Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 May;39(5):513-524.
doi: 10.1016/j.tips.2018.02.007. Epub 2018 Mar 9.

Cysteine Metabolism in Neuronal Redox Homeostasis

Bindu D Paul  1 , Juan I Sbodio  2 , Solomon H Snyder  3
Affiliations
Review

Cysteine Metabolism in Neuronal Redox Homeostasis

Bindu D Paul et al. Trends Pharmacol Sci. 2018 May.

Abstract

Besides its essential role in protein synthesis, cysteine plays vital roles in redox homeostasis, being a component of the major antioxidant glutathione (GSH) and a potent antioxidant by itself. In addition, cysteine undergoes a variety of post-translational modifications that modulate several physiological processes. It is becoming increasingly clear that redox-modulated events play important roles not only in peripheral tissues but also in the brain where cysteine disposition is central to these pathways. Dysregulated cysteine metabolism is associated with several neurodegenerative disorders. Accordingly, restoration of cysteine balance has therapeutic benefits. This review discusses metabolic signaling pathways pertaining to cysteine disposition in the brain under normal and pathological conditions, highlighting recent findings on cysteine metabolism during aging and in neurodegenerative conditions such as Huntington's disease (HD) and molybdenum cofactor (MoCo) deficiency (MoCD) among others.

Keywords: ATF4; Huntington’s disease; cysteine; neurodegeneration.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Metabolism of cysteine
(A) Cysteine is derived from various sources in the brain. It can be obtained from the diet via the transporters system xc−, excitatory amino acid transporter 3 (EAAT3), the alanine, serine, cysteine transporter (ASCT) as well as synthesized endogenous by cystathionine γ-lyase (CSE). Cysteine can also be obtained by breakdown of glutathione and proteins by autophagy. (B) Cysteine is utilized by multiple pathways. Once generated, cysteine is consumed by various metabolic pathways such as protein synthesis, generation of sulfur containing molecules such as glutathione, taurine, lanthionine, coenzyme A and the gasotransmitter hydrogen sulfide (H2S).
Figure 2
Figure 2. Cysteine biosynthesis and import
(A) The reverse transsulfuration pathway. Methionine, derived from the diet, is converted to homocysteine, which is condensed with serine by cystathionine β-synthase (CBS) to generate cystathionine. Cystathionine is acted on by cystathionine γ-lyase (CSE) to generate cysteine. Cysteine is utilized to generate hydrogen sulfide (H2S) by CSE and CBS. H2S can also be generated from homocysteine by CSE and CBS. Cysteine can also be converted to glutathione. In addition, cysteine aminotransferase (CAT), also known as aspartate aminotransferase (AAT) or glutamate oxaloacetate transaminase (GOT) generates 3-mercaptopyruvate from L-cysteine which is utilized by 3-mercaptopyruvate sulfurtransferase (3-MST) to generate H2S in the presence of reducing agents [99] (B) Transport of cyst(e)ine. Cysteine is imported via the excitatory amino acid transporter 3 (EAAT3) and the alanine, serine, cysteine transporter (ASCT). Its oxidized form, cystine, is transported by the transporters system xc−. The EAAT3 and ASCT transporters are Na+-dependent, whereas the system xc− is Na+-independent and Cl−-dependent and functions as an antiporter, exchanging 1 molecule of glutamate for cystine. Once inside the cell, cystine is rapidly reduced to cysteine by either thioredoxin reductase 1 (TRR1) or glutathione (GSH).
Figure 3
Figure 3. Posttranslational modifications of cysteine
Cysteine has a thiol group, where the sulfur atom is nucleophilic and is subject to several post-translational oxidative modifications in cells. Depending on the context, these modifications participate in a diverse array of signaling pathways.
Figure 4
Figure 4. Dysregulated cysteine metabolism in Huntington’s disease
Cysteine and its oxidized form are imported into neurons via the excitatory amino acid transporter 3 (EAAT3) or system xc− respectively under normal conditions. Cysteine is also synthesized endogenously by cystathionine γ-lyase (CSE) whose basal expression is regulated by specificity protein 1 (SP1). In Huntington’s disease (HD), SP1 is sequestered by mutant huntingtin (mHtt) leading to low expression of CSE and cysteine production. In addition, the cystine and cysteine transporters, system xc− and EAAT3/EAAC1 are also dysregulated. During conditions of stress (as in cysteine deprivation), activating transcription factor 4 (ATF4) is induced and regulates CSE expression, leading to increased production of cysteine. System xc−, whose expression is regulated by ATF4, is also induced and transports cystine into neurons. In contrast, HD cells are unable to upregulate ATF4 and induce CSE due to the elevated oxidative stress generated, leading to neuronal cell death.
See this image and copyright information in PMC

References

    1. Droge W. Oxidative stress and ageing: is ageing a cysteine deficiency syndrome? Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2355–72. - PMC - PubMed
    1. Droge W, Kinscherf R. Aberrant insulin receptor signaling and amino acid homeostasis as a major cause of oxidative stress in aging. Antioxid Redox Signal. 2008;10(4):661–78. - PubMed
    1. Griffith OW. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med. 1999;27(9–10):922–35. - PubMed
    1. Miniaci MC, et al. Cysteine Prevents the Reduction in Keratin Synthesis Induced by Iron Deficiency in Human Keratinocytes. J Cell Biochem. 2016;117(2):402–12. - PubMed
    1. Paul BD, Snyder SH. H(2)S signalling through protein sulfhydration and beyond. Nat Rev Mol Cell Biol. 2012;13(8):499–507. - PubMed

LinkOut - more resources