Review
Glutathione during embryonic development☆

https://doi.org/10.1016/j.bbagen.2014.12.001Get rights and content

Highlights

  • •

    We examine the role of GSH during development.

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    We provide information on GSH synthesis and cycling.

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    We give plausible explanation to how GSH regulates specifics of developmental signaling.

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    We provide real life examples of chemical-induced disruption of redox-sensitive elements during limb development.

Abstract

Background

Glutathione (GSH) is a ubiquitous, non-protein biothiol in cells. It plays a variety of roles in detoxification, redox regulation and cellular signaling. Many processes that can be regulated through GSH are critical to developing systems and include cellular proliferation, differentiation and apoptosis. Understanding how GSH functions in these aspects can provide insight into how GSH regulates development and how during periods of GSH imbalance how these processes are perturbed to cause malformation, behavioral deficits or embryonic death.

Scope of review

Here, we review the GSH system as it relates to events critical for normal embryonic development and differentiation.

Major conclusions

This review demonstrates the roles of GSH extend beyond its role as an antioxidant but rather GSH acts as a mediator of numerous processes through its ability to undergo reversible oxidation with cysteine residues in various protein targets. Shifts in GSH redox potential cause an increase in S-glutathionylation of proteins to change their activity. As such, redox potential shifts can act to modify protein function on a possible longer term basis. A broad group of targets such as kinases, phosphatases and transcription factors, all critical to developmental signaling, is discussed.

General significance

Glutathione regulation of redox-sensitive events is an overlying theme during embryonic development and cellular differentiation. Various stresses can change GSH redox states, we strive to determine developmental stages of redox sensitivity where insults may have the most impactful damaging effect. In turn, this will allow for better therapeutic interventions and preservation of normal developmental signaling. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.

Section snippets

Structure, function, and roles of GSH

Glutathione (GSH) is a nearly ubiquitous small molecule made up of three amino acids: glutamate (Glu), cysteine (Cys), and glycine (Gly) which serves in a number of important roles as an antioxidant, cellular protectant, regulatory signaling molecule, and in the maintenance of intracellular redox state [1], [2], [3]. The structural features of GSH that distinguishes it from other small peptides, relates to the relatively unique γ-glutamyl bond formed between Glu and Cys. This covalent bond

Spatial distribution of GSH in the conceptus — steady state

The functional anatomy of the organogenesis-stage rodent conceptus provides a means to separate and effectively isolate cells and tissues between discrete fluid compartments. Diffusible growth factors and other regulators of cell differentiation are secreted within tissues and into fluids across gradients to control cell-specific growth and development. Intracellular redox environments that serve as permissive regulators of signaling are determined mainly through the state of the GSH/GSSG redox

GSH biosynthesis

Most cells lack the capacity to take up GSH directly from extracellular sources. The extracellular glutathionase enzyme, γ-glutamyltranspeptidase (GGT), described below, is a primary contributor of GSH precursor amino acids through the degradation, transport, and resupply of intracellular amino acid precursor pools. This is especially true for the rate-limiting precursor Cys which is generally found in low intracellular concentrations in most biological tissues. A unique feature of the rodent

Determination of GSH redox potential (Eh)

Glutathione, being one the largest intracellular pools of non-protein, biothiol reducing equivalents performs a critical role in regulating redox environments. Because the GSH/GSSG couple is highly responsive to the external, environmental influences, it serves to protect cellular macromolecules from oxidative damage and, due to the dynamic nature of this couple, maintains cellular redox homeostasis. Conserved, stage-specific redox states are required for normal cellular signaling and function

Posttranslational modifications of proteins via S-glutathionylation

Glutathione can interact with many potential intermediates, including those involved in cell signaling. Moreover, there are numerous mechanisms by which this can occur. Under periods of oxidative stress where reactive oxygen species can directly damage and modify proteins, proteins thiols (PSH) can be oxidized to yield a protein sulfenic acid (PrOH). PrOH are reducible through reaction with reduced GSH to give water and protein S-glutathionylated adducts (Pr-SSG; see Reaction (A)); a

Summary

GSH is now recognized as a molecule that is involved in multiple molecular processes, such as enzyme activation and protein folding and more broadly, cellular proliferation, differentiation and apoptosis. As many, if not all of these events are crucial during development, GSH is likely at the nexus of redox-regulation in embryogenesis, organogenesis and dysmorphogenesis. Characterization of GSH function and regulation, on both a direct or permissive basis, requires substantially more study to

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    This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.

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