Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular protein homeostasis is a balance between synthesis and degradation. Protein degradation is regulated by hormones (eg, insulin) and nutrients (eg, amino acids). Certain amino acids are capable of decreasing cellular protein degradation, with evidence that this is mediated through altered lysosomal function. However, proteasomes, the major cytosolic protein degrading machinery, are being shown to play a central role in the control of protein turnover in the cell. In this study we show that the amino acids, isoleucine, leucine, tyrosine, phenylalanine, tryptophan, lysine, and arginine are capable of inhibiting the chymotrypsin-like activity of the proteasome in a dose-dependent manner. Leucine, tyrosine, and phenylalanine have a substantial effect at normal serum concentrations. The effect was greater in a proteasome preparation derived from muscle compared to a similar preparation from liver. On the assumption that amino acid-induced alterations in cellular protein degradation reflect the inhibitory changes in proteasomal activity shown here, we may conclude that amino acid control of cellular protein degradation is mediated, at least in part, through proteasomes.
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PMID:Inhibition of proteasome activity by selected amino acids. 1287 Jan 52

Proteasome inhibitors are novel therapeutic agents for the treatment of cancer and other severe disorders. One of the possible side effects is influencing the metabolism of proteins. The aim of our study was to evaluate the influence of three proteasome inhibitors MG132, ZL(3)VS and AdaAhx(3)L(3)VS on protein metabolism and leucine oxidation in incubated skeletal muscle of control and septic rats. Total proteolysis was determined according to the rates of tyrosine release into the medium during incubation. The rates of protein synthesis and leucine oxidation were measured in a medium containing L-[1-(14)C]leucine. Protein synthesis was determined as the amount of L-[1-(14)C]leucine incorporated into proteins, and leucine oxidation was evaluated according to the release of (14)CO(2) during incubation. Sepsis was induced in rats by means of caecal ligation and puncture. MG132 reduced proteolysis by more than 50% and protein synthesis by 10-20% in the muscles of healthy rats. In septic rats, proteasome inhibitors, except ZL(3)VS, decreased proteolysis in both soleus and extensor digitorum longus (EDL) muscles, although none of the inhibitors had any effect on protein synthesis. Leucine oxidation was increased by AdaAhx(3)L(3)VS in the septic EDL muscle and decreased by MG132 in intact EDL muscle. We conclude that MG132 and AdaAhx(3)L(3)VS reversed protein catabolism in septic rat muscles.
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PMID:Effects of proteasome inhibitors MG132, ZL3VS and AdaAhx3L3VS on protein metabolism in septic rats. 1556 33

Leucine can modulate skeletal muscle metabolism by enhancing protein synthesis and decreasing proteolysis. In this study, we investigated the effects of leucine on the ubiquitin-proteasome system in skeletal muscle of pregnant tumour-bearing rats fed a leucine-rich diet. Pregnant Wistar rats were distributed into three groups that were fed a semi-purified control diet (C, control; W, Walker tumour-bearing; P, pair-fed) and three other groups of pregnant rats fed a semi-purified leucine-rich diet (L, leucine; WL, Walker tumour-bearing; PL, pair-fed). The tumour-bearing rats were injected subcutaneously with a suspension of Walker 256 tumour cells. Protein synthesis and degradation were measured in gastrocnemius muscle; the total protein content and tissue chymotrypsin-like and alkaline phosphatase enzyme activities were also determined. Muscle protein extracts were run on SDS-PAGE to assess the expression of the myosin heavy chain (MHC), 20S alpha proteasome subunit, 19S MSSI ATPase regulator subunit and 11S alpha subunit. Although tumour growth decreased the incorporation of [3H]-Phe, the concomitant feeding of a leucine-rich diet increased the rate of protein synthesis. Muscle proteolysis in both tumour-bearing groups was increased more than in the respective control groups. Conversely, the leucine-rich diet caused less protein breakdown in the WL group than in the W group. Only the W group showed a significant reduction (71%) in the myosin content. In WL rats, the 20S proteasome content (32 kDa band) was reduced, while the expression of the 19S subunit was 3-fold less than in the W group and the 11S proteasome subunit reduced, to around 32% less than in the W group. These findings clearly indicate that leucine can stimulate protein synthesis and inhibit protein breakdown in pregnant rats, probably by modulating the activation of the ubiquitin-proteasome system during tumour growth.
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PMID:Proteasome activity is altered in skeletal muscle tissue of tumour-bearing rats a leucine-rich diet. 1561 61

In skeletal muscle, amino acids, together with hormones, are key regulators of protein metabolism. Leucine, in particular, has inhibitory effects of protein degradation in skeletal muscles, but the mechanisms are poorly understood. The present study addressed the role of leucine as a regulator of myofibrillar proteolysis in cultured chick myotubes and chick skeletal muscles, and aimed to determine which cellular responses regulate the process. In chick myotubes, leucine suppressed myofibrillar proteolysis (as measured by N(tau)-methylhistidine release), while also decreasing ubiquitin and proteasome C2 subunit mRNA. Oral administration of leucine also suppressed myofibrillar proteolysis (as measured by plasma N(tau)-methylhistidine concentration), while also decreasing proteasome C2 subunit mRNA in chick skeletal muscle. Leucine activated the phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) (but not the mammalian target of rapamycin) inhibition of these pathways and increased myofibrillar proteolysis, ubiquitin and proteasome C2 subunit mRNA. Thus, an important component of muscle proteolysis inhibition by leucine, through the PI3K and PKC, is its ability to suppress transcription of the ubiquitin and proteasome C2 subunit, and degradation of myofibrillar protein.
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PMID:Leucine suppresses myofibrillar proteolysis by down-regulating ubiquitin-proteasome pathway in chick skeletal muscles. 1615 8

We tested the hypothesis that skeletal muscle ubiquitin-proteasome-dependent proteolysis is dysregulated in ageing in response to feeding. In Experiment 1 we measured rates of proteasome-dependent proteolysis in incubated muscles from 8- and 22-month-old rats, proteasome activities, and rates of ubiquitination, in the postprandial and postabsorptive states. Peptidase activities of the proteasome decreased in the postabsorptive state in 22-month-old rats compared with 8-month-old animals, while the rate of ubiquitination was not altered. Furthermore, the down-regulation of in vitro proteasome-dependent proteolysis that prevailed in the postprandial state in 8-month-old rats was defective in 22-month-old rats. Next, we tested the hypothesis that the ingestion of a 5% leucine-supplemented diet may correct this defect. Leucine supplementation restored the postprandial inhibition of in vitro proteasome-dependent proteolysis in 22-month-old animals, by down-regulating both rates of ubiquitination and proteasome activities. In Experiment 2, we verified that dietary leucine supplementation had long-lasting effects by comparing 8- and 22-month-old rats that were fed either a leucine-supplemented diet or an alanine-supplemented diet for 10 days. The inhibited in vitro proteolysis was maintained in the postprandial state in the 22-month-old rats fed the leucine-supplemented diet. Moreover, elevated mRNA levels for ubiquitin, 14-kDa ubiquitin-conjugating enzyme E2, and C2 and X subunits of the 20S proteasome that were characteristic of aged muscle were totally suppressed in 22-month-old animals chronically fed the leucine-supplemented diet, demonstrating an in vivo effect. Thus the defective postprandial down-regulation of in vitro proteasome-dependent proteolysis in 22-month-old rats was restored in animals chronically fed a leucine-supplemented diet.
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PMID:A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle. 1621 Mar 47

The effect of amino acid on muscle protein degradation remains unclear. Recent studies have elucidated that proteolysis in catabolic conditions occurs through ubiquitin-proteasome proteolysis pathway and that muscle-specific ubiquitin ligases (atrogin-1 and MuRF1) play an important role in protein degradation. In the present study, we examined the direct effect of 5 mM amino acids (leucine, isoleucine, valine, glutamine and arginine) on atrogin-1 and MuRF1 levels in C2C12 muscle cells and the involved intracellular signal transduction pathway. Leucine, isoleucine and valine suppressed atrogin-1 and MuRF1 mRNA levels (approximately equal to 50%) at 6 and 24 h stimulations. Arginine showed a similar effect except at 24 h-treatment for atrogin-1 mRNA. However, glutamine failed to reduce atrogin-1 and MuRF1 mRNA levels. The inhibitory effect of leucine, isoleucine or arginine on atrogin-1 mRNA level was reversed by rapamycin, although wortmannin did not reverse the effect. PD98059 and HA89 reduced basal atrogin-1 level without influencing the inhibitory effects of those amino acids. The inhibitory effect of leucine, isoleucine or arginine on MuRF1 mRNA levels was not reversed by rapamycin. Taken together, these findings indicated that leucine, isoleucine and arginine decreased atrogin-1 mRNA levels via mTOR and that different pathways were involved in the effect of those amino acids on MuRF1 mRNA levels.
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PMID:Branched-chain amino acids and arginine suppress MaFbx/atrogin-1 mRNA expression via mTOR pathway in C2C12 cell line. 1861 83

TIS21(/BTG2/PC3) has been shown to work as a pan-cell cycle inhibitor and a negative regulator of cyclin B1/cdk1 and forkhead box M1 (FoxM1). Moreover, loss of TIS21 expression has been suggested as an early event in carcinogenesis of thymus, prostate, kidney, and liver. However, there is no report yet what regulates the in vivo stability of TIS21 protein. Here, TIS21 was found to be a target of ubiquitin ligase, S phase kinase associated protein 2 (Skp2), the expression of which was regulated by FoxM1. Leucine rich repeat (LRR) domain of Skp2 could bind to TIS21 C-terminus and facilitated TIS21 degradation via ubiquitin-proteasome pathway. Skp2 without LRR and C-terminus deleted TIS21 (TIS21DeltaC) failed to interact with each other, and failure of their interaction prolonged half-life of TIS21 protein. Furthermore, in vivo function of TIS21, inhibition of cell growth, was regulated by expressions of Skp2 and FoxM1; It was significantly enhanced by knock down of Skp2 expression in the TIS21 adenovirus infected cells, whereas it was significantly ameliorated by co-expression of FoxM1 with TIS21. These data indicate that TIS21 is a novel target of SCF-Skp2 ubiquitin ligase, which is regulated by expression of FoxM1.
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PMID:Skp2 enhances polyubiquitination and degradation of TIS21/BTG2/PC3, tumor suppressor protein, at the downstream of FoxM1. 1961 63

The proteasome inhibitors are used as research tools to study of the ATP-dependent ubiquitin-proteasome system. Some of them are at present undergoing clinical trials to be used as therapeutic agents for cancer or inflammation. These diseases are often accompanied by muscle wasting. We herein demonstrate findings about new proteasome inhibitors, belactosin A and C, and their direct effect on protein metabolism in rat skeletal muscle. M. soleus (SOL) and m. extensor digitorum longus (EDL) were dissected from both legs of male rats (40-60 g) and incubated in a buffer containing belactosin A or C (30 microM) or no inhibitor. The release of amino acids into the medium was estimated using high performance liquid chromatography to calculate total and myofibrillar proteolysis. Chymotrypsin-like activity (CTLA) of proteasome and cathepsin B, L activity were determined by fluorometric assay. Protein synthesis and leucine oxidation were detected using specific activity of L-[1-14C] leucine added to medium. Inhibited and control muscles from the same rat were compared using paired t-test. The results indicate that after incubation with both belactosin A and C total proteolysis and CTLA of proteasome decreased while cathepsin B, L activity did not change in both SOL and EDL. Leucine oxidation was significantly enhanced in SOL, protein synthesis decreased in EDL. Myofibrillar proteolysis was reduced in both muscles in the presence of belactosin A only. In summary, belactosin A and C affected basic parameters of protein metabolism in rat skeletal muscle. The response was both muscle- and belactosin-type-dependent.
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PMID:The effect of new proteasome inhibitors, belactosin A and C, on protein metabolism in isolated rat skeletal muscle. 1988 92

Essential amino acids (EAA) stimulate skeletal muscle protein synthesis (MPS) in humans. Leucine may have a greater stimulatory effect on MPS than other EAA and/or decrease muscle protein breakdown (MPB). To determine the effect of 2 different leucine concentrations on muscle protein turnover and associated signaling, young men (n = 6) and women (n = 8) ingested 10 g EAA in 1 of 2 groups: composition typical of high quality proteins (CTRL; 1.8 g leucine) or increased leucine concentration (LEU; 3.5 g leucine). Participants were studied for 180 min postingestion. Fractional synthetic rate and leg phenylalanine and leucine kinetics were assessed on muscle biopsies using stable isotopic techniques. Signaling was determined by immunoblotting. Arterial leucine concentration and delivery to the leg increased in both groups and was significantly higher in LEU than in CTRL; however, transport into the muscle and intracellular availability did not differ between groups. MPS increased similarly in both groups 60 min postingestion. MPB decreased at 60 min only in LEU, but net muscle protein balance improved similarly. Components of mammalian target of rapamycin (mTOR) signaling were improved in LEU, but no changes were observed in ubiquitin-proteasome system signaling. Changes in light chain 3 and mTOR association with Unc-51-like kinase 1 indicate autophagy decreased more in LEU. We conclude that in 10 g of EAA, the leucine content typical of high quality proteins (~1.8 g) is sufficient to induce a maximal skeletal muscle protein anabolic response in young adults, but leucine may play a role in autophagy regulation.
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PMID:Excess leucine intake enhances muscle anabolic signaling but not net protein anabolism in young men and women. 2084 86

Leucine-supplemented diet can recover lean body mass and preserve muscle protein mass. Additionally, physical exercise can be an excellent alternative to improve the rehabilitation of cancer patients. Knowing these facts, we examined the effects of a leucine-rich diet with or without physical aerobic exercise on muscle protein metabolism in Walker tumor-bearing rats. Young rats were divided into 4 groups that did or did not perform light aerobic exercise (swim training) and were on a leucine-rich diet or a control diet for 2 mo. After this time, these animals were implanted or not with tumors (subcutaneously) following groups for either control diet or leucine-rich diet fed rats: control, trained, tumor-bearing, and trained tumor-bearing. Twenty-one days after implantation, the tumor growth induced a decrease in the muscle protein synthesis and increased the catabolic process, which was associated with an increase in the expression of the ubiquitin-proteasome subunits (20S, 19S, and 11S). In contrast, the exercise program minimized the muscle degradation process and increased muscle myosin content. Additionally, leucine supplementation also modulated proteasome subunits, especially the 19S and 11S. In summary, the exercise has beneficial effects by reducing tumor growth, leading to an improvement in protein turnover especially when in conjunction with a leucine-rich diet.
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PMID:Physical exercise and a leucine-rich diet modulate the muscle protein metabolism in Walker tumor-bearing rats. 2105 97


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