Amino Acid Metabolism

Proteins exert essential functions in biology, from structural roles, secreted signaling molecules, ion channels, transport, or catalysts of biochemical reactions (enzymes). The unique characteristics of a protein are dictated by its linear sequence of amino acids, termed its primary structure. This sequence can determine the final conformation of a protein and also its interactions with other proteins or molecules to exert their function inside and outside the cells. It is generally accepted that only 20 proteinogenic amino acids are included in the genetic code and therefore regularly found in proteins. However, it is now accepted that a 21st amino acid, selenocyteine, exists in mammalian proteins. Hence, every mammalian protein is constructed from a set of 21 amino acids [4]. Beyond their importance for the synthesis of proteins, amino acids can also be fully or partially oxidized in order to produce energy or to be converted into other compounds such as glucose, fatty acids, ketone bodies, and purine and pyrimidine bases (used for nucleotide synthesis from which RNA and DNA are formed). In this article, we describe the structure, the characteristics, and the metabolism of the key amino acids, and also discuss the importance of their availability in health and disease conditions

Cystine accumulation attenuates insulin release from the pancreatic beta-cell due to elevated oxidative stress and decreased ATP levels.

The pancreatic beta-cell has reduced antioxidant defences making it more susceptible to oxidative stress. In cystinosis, a lysosomal storage disorder, an altered redox state may contribute to cellular dysfunction. This rare disease is caused by an abnormal lysosomal cystine transporter, cystinosin, which causes excessive accumulation of cystine in the lysosome. Cystinosis associated kidney damage and dysfunction leads to the Fanconi syndrome and ultimately end-stage renal disease. Following kidney transplant, cystine accumulation in other organs including the pancreas leads to multi-organ dysfunction. In this study, a Ctns gene knockdown model of cystinosis was developed in the BRIN-BD11 rat clonal pancreatic beta-cell line using Ctns-targeting siRNA. Additionally there was reduced cystinosin expression, while cell cystine levels were similarly elevated to the cystinotic state. Decreased levels of chronic (24 h) and acute (20 min) nutrient stimulated insulin secretions were observed. This decrease may be due to depressed ATP generation particularly from glycolysis. Increased ATP production and the ATP/ADP ratio are essential for insulin secretion. Oxidised glutathione levels were augmented, resulting in a lower [glutathione/oxidised glutathione] redox potential. Additionally, the mitochondrial membrane potential was reduced, apoptosis levels were elevated, as were markers of oxidative stress, including reactive oxygen species, superoxide and hydrogen peroxide. Furthermore, the basal and activated phosphorylated forms of the redox-sensitive transcription factor NF-?B were increased in cells with silenced CTNS. From this study, the cystinotic-like pancreatic beta-cell model demonstrated that the altered oxidative status of the cell, resulting in depressed mitochondrial function and pathways of ATP production, causing reduced nutrient-stimulated insulin secretion. This article is protected by copyright. All rights reserved