12. Metabolic Pathways of Glutamine

 

Glutamine transporters i.e. SLCIA5, SLC38A1 and SLC38A2 are responsible for transferring glutamine interacellularly through plasma membrane in to the cytoplasm, where they take part in the biosynthesis of hexosamine, nucleotides and asparagine (Scalis M et al., 2017) (Yoo H C et al., 2020b). 

 

SLCIA5 variant plays role in transferring cytosolic glutamine through inner mitochondrial membrane, the process of which is known as mitochondrial glutaminolysis (Yoo H C et al., 2020a) (Yoo H C et al., 2020b). Then glutaminases (GLSs) with at least three isoforms, GLS1, GLS2 and GAC (a splicing isoform of GLS1), which are localised in mitochondria, plays role in switching glutamine to glutamate. GLS is known as an amidohydrolase enzyme, responsible for discharging ammonium ions through catalysis and changing of glutamine to glutamate (Yoo H C et al., 2020b). Production of mitochondrial glutamate through the above catabolic pathways and procedures leads to SLC25A18 and SLC25A22 transporters transferring glutamate from mitochondria to cytosol, which then proceeds to involvement of cytosolic glutamate in glutathione biosynthesis (Stine Z E and Dang C V., 2020) (Yoo H C et al., 2020b). 

 

Further to the above processes, Glutamate Dehydrogenase 1 (GLUD1or GDH1) or a number of mitochondrial aminotransferases such as Glutamic-Pyruvic Transaminase 2 (GPT2) and Glutamic-Oxaloacetic Transaminase 2 (GOT2) play role in transforming the produced mitochondrial glutamate to alpha-ketoglutarate (α-KG) (Yoo H C et al., 2020b). Moreover, α-KG gets involved in synthesis of fatty acid and production of NADH as SLC25A11 translocates α-KG from mitochondria to cytosol (Mullen A R et al., 2014) (Stine Z E and Dang C V., 2020) (Yoo H C et al., 2020b).  This is followed by involvement of mitochondrial α-KG in reinforcing the Oxidative Phosphorylation (OXPHOS) pathway or the reductive carboxylation, as it takes part in TCA cycle (Yang L F et al., 2017) (Yoo H C et al., 2020b).

 

In the oxidative phosphorylation pathway, as the synthesis of GTP and ATP ended, then production of NADH or FADH2 electron donors takes place, which is the result of involvement of glutamine metabolites in this process (Yoo H C et al., 2020b).

 

Metabolic Pathways of Glutamine References

 

1.        Mullen, A. R. et al. Oxidation of Alpha-Ketoglutarate Is Required for Reductive Carboxylation in Cancer Cells with Mitochondrial Defects. Cell Rep. 7, 1679–1690 (2014).

2.        Scalise, M., Pochini, L., Galluccio, M., Console, L. & Indiveri, C. Glutamine Transport and Mitochondrial Metabolism in Cancer Cell Growth. Front. Oncol. 7, (2017).

3.        Stine, Z. E. & Dang, C. V. Glutamine Skipping the Q into Mitochondria. Trends Mol. Med. 26, 6–7 (2020).

4.        Yang, L., Venneti, S. & Nagrath, D. Glutaminolysis: A Hallmark of Cancer Metabolism. Annu. Rev. Biomed. Eng.19, 163–194 (2017).

5.        Yoo, H. C. et al. A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells. Cell Metab. 31, 267-283.e12 (2020a).

6.        Yoo, H. C., Yu, Y. C., Sung, Y. & Han, J. M. Glutamine reliance in cell metabolism. Exp. Mol. Med. 52, 1496–1516 (2020b).