- Methionine is required for cAMP-PKA mediated morphogenesis and virulence of Candida albicans. [Journal Article]
- MMMol Microbiol 2018 Feb 17
- Candida albicans is a major human fungal pathogen, causing superficial, as well as life-threatening invasive infections. Therefore, it has to adequately sense and respond to the host defense by expre...
Candida albicans is a major human fungal pathogen, causing superficial, as well as life-threatening invasive infections. Therefore, it has to adequately sense and respond to the host defense by expressing appropriate virulence attributes. The most important virulence factor of C. albicans is the yeast-to-hyphae morphogenetic switch, which can be induced by numerous environmental cues, including the amino acid methionine. Here, we show an essential role for methionine permease Mup1 in methionine-induced morphogenesis, biofilm formation, survival inside macrophages and virulence. Furthermore, we demonstrate that this process requires conversion of methionine into S-adenosylmethionine (SAM) and its decarboxylation by Spe2. The resulting amino-propyl group is then used for biosynthesis of polyamines, which have been shown to activate adenylate cyclase. Inhibition of the SPE2 SAM decarboxylase gene strongly impairs methionine-induced morphogenesis on specific media and significantly delays virulence in the mouse systemic infection model system. Further proof of the connection between methionine uptake and initial metabolism and the cAMP-PKA pathway was obtained by showing that both Mup1 and Spe2 are required for cAMP production in response to methionine. Our results suggest that amino acid transport and further metabolism are interesting therapeutic targets as inhibitors of this may prevent the morphogenetic switch, thereby preventing virulence. This article is protected by copyright. All rights reserved.
- Probiotics Affect One-Carbon Metabolites and Catecholamines in a Genetic Rat Model of Depression. [Journal Article]
- MNMol Nutr Food Res 2018 Feb 17
- CONCLUSIONS: Probiotics reduced the flow of methyl groups via betaine, increased liver SAM, and decreased plasma dopamine and norepinephrine. Since these changes in methylation and catecholamine pathways are known to be involved in several diseases, future investigation of the effect of probiotics is warranted. This article is protected by copyright. All rights reserved.
- Natural noncanonical protein splicing yields products with diverse β-amino acid residues. [Journal Article]
- SciScience 2018 Feb 16; 359(6377):779-782
- Current textbook knowledge holds that the structural scope of ribosomal biosynthesis is based exclusively on α-amino acid backbone topology. Here we report the genome-guided discovery of bacterial pa...
Current textbook knowledge holds that the structural scope of ribosomal biosynthesis is based exclusively on α-amino acid backbone topology. Here we report the genome-guided discovery of bacterial pathways that posttranslationally create β-amino acid-containing products. The transformation is widespread in bacteria and is catalyzed by an enzyme belonging to a previously uncharacterized radicalS-adenosylmethionine family. We show that the β-amino acids result from an unusual protein splicing process involving backbone carbon-carbon bond cleavage and net excision of tyramine. The reaction can be used to incorporate diverse and multiple β-amino acids into genetically encoded precursors inEscherichia coliIn addition to enlarging the set of basic amino acid components, the excision generates keto functions that are useful as orthogonal reaction sites for chemical diversification.
- Oxidation Resistance of the Sulfur Amino Acids: Methionine and Cysteine. [Review]
- BRBiomed Res Int 2017; 2017:9584932
- Sulfur amino acids are a kind of amino acids which contain sulfhydryl, and they play a crucial role in protein structure, metabolism, immunity, and oxidation. Our review demonstrates the oxidation re...
Sulfur amino acids are a kind of amino acids which contain sulfhydryl, and they play a crucial role in protein structure, metabolism, immunity, and oxidation. Our review demonstrates the oxidation resistance effect of methionine and cysteine, two of the most representative sulfur amino acids, and their metabolites. Methionine and cysteine are extremely sensitive to almost all forms of reactive oxygen species, which makes them antioxidative. Moreover, methionine and cysteine are precursors of S-adenosylmethionine, hydrogen sulfide, taurine, and glutathione. These products are reported to alleviate oxidant stress induced by various oxidants and protect the tissue from the damage. However, the deficiency and excess of methionine and cysteine in diet affect the normal growth of animals; thereby a new study about defining adequate levels of methionine and cysteine intake is important.
- The mysterious polyamines, the enigmatic Barr body, and lupus: comment on the article by Kim et al. [Journal Article]
- LLupus 2018 Jan 01; :961203318757929
- "Polyamine patterns in plasma of patients with systemic lupus erythematosus and fever" by Kim et al. provides insight into possible involvement of polyamines in systemic lupus erythematosus (SLE). Th...
"Polyamine patterns in plasma of patients with systemic lupus erythematosus and fever" by Kim et al. provides insight into possible involvement of polyamines in systemic lupus erythematosus (SLE). The authors report decreases in N1-acetylspermidine, spermidine, spermine, and N1-acetylcadaverine and increased cadaverine in SLE. Polyamine involvement in many cellular processes and their unique characteristics (high charge, length, flexibility, and ubiquity) give polyamines importance in health and disease. In this editorial, I describe a scenario, the "X chromosome-nucleolus nexus" hypothesis, in which polyamines could initially rise because of cellular stress. This rise in polyamines increases nucleolar size and activity. Polyamines are critical in the nucleolar assembly of ribonucleoprotein complexes, such as ribosomes. However, the expanding nucleolus could disrupt a neighboring inactive X chromosome (Barr body). This disruption opens additional polyamine genes that alter polyamine levels and types through wasteful synthesis and recycling of polyamines. This could include a decrease in the key polyamines spermidine and spermine, which are critical to nucleolar functioning. And this can decrease S-adenosylmethionine needed for cellular methylation leading to hypomethylation seen in SLE. As a result, the nucleolus can no longer respond properly to future stresses. With altered polyamine levels and types in the nucleolus, many RNA transcripts, proteins, and ribonucleoprotein complexes assembled in the nucleolus may be trapped in autoantigenic conformations. Many of the major autoantigens in SLE are, at least transiently, components of the nucleolus. Therefore, the observations of decreased polyamines reported by Kim et al. could be important in the formation of autoantigens.
- Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasis in vivo; therapeutic and chemopreventive applications. [Journal Article]
- OOncotarget 2018 Jan 12; 9(4):5169-5183
- DNA hypomethylation coordinately targets various signaling pathways involved in tumor growth and metastasis. At present, there are no approved therapeutic modalities that target hypomethylation. In t...
DNA hypomethylation coordinately targets various signaling pathways involved in tumor growth and metastasis. At present, there are no approved therapeutic modalities that target hypomethylation. In this regard, we examined the therapeutic plausibility of using universal methyl group donor S-adenosylmethionine (SAM) to block breast cancer development, growth, and metastasis through a series of studies in vitro using two different human breast cancer cell lines (MDA-MB-231 and Hs578T) and in vivo using an MDA-MB-231 xenograft model of breast cancer. We found that SAM treatment caused a significant dose-dependent decrease in cell proliferation, invasion, migration, anchorage-independent growth and increased apoptosis in vitro. These results were recapitulated in vivo where oral administration of SAM reduced tumor volume and metastasis in green fluorescent protein (GFP)-tagged MDA-MB-231 xenograft model. Gene expression analyses validated the ability of SAM to decrease the expression of several key genes implicated in cancer progression and metastasis in both cell lines and breast tumor xenografts. SAM was found to be bioavailable in the serum of experimental animals as determined by enzyme-linked immunosorbent assay and no notable adverse side effects were seen including any change in animal behavior. The results of this study provide compelling evidence to evaluate the therapeutic potential of methylating agents like SAM in patients with breast cancer to reduce cancer-associated morbidity and mortality.
- Open-label study of ademetionine for the treatment of intrahepatic cholestasis associated with alcoholic liver disease. [Journal Article]
- MGMinerva Gastroenterol Dietol 2018 Feb 08
- CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.
- S-Adenosylmethionine attenuates bile duct early warm ischemia reperfusion injury after rat liver transplantation. [Journal Article]
- MIMol Immunol 2018 Feb 08; 95:83-90
- Warm ischemia reperfusion injury (IRI) plays a key role in biliary complication, which is a substantial vulnerability of liver transplantation. The early pathophysiological changes of IRI are charact...
Warm ischemia reperfusion injury (IRI) plays a key role in biliary complication, which is a substantial vulnerability of liver transplantation. The early pathophysiological changes of IRI are characterized by an excessive inflammatory response. S-Adenosylmethionine (SAM) is an important metabolic intermediate that modulates inflammatory reactions; however, its role in bile duct warm IRI is not known. In this study, male rats were treated with or without SAM (170 μmol/kg body weight) after orthotopic autologous liver transplantation. The histopathological observations showed that bile duct injury in the IRI group was more serious than in the SAM group. The alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DBIL) levels in the serum of the IRI group were significantly increased compared to the SAM group (P < .05). Simultaneously, SAM effectively improved the survival of the transplant recipients. Furthermore, the H2O2and malondialdehyde (MDA) of the IRI group were much higher compared to the SAM group (P < .05). The GSH/GSSG ratio in the SAM group was significantly increased by SAM treatment compared to the IRI group (P < .05). SAM administration significantly inhibited macrophage infiltration in liver and bile duct tissues, down-regulated TNF-α levels and up-regulated IL-10 expression in bile duct tissues compared to the IRI group (P < .05). The number of apoptotic biliary epithelial cells and caspase-3-positive cells in IRI rat livers were much higher compared to those in SAM-treated rats at 24 h after liver transplantation (P < .05). These data suggested that SAM protected bile ducts against warm IRI by suppressing oxidative stress, inflammatory reactions and apoptosis of biliary epithelial cells after liver transplantation.α.
- Analytical and clinical validation of an LC-MS/MS method to measure thiopurine S-methyltransferase activity by quantifying d3-6-MMP. [Journal Article]
- CBClin Biochem 2018 Feb 06
- CONCLUSIONS: With the inclusion of isotope labelled substrate, interfering non-enzymatic methylation no longer results in potential false assignment of abnormal patients. Furthermore, the method can be applied to patients who have already been prescribed thiopurine drugs. This new LC-MS/MS is therefore a favourable clinical routine application to test TPMT activity, as it shows excellent performance in identifying patients with TPMT deficiency.
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- [Cofactor engineering strategy for enhanced S-adenosylmethionine production in Saccharomyces cerevisiae]. [Journal Article]
- SWSheng Wu Gong Cheng Xue Bao 2018 Feb 25; 34(2):246-254
- In order to study the role of cofactor engineering in enhancing the production of S-adenosylmethionine (SAM), we altered the form and concentration of cofactor in Saccharomyces cerevisiae through gen...
In order to study the role of cofactor engineering in enhancing the production of S-adenosylmethionine (SAM), we altered the form and concentration of cofactor in Saccharomyces cerevisiae through gene recombination. Effects of cofactor on product synthesis, carbon and energy metabolism were analyzed aiming to provide a theoretical basis for a successful metabolic engineering of SAM producing strains. Because NADPH metabolism in mitochondrion and cytoplasm of S. cerevisiae is relatively independent, the effect of intracellular NADPH availability on the production of SAM was studied in different compartments of S. cerevisiae BY4741. The expression of NADH kinase in mitochondria (POS5 encoded) and cytoplasm (POS5Δ17 encoded) was separately confirmed using a laser scanning confocal microscope. NADPH regulation strategy enhanced SAM production. Compared with the control strain, the intracellular SAM concentration of strain NBYSM-1 was increased by 3.28 times, and the intracellular SAM concentration of strain NBYSM-2 was increased by 1.79 times at 24 h fermentation. In addition, SAM titer and NADPH/NADP⁺ ratio in strain NBYSM-1 were significantly higher than that of strain NBYSM-2. Therefore, NADPH regulation strategy will be a valuable tool for SAM production and could further improve the synthesis of a large range of cofactor-driven chemicals.