renal proximal tubules were incubated for 180 min with 5 mM alanine with and without 5 and 10 mM cephaloridine, glutamate accumulation and glutamine synthesis were also inhibited in the three renal proximal segments studied; the latter cephaloridine-induced inhibitions observed were concentration-dependent except for glutamine in the S3 segment. These results are consistent with the view that cephaloridine accumulates and is toxic along the entire rabbit renal proximal tubule. They also demonstrate that cephaloridine interferes in a concentration-dependent and reversible manner mainly with alanine aminotransferase and glutamate dehydrogenase, which are therefore newly-identified targets of the toxic effects of cephaloridine in the rabbit renal proximal tubule.

Alanine↗
PubMed2005

Growth and metabolism of marine fish Chinook salmon embryo cells: response to lack of glucose and glutamine.

A peculiar phenomenon, differing from the response of mammalian cells, occurred when Chinook salmon embryo (CHSE) cells were passaged in the medium lacking of both glucose and glutamine. To elucidate metabolic mechanism of CHSE cells, the metabolism parameters, key metabolic enzymes, and ATP levels were measured at different glucose and glutamine concentrations. In the glutamine-free culture, hexokinase activity kept constant, and lactate dehydrogenase (LDH) activity decreased. This indicated that lack of glutamine did not expedite glucose consumption but made it shift to lower lactate production and more efficient energy metabolism. The results coincided with the experimental results of unaltered specific glucose consumption rate and decreased yield coefficients of lactate to glucose. In the glucose-free culture, simultaneous increase of glutaminase activity and of specific ammonia production rate suggested an increased flux into the glutaminolysis pathway, and increases of both glutamate dehydrogenase activity and yield coefficient of ammonia to glutamine showed an increased flux into deamination pathway. However, when glucose and glutamine were both lacking, the specific consumption rates of most of amino acids increased markedly, together with decrease of LDH activity, indicating that pyruvate derived from amino acids, away from lactate production, remedied energy deficiency. When both glucose and glutamine were absent, intracellular ATP contents and the energy charge remained virtually unaltered.

Adenosine Triphosphate↗
PubMedDate not supplied

Inborn error of amino acid synthesis: human glutamine synthetase deficiency.

Glutamine synthetase (GS) is ubiquitously expressed in human tissues, being involved in ammonia detoxification and interorgan nitrogen flux. Inherited systemic deficiency of glutamine based on a defect of glutamine synthetase was recently described in two newborns with an early fatal course of disease. Glutamine was largely absent in their serum, urine and cerebrospinal fluid. Each of the patients had a homozygous mutation in the glutamine synthetase gene and enzymatic investigations confirmed that these mutations lead to a severely reduced glutamine synthetase activity. From the observation in the first patients with congenital glutamine synthetase deficiency, brain malformation can be expected as one of the leading signs. In addition, other organ systems are probably involved as observed in one of the index patients who suffered from severe enteropathy and necrolytic erythema of the skin. Deficiency of GS has to be added to the list of inherited metabolic disorders as a rare example of a defect in the biosynthesis of an amino acid.

Amino Acid Metabolism, Inborn Errors↗