Membrane glycine transport proteins

Tunnicliff, G.

doi:10.1007/bf02255994

Cited by 18 publications

(7 citation statements)

References 79 publications

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“…Transport Processes-Cysteine, glycine, and alanine all enter the erythrocyte by the Na ϩ -dependent ASC transporter, and glycine also crosses the erythrocyte membrane via the so called Gly transporter, which is Na ϩ -and Cl Ϫ -dependent (41,42). The main route for glutamine is the N-transport protein, which is also Na ϩ -dependent (24).…”

Section: Refinement Of Parameter Values-experimentally Measured Steadmentioning

confidence: 99%

“…To represent the ability of secondary active transport to concentrate amino acids inside erythrocytes (43), selected V max values were made lower for efflux than for influx, on the supposition that the low intracellular Na ϩ in erythrocytes would reduce the number of effective (Na ϩ bound) carriers (Table 3). Cysteine and glycine also cross the membrane via the high capacity, low affinity L transport system (44), which is not Na ϩ -dependent and appears to contribute only a small proportion of amino acid transport (e.g., ϳ16% of glycine) at the concentrations of amino acids found in the plasma (42,43). However, L transporters would be expected to have a considerable effect at the higher concentrations of amino acids used experimentally.…”

Section: Refinement Of Parameter Values-experimentally Measured Steadmentioning

confidence: 99%

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Glutathione Synthesis and Turnover in the Human Erythrocyte

Raftos

Whillier

Kuchel

2010

Journal of Biological Chemistry

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The erythrocyte is exposed to reactive oxygen species in the circulation and also to those produced by autoxidation of hemoglobin. Consequently, erythrocytes depend on protection by the antioxidant glutathione. Mathematical models based on realistic kinetic data have provided valuable insights into the regulation of biochemical pathways within the erythrocyte but none have satisfactorily accounted for glutathione metabolism. In the current model, rate equations were derived for the enzyme-catalyzed reactions, and for each equation the nonlinear algebraic relationship between the steady-state kinetic parameters and the unitary rate constants was derived. The model also includes the transport processes that supply the amino acid constituents of glutathione and the export of oxidized glutathione. Values of the kinetic parameters for the individual reactions were measured predominately using isolated enzymes under conditions that differed from the intracellular environment. By comparing the experimental and simulated results, the values of the enzyme-kinetic parameters of the model were refined to yield conformity between model simulations and experimental data. Model output accurately represented the steady-state concentrations of metabolites in erythrocytes suspended in plasma and the changing glutathione concentrations in whole and hemolyzed erythrocytes under specific experimental conditions. Analysis indicated that feedback inhibition of ␥-glutamate-cysteine ligase by glutathione had a limited effect on steady-state glutathione concentrations and was not sufficiently potent to return glutathione concentrations to normal levels in erythrocytes exposed to sustained increases in oxidative load.Erythrocyte glutathione plays a vital role in mitigating the damaging effects of reactive oxygen species (ROS) 4 encountered in the circulation (1) and produced by continuous oxidation of hemoglobin within the cytosol of the erythrocyte (2, 3). Reduced glutathione (GSH) reacts with superoxide reaction products, and via specific enzymes, it degrades hydrogen peroxide and lipid peroxides (glutathione peroxidase, EC 1.11.1.9), and covalently modifies toxic xenobiotics and endogenous electrophiles (glutathione S-transferase, EC 2.5.1.18) to form water-soluble conjugates that are exported from the erythrocyte for excretion (4). In diseases associated with increased production of ROS that results in GSH depletion, restoration of the normal erythrocyte GSH concentration has been shown to have positive therapeutic effects (5, 6).Experimental studies have provided a wealth of information on the individual reactions that together underlie the metabolic processes of the human erythrocyte (7)(8)(9)(10)(11)(12)(13)(14). This information has been used to develop mathematical models to analyze and then predict the way in which the kinetic characteristics and control mechanisms for each reaction combine to regulate particular metabolic processes. Comprehensive models of erythrocyte glycolysis, the pentose phosphate pathway, 2,3-bisphosphogl...

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Section: Refinement Of Parameter Values-experimentally Measured Steadmentioning

confidence: 99%

Section: Refinement Of Parameter Values-experimentally Measured Steadmentioning

confidence: 99%

Glutathione Synthesis and Turnover in the Human Erythrocyte

Raftos

Whillier

Kuchel

2010

Journal of Biological Chemistry

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“…Of interest, previous studies determined that the components of System Gly (currently known as GlyT1 and GlyT2) are localized in red blood cell membranes. 30 , 31 Our finding of augmented GlyT1 expression, both in vitro and in vivo , suggests that this transporter is likely required for erythroid differentiation.…”

Section: Resultsmentioning

confidence: 79%

Extracellular glycine is necessary for optimal hemoglobinization of erythroid cells

et al. 2017

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Vertebrate heme synthesis requires three substrates: succinyl-CoA, which regenerates in the tricarboxylic acid cycle, iron and glycine. For each heme molecule synthesized, one atom of iron and eight molecules of glycine are needed. Inadequate delivery of iron to immature erythroid cells leads to a decreased production of heme, but virtually nothing is known about the consequence of an insufficient supply of extracellular glycine on the process of hemoglobinization. To address this issue, we exploited mice in which the gene encoding glycine transporter 1 (GlyT1) was disrupted. Primary erythroid cells isolated from fetal livers of GlyT1 knockout (GlyT1 −/− ) and GlyT1-haplodeficient (GlyT1 +/− ) embryos had decreased cellular uptake of [2 −14 C]glycine and heme synthesis as revealed by a considerable decrease in [2- 14 C]glycine and 59 Fe incorporation into heme. Since GlyT1 −/− mice die during the first postnatal day, we analyzed blood parameters of newborn pups and found that GlyT1 −/− animals develop hypochromic microcytic anemia. Our finding that Glyt1-deficiency causes decreased heme synthesis in erythroblasts is unexpected, since glycine is a non-essential amino acid. It also suggests that GlyT1 represents a limiting step in heme and, consequently, hemoglobin production.

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“…The major plasma membrane transporters for glycine are GLYT1 and GLYT2, although other transporters can be involved, albeit less effectively [8]. We have shown that Each inhibitor was present at a concentration of 1 mmol/l.…”

Section: Introductionmentioning

confidence: 92%

Irreversible Inhibition of [<sup>3</sup>H]Glycine Transport into Channel Catfish Erythrocytes by Thiol Group Modifiers

McCormick¹,

Tunnicliff²

2004

Pharmacology

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Erythrocytes can take up amino acids from the blood by using a variety of transport systems. GLYT is a key transport protein in the plasma membrane responsible for the Na²⁺-dependent uptake of glycine needed for glutathione biosynthesis. Certain cysteine-specific compounds, particularly mercuric chloride and 5,5′-dithiobis(2-nitrobenzoate), irreversibly inhibited the [³H]glycine transport via GLYT by red blood cells isolated from channel catfish. Bimolecular rate constants (k₂) of 0.556 (mmol/l)^–1 min^–1 and 0.032 (mmol/l)^–1 min^–1, respectively, were calculated for the two inhibitors. Addition of 2-mercaptoethanol 1 min after the initiation of inactivation by mercuric chloride stopped further inactivation, but did not reverse the inhibition. The presence of glycine, but not Na⁺ ions, during the preincubation of the cells with each inhibitor markedly reduced the degree of inhibition. Thus cysteinyl residues within the transport protein appear to be vital for the binding and uptake of glycine by channel catfish erythrocytes.

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Membrane glycine transport proteins

Cited by 18 publications

References 79 publications

Glutathione Synthesis and Turnover in the Human Erythrocyte

Glutathione Synthesis and Turnover in the Human Erythrocyte

Extracellular glycine is necessary for optimal hemoglobinization of erythroid cells

Irreversible Inhibition of [<sup>3</sup>H]Glycine Transport into Channel Catfish Erythrocytes by Thiol Group Modifiers

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