Keywords: amino acids; gut; leukocytes; liver; nutrition; skeletal muscle.
Conflict of interest statement
Figure 2: Intertissue glutamine production and utilisation in health and catabolic/hypercatabolic situations. Filled arrows indicate tissues that exhibit GS activity and thus produce glutamine; white arrows indicate tissues that exhibit GLS activity, and thus consume glutamine. In health and/or fed states, glutamine stores are in equilibrium in plasma/bloodstream and tissues, and are maintained constantly mainly by the liver and skeletal muscles, two major stores of glutamine in the body. On the other hand, cells of the immune system are extremely dependent on glucose and glutamine in situation (A), and even more in situation (B). Although the gut is a major site of glutamine consumption, in situation (B), there is a dramatic increase in glutamine consumption from both the luminal and basolateral membrane, when compared to situation (A). In addition, the liver switches the role of a major producer to a major glutamine consumer to maintain gluconeogenesis, and the whole body relies on the skeletal muscle’s ability/stores to maintain glutamine levels. However, this process is usually accompanied by a dramatic increase in muscle proteolysis, atrophy, and cachexia. The lungs and adipose tissue exhibit both GS and GLS enzymes, and hence can produce and consume glutamine in situations (A) and (B). The brain and the kidneys do not exhibit GS, only GLS, and hence are mainly dependent on plasma glutamine availability in situations (A) and (B).
Figure 3: Glutamine inter-tissue metabolic flux starting in skeletal muscle, liver, and gut continues in the immune cells. Abbreviations: Glutamine, GLN; glutamate, GLU; aspartate, ASP; arginine, ARG; leucine, LEU; alanine, ALA; glucose, Gluc; pyruvate, Pyr; pyruvate dehydrogenase; PDC; pyruvate carboxylase, PC; malate dehydrogenase, MD; glyceraldehyde-3-Phosphate, G3-P; lactate, Lac; triacylglycerol, TG; ribose 5-phosphate, R5P; alanine aminotransferase, ALT; glutamate dehydrogenase, GDH; glutamine synthetase, GS; glutaminase, GLS; inducible nitric oxide synthase, iNOS; intracellular heat shock protein, iHSP; heat Shock Factor 1, HSF-1; heat shock elements, HSEs; sirtuin 1, SIRT1; hexosamine biosynthetic pathway, HBP; ammonia, NH3; glutathione, GSH; oxidized GSH, GSSG; glutathione S-reductase, GSR; protein kinase B, Akt; AMP-activated protein kinase, AMPK; mTOR complex 1 and 2, mTORC1/2, extracellular signal-regulated kinases, ERK; c-Jun N-terminal kinases, JNK; gamma-Aminobutyric acid, GABA.
Figure 4: Mechanisms of enteral and parenteral glutamine (GLN) supply. Glutamine is an important substrate for rapidly dividing cells, such as enterocytes. This is a major site of glutamine consumption obtained from both exogenous/diet (luminal membrane) and/or endogenous glutamine synthesis (basolateral membrane). Free glutamine supplementation is mainly metabolized in the gut and poorly contribute to glutaminemia and tissue stores. On the other hand, glutamine dipeptides (e.g., Ala-Gln, Gly-Gln, Arg-Gln) escape from the gut metabolization and quickly supply glutamine to the plasma and target tissues. This effect is mainly attributed to the oligopeptide transporter 1 (Pept-1) located in the luminal membrane of the enterocytes.
- Glutamine Metabolism and Its Role in Immunity, a Comprehensive Review.
- Glutamine-enriched enteral nutrition in very low birth weight infants. Design of a double-blind randomised controlled trial [ISRCTN73254583].
- The clinical role of glutamine supplementation in patients with multiple trauma: a narrative review.
- Specific amino acids in the critically ill patient–exogenous glutamine/arginine: a common denominator?
- [Glutamine–its metabolic role and possibilities for clinical use].
- Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer.
- Effects of oral glutamine supplementation on jejunal morphology, development, and amino acid profiles in male low birth weight suckling piglets.
- Seafood Discards: A Potent Source of Enzymes and Biomacromolecules With Nutritional and Nutraceutical Significance.
- Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.
- Inflammatory Bowel Disease and COVID-19: How Microbiomics and Metabolomics Depict Two Sides of the Same Coin.
- Grohmann U., Mondanelli G., Belladonna M.L., Orabona C., Pallotta M.T., Iacono A., Puccetti P., Volpi C. Amino-acid sensing and degrading pathways in immune regulation. Cytokine Growth Factor Rev. 2017;35:37–45. doi: 10.1016/j.cytogfr.2017.05.004. – DOI – PubMed
- Curi R., Lagranha C.J., Doi S.Q., Sellitti D.F., Procopio J., Pithon-Curi T.C., Corless M., Newsholme P. Molecular mechanisms of glutamine action. J. Cell. Physiol. 2005;204:392–401. doi: 10.1002/jcp.20339. – DOI – PubMed
- Curi R., Newsholme P., Marzuca-Nassr G.N., Takahashi H.K., Hirabara S.M., Cruzat V., Krause M., de Bittencourt P.I.H., Jr. Regulatory principles in metabolism-then and now. Biochem. J. 2016;473:1845–1857. doi: 10.1042/BCJ20160103. – DOI – PubMed
- Cruzat V.F., Pantaleao L.C., Donato J., Jr., de Bittencourt P.I.H., Jr., Tirapegui J. Oral supplementations with free and dipeptide forms of l-glutamine in endotoxemic mice: Effects on muscle glutamine-glutathione axis and heat shock proteins. J. Nutr. Biochem. 2014;25:345–352. doi: 10.1016/j.jnutbio.2013.11.009. – DOI – PubMed
- Newsholme P. Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J. Nutr. 2001;131:2514S–2523S. doi: 10.1093/jn/131.9.2515S. – DOI – PubMed