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Main pathways involving glycine in host metabolism. Note: ALAS = delta-aminolevulinic acid synthase; BHMT = betaine-homocysteine S-methyltransferase; CBS = cystathionine β-synthase; CGL = cystathionine γ-lyase; GNMT = glycine N-methyltransferase; GCL = glutamate-cysteine ligase; GS = glutathione synthase; MAT = methionine adenosyltransferase; MS = methionine synthase; SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine; SDH = sarcosine dehydrogenase; SHMT = serine hydroxymethyltransferase; THF = tetrahydrofolate; CH2-THF = N 5 , N 10 -methylene tetrahydrofolate; 5-methyl-THF = 5-methyltetrahydrofolate.
Source publication
Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, b...
Contexts in source publication
Context 1
... was suggested that glycine availability may be the limiting factor for glutathione synthesis (Figure 3) [130]. Indeed, the tissue glycine concentration is lower than the Michael constant (Km) of glutathione synthase. ...
Context 2
... was suggested that glycine availability may be the limiting factor for glutathione synthesis (Figure 3) [130]. Indeed, the tissue glycine concentration is lower than the Michael constant (Km) of glutathione synthase. ...
Context 3
... an in vitro setting, improving the transport of glycine in diabetic β-cells has been shown to increase glutathione synthesis and protect against oxidative stress [135]. Finally, a modeling approach in 86 patients with varying degrees of hepatic steatosis pointed out a causative involvement Figure 3. Main pathways involving glycine in host metabolism. ...
Similar publications
It is well known that an unhealthy lifestyle is a major risk factor for metabolic diseases, while in recent years, accumulating evidence has demonstrated that the gut microbiome and its metabolites also play a crucial role in the onset and development of many metabolic diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease,...
Citations
... Therefore, we measured glycine levels under ALF and TRF in WT, HFD, and Sk2 models (Fig. 2c). We found that HFD-ALF flies had significantly reduced glycine levels as previously observed from HFD-induced obesity in humans 26 , while Sk2-ALF flies had significantly increased glycine compared to WT-ALF flies. Interestingly, HFD-TRF had a modest but not statistically significant increase while Sk2-TRF displayed a significant increase in glycine levels compared to their respective ALF conditions (Fig. 2c). ...
Obesity caused by genetic and environmental factors can lead to compromised skeletal muscle function. Time-restricted feeding (TRF) has been shown to prevent muscle function decline from obesogenic challenges; however, its mechanism remains unclear. Here we demonstrate that TRF upregulates genes involved in glycine production (Sardh and CG5955) and utilization (Gnmt), while Dgat2, involved in triglyceride synthesis is downregulated in Drosophila models of diet- and genetic-induced obesity. Muscle-specific knockdown of Gnmt, Sardh, and CG5955 lead to muscle dysfunction, ectopic lipid accumulation, and loss of TRF-mediated benefits, while knockdown of Dgat2 retains muscle function during aging and reduces ectopic lipid accumulation. Further analyses demonstrate that TRF upregulates the purine cycle in a diet-induced obesity model and AMPK signaling-associated pathways in a genetic-induced obesity model. Overall, our data suggest that TRF improves muscle function through modulations of common and distinct pathways under different obesogenic challenges and provides potential targets for obesity treatments.
... The increase of aromatic amino acids and branched-chain amino acids in obese individuals is thought to be related to liver dysfunction in catalyzing the metabolites and abnormal expression of amino acid catabolic genes in adipose tissue [29]. Additionally, the reduction of glycine levels with obesity is likely attributed to decreased gut absorption, weakened biosynthesis, and increased catabolism or urine excretion [34]. ...
Obesity is a leading contributor to colorectal cancer (CRC) risk, but the metabolic mechanisms linking obesity to CRC are not fully understood. We leveraged untargeted metabolomics data from two 1:1 matched, nested case–control studies for CRC, including 223 pairs from the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 190 pairs from a prospective Chinese cohort. We explored serum metabolites related to body mass index (BMI), constructed a metabolomic signature of obesity, and examined the association between the signature and CRC risk. In total, 72 of 278 named metabolites were correlated with BMI after multiple testing corrections (p FDR < 0.05). The metabolomic signature was calculated by including 39 metabolites that were independently associated with BMI. There was a linear positive association between the signature and CRC risk in both cohorts (p for linear < 0.05). Per 1-SD increment of the signature was associated with 38% (95% CI: 9–75%) and 28% (95% CI: 2–62%) higher risks of CRC in the US and Chinese cohorts, respectively. In conclusion, we identified a metabolomic signature for obesity and demonstrated the association between the signature and CRC risk. The findings offer new insights into the underlying mechanisms of CRC, which is critical for improved CRC prevention.
... Serine is not significantly changed in any groups. This is notable because serine is a major nondietary source of glycine by serving as a substrate for Shmt2, a gene whose product is the major source of glycine synthesis in the liver [22]. In these models, plasma serine does not seem to change concomitantly with plasma glycine. ...
... Glycine metabolism is a complex process, as glycine can be synthesized from multiple molecules and can be converted into numerous others. As mentioned above, a major source of circulating glycine is the diet [22]. Thus, the diet is unlikely to have a major effect on the results of this experiment, as all of the mice were given ad libitum access to the same diet. ...
... Another possible explanation for increased plasma glycine in GHRKO mice is a decrease in glycine catabolism or excretion. Glycine can be converted to glutathione through GSS or cleaved in a process involving GLDC [22]. The expression of GSS in the liver is unchanged, while the only significant change in liver GLDC expression is a decrease in bGH males, which would indicate a decrease in glycine cleavage in bGH mice that does not correspond to the decreased plasma glycine seen in those animals. ...
Growth hormone (GH) has established effects on protein metabolism, such as increasing protein synthesis and decreasing amino acid degradation, but its effects on circulating amino acid levels are less studied. To investigate this relationship, metabolomic analyses were used to measure amino acid concentrations in plasma and feces of mice with alterations to the GH axis, namely bovine GH transgenic (bGH; increased GH action) and GH receptor knockout (GHRKO; GH resistant) mice. To determine the effects of acute GH treatment, GH-injected GH knockout (GHKO) mice were used to measure serum glycine. Furthermore, liver gene expression of glycine metabolism genes was assessed in bGH, GHRKO, and GH-injected GHKO mice. bGH mice had significantly decreased plasma glycine and increased hydroxyproline in both sexes, while GHRKO mice had increased plasma glycine in both sexes and decreased hydroxyproline in males. Glycine synthesis gene expression was decreased in bGH mice (Shmt1 in females and Shmt2 in males) and increased in GHRKO mice (Shmt2 in males). Acute GH treatment of GHKO mice caused decreased liver Shmt1 and Shmt2 expression and decreased serum glycine. In conclusion, GH alters circulating glycine and hydroxyproline levels in opposing directions, with the glycine changes at least partially driven by decreased glycine synthesis.
... Impaired glycine biosynthesis was observed in NASH patients and mouse models resulting in increased hyperlipidemia and steatohepatitis, along with mitochondrial dysfunction and inhibition of fatty acid b-oxidation (FAO). However, glycine-based compounds improved FAO pathway, stimulated the new GSH synthesis, improved the gut microbiota diversity and steatohepatitis via targeting NF-kB and TGFb (Alves et al., 2019;Rom et al., 2020). Glutamic acid is also involved in the synthesis of glutathione (GSH), which can combat oxidative stress, and reduce the release of inflammatory cytokines in diet-induced NAFLD animals (Lin et al., 2014). ...
Background
Lingguizhugan decoction is a traditional Chinese medicine prescription that has been used to improve non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and underlying mechanisms of Lingguizhugan decoction remain unclear.
Methods
Male Sprague-Dawley rats were fed a methionine- and choline-deficient (MCD) diet to induce NASH, and then given Lingguizhugan decoction orally for four weeks. NASH indexes were evaluated by histopathological analysis and biochemical parameters including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides (TG), etc. Fecal samples of rats were subjected to profile the changes of gut microbiota and metabolites using 16S rRNA sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS). Bioinformatics was used to identify Lingguizhugan decoction reversed candidates, and Spearman’s correlation analysis was performed to uncover the relationship among gut microbiota, fecal metabolites, and NASH indexes.
Results
Four-week Lingguizhugan decoction treatment ameliorated MCD diet-induced NASH features, as evidenced by improved hepatic steatosis and inflammation, as well as decreased serum AST and ALT levels. Besides, Lingguizhugan decoction partially restored the changes in gut microbial community composition in NASH rats. Meanwhile, the relative abundance of 26 genera was significantly changed in NASH rats, and 11 genera (such as odoribacter, Ruminococcus_1 , Ruminococcaceae_UCG-004, etc. ) were identified as significantly reversed by Lingguizhugan decoction. Additionally, a total of 99 metabolites were significantly altered in NASH rats, and 57 metabolites (such as TDCA, Glutamic acid, Isocaproic acid, etc. ) enriched in different pathways were reversed by Lingguizhugan decoction. Furthermore, Spearman’s correlation analyses revealed that most of the 57 metabolites were significantly correlated with 11 genera and NASH indexes.
Conclusion
Lingguizhugan decoction may exert protective effects on NASH partially by modulating gut microbiota and correlated metabolites.
... Glycine is a non-essential amino acid with many metabolic roles. However, Nutrients 2023, 15, 96 2 of 14 the involvement of glycine in metabolic diseases associated with obesity is still poorly understood, and part of the mechanisms responsible for its metabolic effects have not yet been elucidated [10]. ...
... Based on the alteration of MAMs and the variation of glycine concentration in the serum of obese and diabetic patients, we hypothesized that glycine may be involved in the regulation of hepatic MAM integrity, and we anticipated that restoring glycine availability in obese mice may restore hepatic insulin resistance by supporting MAM integrity in the liver. Indeed, glycine interacts with one-carbon metabolism through the enzyme glycine N-methyltransferase (GNMT), thereby potentially regulating methylation processes which can regulate gene and protein expression [10,17]. GNMT catalyzes the methylation of glycine using S-adenosylmethionine to form sarcosine with the concomitant production of S-adenosylhomocysteine. ...
... GNMT catalyzes the methylation of glycine using S-adenosylmethionine to form sarcosine with the concomitant production of S-adenosylhomocysteine. Therefore, it plays an important role in the balance of methyl groups in the liver [10,17]. ...
Interactions between mitochondria and the endoplasmic reticulum, known as MAMs, are altered in the liver in obesity, which contributes to disruption of the insulin signaling pathway. In addition, the plasma level of glycine is decreased in obesity, and the decrease is strongly correlated with the severity of insulin resistance. Certain nutrients have been shown to regulate MAMs; therefore, we tested whether glycine supplementation could reduce insulin resistance in the liver by promoting MAM integrity. Glycine (5 mM) supported MAM integrity and insulin response in primary rat hepatocytes cultured under control and lipotoxic (palmitate 500 µM) conditions for 18 h. In contrast, in C57 BL/6 JOlaHsd mice (male, 6 weeks old) fed a high-fat, high-sucrose diet (HFHS) for 16 weeks, glycine supplementation (300 mg/kg) in drinking water during the last 6 weeks (HFHS-Gly) did not reverse the deleterious impact of HFHS-feeding on liver MAM integrity. In addition, glycine supplementation worsened fasting glycemia and glycemic response to intraperitoneal pyruvate injection compared to HFHS. The adverse impact of glycine supplementation on hepatic gluconeogenesis was further supported by the higher oxaloacetate/acetyl-CoA ratio in the liver in HFHS-Gly compared to HFHS. Although glycine improves MAM integrity and insulin signaling in the hepatocyte in vitro, no beneficial effect was found on the overall metabolic profile of HFHS-Gly-fed mice.
... In rodents, supplementation studies with these AA have reported reduced oxidative stress, a potential explanatory mechanism for preserved insulin sensitivity [67][68][69][70]. Beneficial effects of glycine and arginine supplementation on insulin sensitivity have also been reported in humans [71,72], their respective circulating concentrations being rather low in T2D [73,74], often in conjunction with elevated BCAA levels regarding glycine [75]. ...
Background
Plant proteins (PP) have been associated with better cardiovascular health than animal proteins (AP) in epidemiological studies. However, the underlying metabolic mechanisms remain mostly unknown.
Objective
Using a combination of cutting-edge isotopic methods, we aimed at better characterizing the differences in protein and energy metabolisms induced by dietary protein sources (PP vs AP), in a prudent or western dietary context.
Methods
Male Wistar rats (n=44, 8 weeks old) were fed for 4.5 months with isoproteic diets differing in their protein isolate sources, either AP (100% milk) or PP (50%:50% pea: wheat), and being normal (NSF) or high (HFS) in sucrose (6 or 15%kcal, respectively) and saturated fat (7 or 20%kcal, respectively). We measured body weight and composition, hepatic enzyme activities and lipid content, and plasma metabolites. In the intestine, liver, adipose tissues and skeletal muscles, we concomitantly assessed the extent of amino acid (AA) trafficking using a 15N natural abundance method, the rates of macronutrient routing to dispensable AA using a 13C natural abundance method, and the metabolic fluxes of protein synthesis (PS) and de novo lipogenesis (DNL) using a 2H labelling method. Data were analyzed using ANOVA and mixed models.
Results
At the whole-body level, PP limited HFS-induced insulin resistance (-27% in HOMA-IR between HFS groups, P<0.05). In the liver, PP induced lower lipid content (-17%, P<0.01) and DNL (-24%, P<0.05). In the different tissues studied, PP induced higher AA transamination accompanied by higher routings of dietary carbohydrate and lipid towards dispensable AA synthesis by glycolysis and β-oxidation, resulting in similar tissue PS and protein mass.
Conclusions
In growing rats, compared to AP, a balanced blend of PP similarly supports protein anabolism while better limiting whole-body and tissue metabolic dysregulations, through mechanisms related to their less optimal AA profile for direct channeling to PS.
... Glycine and serine could transform each other rapidly, and hence their changes were consistent [33]. Glycine is not only the precursor of GAA, but also participates in the synthesis of glutathione, purines, creatine, porphyrins of heme, and primary bile salts [34]. The decrease in the plasma glycine content might be due to the increase in its ability to synthesize other metabolites by GAA supplementation. ...
Abstract Background As a nutritive feed additive, guanidine acetic acid (GAA) participates in the metabolism of energy and proteins. This study aimed to investigate the effects of GAA on growth performance, organ index, plasma and tissue free amino acid profiles, and related metabolites in finishing pigs. A total of 72 crossbred pigs (body weight 86.59 ± 1.16 kg) were randomly assigned to 1 of 4 dietary treatments (GAA0, GAA500, GAA1000, and GAA1500). They were fed the basal diets supplemented with 0, 500, 1000, or 1500 mg/kg GAA for 42 days, respectively. The growth performance and organ weight were evaluated, and the contents of crude protein, free amino acids, and metabolites in plasma and tissues were determined. Spearman correlation between plasma and tissue free amino acids and related metabolites was also analyzed. Results Growth performance in pigs was not altered by GAA (P > 0.05). The absolute and relative weight of kidneys increased (quadratic, P
... Glycine inhibits the intestinal injury caused by tumor necrosis factor alpha (TNF-a) in the chemical colitis model (McCole, 2010), and restores the glutathione (GSH) to oxidized GSH (GSSG) ratio reduced by oxidative stress (Wessner et al., 2003). Glycine's application has been widely recognized in various disease model of the medical field, such as ischemia-reperfusion injury, shock, organ transplantation, alcoholic hepatitis, liver fibrosis, arthritis, tumor, and drug toxicity (Amelio et al., 2014;Effenberger-Neidnicht et al., 2014;Al-Saeedi et al., 2019;Alves et al., 2019;Shafiekhani et al., 2019). However, there are few studies on the application of glycine under stressful conditions in poultry over the past 20 yr. ...
This study tested the hypothesis that glycine improves intestinal barrier function through regulating oxidative stress in broilers exposed to heat stress. A total of 300 21-day-old female Arbor Acres broilers (600 ± 2.5g) was randomly allocated to five treatments (6 replicate of 10 birds each). The 5 treatments were as follows, the control group (CON) was kept under thermoneutral condition (24 ± 1 °C) and was fed a basal diet. Broilers fed a basal diet and reared under high ambient temperature (HT) were considered as the HT group (34 ± 1 °C for 8 h/d). Broilers fed a basal diet supplemented with 0.5%, 1.0%, and 2.0% glycine and exposed to HT were regarded as the HT + glycine treatments. The results exhibited that heat stress reduced growth performance, serum total antioxidant capacity (T-AOC) and glutathione (GSH) concentration (P < 0.05); increased activity of serum catalase (CAT) and the contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA) (P < 0.05). HT exposure led to downregulating the mRNA expression of NAD(P)H quinone dehydrogenase 1 (NQO1), Occludin, and zonula occludens-1 (ZO-1) (P < 0.05), enhanced the mRNA levels of Kelch-like ECH-associated protein 1 (Keap1), CAT, glutathione synthetase (GSS), and glutamate-cysteine ligase modifier subunit (GCLM) (P < 0.05), impaired the intestinal morphology (P < 0.05), and altered the diversity and community of gut microbiota (P < 0.05). The final body weight (FBW), ADFI, ADG and gain-to-feed ratio (G: F) increased linearly or quadratically, and the antioxidant capacity was improved (P < 0.05) with glycine supplementation. Glycine treatment increased the villus height (VH), and villus height to crypt depth ratio (V/C) of the duodenum linearly or quadratically, and linearly increased the VH of jejunum and ileum. The mRNA expression of Occludin, and ZO-1 were increased linearly in the ileum mucosa of broilers subjected to HT. Collectively, these results demonstrated that glycine supplementation alleviates heat stress-induced dysfunction of antioxidant status and intestinal barrier in broilers.
... Their finding might be different from previous view that glycine could increase oxalate. Consequently, we considered that glycine metabolism was relatively complex in human beings [16]. The 22:190 conversion of glycine to oxalate may be reversible and depend on many factors. ...
Background
Hyperglycinuria is a rare disorder, with few reported cases, caused by either a defect in glycine metabolism or a disturbance in renal glycine reabsorption. Genetic findings of hyperglycinuria are rare and have not previously been reported in Chinese young men.
Case presentation
A 24-year-old man presented with a compliant of bilateral lumbago for 1 month. Abdominal computed tomography revealed bilateral kidney stones and right upper ureteral dilatation. The 24-h urine analysis showed high urine oxalate levels of 63 mg/day. Analysis of amino acids in urine revealed that his urinary glycine levels were abnormally high (2.38 µmol/mg creatinine). Whole-exome sequencing detected the SLC6A19 variant c.1278 C > T p. (Cys426). Flexible ureteroscopy with holmium laser lithotripsy was conducted twice to remove his bilateral nephrolithiasis. Postoperative stone biochemical composition analysis revealed that the stones were composed of approximately 70% calcium oxalate monohydrate and 30% calcium oxalate dihydrate. The patient was subsequently diagnosed with hyperglycinuria. Three months after the stone surgery, ultrasonography revealed one nodule under the right thyroid lobe during a health checkup. His serum parathyroid hormone (PTH) levels increased to 392.3 pg/mL. Resection of the right parathyroid nodule was performed, and the histopathological examination confirmed right parathyroid adenoma. During the 2-year follow-up period, nephrolithiasis did not relapse, and serum PTH, calcium, and phosphorus levels were normal.
Conclusion
The SLC6A19 gene may have been significant in the development of hyperglycinuria in a Chinese young man. Further evaluation for the possibility of a glycine excretion disorder could be considered when encountering nephrolithiasis.
... Moreover, glycine is a gluconeogenic substrate and its reduced levels in GDM may reflect an enhanced gluconeogenesis [9]. Several studies revealed a decrease in glycine in patients with impaired insulin sensitivity, DM2 as well as in GDM pregnancies [9,46]. Glycine synthesis from serine is compartmentalized, being catalyzed by serine hydroxymethyltransferase (SHMT). ...
... However, alterations in the rate of conversion of serine to glycine have not been reported yet in obesity and associated metabolic disorders. A decrease in the plasma level of serine reported in those conditions may suggest a potential reduction in the activity of this pathway [46]. Disturbances in the de novo synthesis of purine due to the lack of one-carbon units [47] may be reflected by the significantly reduced levels of hypoxanthine in GDM women. ...
Background:
Gestational diabetes mellitus (GDM) remains incompletely understood and increases the risk of developing Diabetes mellitus type 2 (DM2). Metabolomics provides insights etiology and pathogenesis of disease and discovery biomarkers for accurate detection. Nuclear magnetic resonance (NMR) spectroscopy is a key platform defining metabolic signatures in intact serum/plasma. In the present study, we used NMR-based analysis of macromolecules free-serum to accurately characterize the altered metabolic pathways of GDM and assessing their similarities to DM2. Our findings could contribute to the understanding of the pathophysiology of GDM and help in the identification of metabolomic markers of the disease.
Methods:
Sixty-two women with GDM matched with seventy-seven women without GDM (control group). 1H NMR serum spectra were acquired on an 11.7 T Bruker Avance DRX NMR spectrometer.
Results:
We identified 55 metabolites in both groups, 25 of which were significantly altered in the GDM group. GDM group showed elevated levels of ketone bodies, 2-hydroxybutyrate and of some metabolic intermediates of branched-chain amino acids (BCAAs) and significantly lower levels of metabolites of one-carbon metabolism, energy production, purine metabolism, certain amino acids, 3-methyl-2-oxovalerate, ornithine, 2-aminobutyrate, taurine and trimethylamine N-oxide.
Conclusion:
Metabolic pathways affected in GDM were beta-oxidation, ketone bodies metabolism, one-carbon metabolism, arginine and ornithine metabolism likewise in DM2, whereas BCAAs catabolism and aromatic amino acids metabolism were affected, but otherwise than in DM2.
