Amino Acids as Regulators of Proteolysis

Abstract

Proteolysis, as well as protein synthesis, is a major process that contributes to the body protein turnover. Despite the huge variety of proteases in the body, there are very few proteolytic systems contributing to the complete hydrolysis of proteins to amino acids. The autophagic-lysosomal pathway is responsible for bulk proteolysis, whereas the ubiquitin-proteasome pathway plays a significant role in the fine control of the degradation of specific proteins. Both systems can produce free amino acids as a final product, but only the autophagy system is physiologically controlled by plasma amino acids. Recently, the study of amino acids as regulators of macromolecular turnover has been focused on for their signal transduction mechanism. In autophagic proteolysis, several amino acids have a direct regulatory potential: Leu, Gln, Tyr, Phe, Pro, Met, Trp and His in the liver, and Leu in the skeletal muscle. These amino acids are recognized at the plasma membrane, indicating the possible existence of an amino acid receptor/sensor for their recognition and subsequent intracellular signaling. Another line of evidence has emerged that protein kinase cascades such as mTOR, Erk, eIF2alpha etc. may be involved in the regulation of autophagy, and that amino acids, in combination with insulin, may exert their effects through these pathways. From the viewpoint of amino acid safety, the contribution of proteolysis to possible adverse effects caused by excessive amino acid intake is not clear. At present, there is one report that excess glutamine at 10-fold the plasma level has an abnormal inhibitory effect on hepatic proteolysis, due to a lysosomotropic toxicity of ammonia derived from glutamine degradation. Whether this may lead to an adverse effect in humans remains to be clarified.

Atrophic Remodeling of the Heart In Vivo Simultaneously Activates Pathways of Protein Synthesis and Degradation

“…21 Amino acids are thought to regulate proteolysis by autophagy in multiple organs through activation of mTOR-mediated protein translation. 22 The observation in this study that rapamycin treatment for 7 days augments atrophy by nearly 15% supports this speculation.…”

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

“…As depletion of steady-state concentrations of amino acids is known to induce autophagy [51,52], the induction of ATG12 could relate to the significant decreases in several amino acids that we observed in the mutant cells. To determine whether the induction of ATG12 was a specific consequence of mtDNA deletions, we quantified ATG12 transcript levels in 143B osteosarcoma cybrid fusion controls (i.e.…”

“…Amino acid deprivation is known to induce autophagy via inhibition of the mTOR pathway [51,52]. Amino acid deprivation is also known to signal GCN2 and stimulate eIF2-alpha phosphorylation [76][77][78], resulting in increased expression of unfolded protein response (UPR) genes and endoplasmic reticulum (ER) stress-related genes, many of which are induced in mutant cells.…”

“…A second generally accepted consequence is the reduction of ATP synthesis [26,79]; and ATP depletion is known to activate the AMPK response [80] as a protective mechanism. Both amino acid depletion and AMPK activation can result in inhibition of mTOR [51,81] which in turn inhibits translation, protein synthesis, and cellular growth, and induces autophagy ( Figure 6). …”

Mechanism-Based Therapeutic Approaches to Cachexia

“…On the other side, anabolism is regulated by a complex interplay among amino acids and hormones/growth factors such as insulin and IGF-1. In this regard, amino acids, in addition to be necessary for the synthesis of new proteins, were shown to interfere with the regulation of mRNA translation (Kadowaki & Kanazawa, 2003). The stimulation of protein synthesis by anabolic signals such as insulin or IGF-1 results from a transduction pathway involving several kinases such as Akt, phosphoinositide-3-kinase (PI3K), glycogen synthase kinase (GSK)-3β, mammalian Target Of Rapamycin (mTOR), and p70 ribosomal S6 kinase (p70 S6K ).…”