How do cartilage cells make glutathione?
Cartilage cells make glutathione in two enzyme steps. Glutamate cysteine ligase joins glutamate to cysteine, then glutathione synthetase adds glycine. How much a cell can make depends mainly on its cysteine supply and on that first enzyme (Lu 2013). Once used, glutathione is turned back into its working form by glutathione reductase (Del Carlo 2003).
Three building blocks, two steps
Glutathione is built from glutamate, cysteine and glycine. The first enzyme, glutamate cysteine ligase, links glutamate and cysteine; the second, glutathione synthetase, adds glycine to finish the molecule. Both steps happen in the cell's cytoplasm (Lu 2013).
Cysteine is the bottleneck
A 2013 review names the availability of cysteine, along with the activity of glutamate cysteine ligase, as the key determinants of glutathione synthesis (Lu 2013). In human cartilage cells, simply removing cystine (the paired form of cysteine) from the culture medium was enough to deplete glutathione and make the cells more likely to die under oxidant stress (Del Carlo 2003).
N-acetylcysteine (NAC) is a stable form of cysteine. In cartilage cells, NAC's protection against nitric oxide-induced death disappeared when glutathione synthesis was blocked, which shows it worked by feeding glutathione production (Nakagawa 2010). Alpha-lipoic acid takes a different route: once reduced, it helps cells take up cysteine and so raises their glutathione, mainly in cells that were short of it (Han 1997).
Where the glutamate comes from
Cells make glutamate from glutamine. In growth-plate cartilage, the cell's identity switch SOX9 raised glutamine uptake, and glutathione made from glutamine kept reactive oxygen species in check so the cells could survive without a blood supply (Stegen 2020).
Glycine, the third piece
Glycine finishes the molecule, and cartilage cells also need large amounts of it for collagen. One analysis estimated the body makes about 3 g of glycine a day and food adds 1.5 to 3 g, which may fall around 10 g a day short of all its uses (Meléndez-Hevia 2009). In cow cartilage cells, extra glycine raised type II collagen production by 60 to 75% (de Paz-Lugo 2018).
Recycling the used form
When glutathione neutralises an oxidant, two molecules pair up into oxidised glutathione (GSSG). Glutathione reductase is the main enzyme that turns GSSG back into the working form, GSH. In human cartilage cells, oxidative stress itself lowered glutathione reductase activity (Del Carlo 2003).
Other questions people ask
Which building block runs out first?
Usually cysteine. Its supply is one of the two main controls on glutathione synthesis (Lu 2013), and in cartilage cells removing it from the medium was enough to drain their glutathione (Del Carlo 2003).
Does the body make enough glycine?
Possibly not for every use. One metabolic analysis estimated a shortfall of around 10 g a day once collagen synthesis is counted (Meléndez-Hevia 2009). It is an estimate from published flux data, not a measurement in individuals.
Sources
- Lu SC. Glutathione synthesis. Biochim Biophys Acta 2013.
- Carlo MD Jr, Loeser RF. Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels. Arthritis Rheum 2003.
- Nakagawa S, Arai Y, Mazda O et al. N-acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis. J Orthop Res 2010.
- Han D, Handelman G, Marcocci L et al. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 1997.
- Stegen S, Rinaldi G, Loopmans S et al. Glutamine Metabolism Controls Chondrocyte Identity and Function. Dev Cell 2020.
- Meléndez-Hevia E, De Paz-Lugo P, Cornish-Bowden A et al. A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis. J Biosci 2009.
- de Paz-Lugo P, Lupiáñez JA, Meléndez-Hevia E. High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. Amino Acids 2018.
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