scholarly journals Loss of Glyoxalase 1 Induces Compensatory Mechanism to Achieve Dicarbonyl Detoxification in Mammalian Schwann Cells

2016 ◽  
Vol 292 (8) ◽  
pp. 3224-3238 ◽  
Author(s):  
Jakob Morgenstern ◽  
Thomas Fleming ◽  
Dagmar Schumacher ◽  
Volker Eckstein ◽  
Marc Freichel ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Aldose Reductase ◽  
Mammalian Cells ◽  
Clinical Importance ◽  
Catalytic Efficiency ◽  
Compensatory Mechanism ◽  
Glyoxalase System ◽  
Compensatory Mechanisms ◽  
Knock Out ◽  
Glyoxalase 1

The glyoxalase system is a highly specific enzyme system existing in all mammalian cells that is responsible for the detoxification of dicarbonyl species, primarily methylglyoxal (MG). It has been implicated to play an essential role in preventing the increased formation of advanced glycation end products under certain pathological conditions. We have established the first glyoxalase 1 knock-out model (GLO1−/−) in mammalian Schwann cells using the CRISPR/Cas9 technique to investigate compensatory mechanisms. Neither elevated concentrations of MG nor associated protein modifications were observed in GLO1−/− cells. Alternative detoxification of MG in GLO1−/− is achieved by increased catalytic efficiency of aldose reductase toward hemithioacetal (product of glutathione and MG), which is most likely caused by S-nitrosylation of aldose reductase. The hemithioacetal is mainly converted into lactaldehyde, which is paralleled by a loss of reduced glutathione. Inhibition of aldose reductase in GLO1−/− cells is associated with an increased sensitivity against MG, elevated intracellular MG levels, associated modifications, as well as increased oxidative stress. Our data suggest that aldose reductase can compensate for the loss of GLO1. This might be of clinical importance within the context of neuronal diseases caused by an impaired glyoxalase system and elevated levels of dicarbonyl species, such as MG.

scholarly journals Phosphorylation of Threonine 107 by Calcium/Calmodulin dependent Kinase II δ Regulates the Detoxification Efficiency and Proteomic Integrity of Glyoxalase 1

2020 ◽  
Author(s):  
Jakob Morgenstern ◽  
Sylvia Katz ◽  
Jutta Krebs-Haupenthal ◽  
Jessy Chen ◽  
Alireza Saadatmand ◽  
...  
Keyword(s):  
Regulatory Mechanism ◽  
Enzyme System ◽  
Catalytic Efficiency ◽  
Glyoxalase System ◽  
Knock Out ◽  
Glyoxalase 1 ◽  
Calcium Calmodulin Dependent ◽  
Protective System ◽  
Rate Limiting ◽  
Kinetics Of

AbstractThe glyoxalase system is a ubiquitously expressed enzyme system with narrow substrate specificity and is responsible for the detoxification of harmful methylglyoxal (MG), a spontaneous by-product of energy metabolism. Glyoxalase 1 (Glo1) is the first and therefore rate limiting enzyme of this protective system. In this study we were able to show that a phosphorylation of threonine-107 in the Glo1 protein, mediated by Ca2+/Calmodulin-dependent Kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1. In fact, Michaelis-Menten kinetics of Glo1 mutants revealed that a permanent phosphorylation of Glo1 was associated with increased Vmax (1.23 µmol/min/mg) and decreased Km (0.19 mM HTA), whereas the non-phosphorylatable Glo1 showed significantly lower Vmax (0.66 µmol/min/mg) and increased Km (0.31 mM HTA). This was also confirmed with human recombinant Glo1 (Vmax (Glo1phos) = 999 µmol/min/mg; Km (Glo1phos) = 0.09 mM HTA vs. Vmax (Glo1red) = 497 µmol/min/mg; Km (Glo1red) = 0.12 mM HTA). Additionally, proteasomal degradation of non-phosphorylated Glo1 via ubiquitination occurred more rapidly as compared to native Glo1. The absence of the responsible kinase CamKIIδ was associated with poor MG detoxification capacity and decreased protein content of Glo1 in a murine CamKIIδ knock-out model. Furthermore, this regulatory mechanism is also related to an altered Glo1 status in cancer, diabetes and during aging. In summary, phosphorylation of threonine-107 in the Glo1 protein by CamKIIδ is a quick and precise mechanism regulating Glo1 activity.

Increased glyoxalase-1 levels in Fkbp5 knock-out mice caused by Glo1 gene duplication

2013 ◽  
Vol 46 (06) ◽  
Author(s):  
LK Kollmannsberger ◽  
NC Gassen ◽  
A Bultmann ◽  
J Hartmann ◽  
P Weber ◽  
...  
Keyword(s):  
Gene Duplication ◽  
Knock Out ◽  
Glyoxalase 1 ◽  
Knock Out Mice

scholarly journals Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

2021 ◽  
Vol 22 (3) ◽  
pp. 1031
Author(s):  
Naoko Niimi ◽  
Hideji Yako ◽  
Shizuka Takaku ◽  
Sookja K. Chung ◽  
Kazunori Sango
Keyword(s):  
Schwann Cells ◽  
Aldose Reductase ◽  
Critical Role ◽  
Polyol Pathway ◽  
Glucose Flux ◽  
Rate Limiting ◽  
Deficient Mice ◽  
Excess Glucose ◽  
Shed Light ◽  
Immortalized Schwann Cells

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

Depression of nuclear transcription and extension of mRNA half-life under anoxia in Artemia franciscana embryos

2000 ◽  
Vol 203 (7) ◽  
pp. 1123-1130 ◽  
Author(s):  
F. van Breukelen ◽  
R. Maier ◽  
S.C. Hand
Keyword(s):  
Half Life ◽  
Mammalian Cells ◽  
Transcriptional Activity ◽  
Artemia Franciscana ◽  
Mrna Levels ◽  
Compensatory Mechanisms ◽  
Depressed State ◽  
Initiation Of Transcription ◽  
Mrna Half Life

Transcriptional activity, as assessed by nuclear run-on assays, was constant during 10 h of normoxic development for embryos of the brine shrimp Artemia franciscana. Exposure of embryos to only 4 h of anoxia resulted in a 79.3+/−1 % decrease in levels of in-vivo-initiated transcripts, and transcription was depressed by 88. 2+/−0.7 % compared with normoxic controls after 24 h of anoxia (means +/− s.e.m., N=3). Initiation of transcription was fully restored after 1 h of normoxic recovery. Artificially lowering the intracellular pH of aerobic embryos to the value reflective of anoxia (pH 6.7) showed that acidification alone explained over half the transcriptional arrest. Initiation of transcription was not rescued by application of 80 % carbon monoxide under anoxia, which suggests that heme-based oxygen sensing is not involved in this global arrest. When these transcriptional data are combined with the finding that mRNA levels are unchanged for at least 6 h of anoxia, it is clear that the half-life of mRNA is extended at least 8.5-fold compared with that in aerobic embryos. In contrast to the activation of compensatory mechanisms to cope with anoxia that occurs in mammalian cells, A. franciscana embryos enter a metabolically depressed state in which gene expression and mRNA turnover are cellular costs apparently not compatible with survival and in which extended tolerance supercedes the requirement for continued metabolic function.

Mitophagy in Carcinogenesis and Tumor progression- A New paradigm with Emerging Importance

2021 ◽  
Vol 21 ◽  
Author(s):  
Suman K. Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Mammalian Cells ◽  
Mitochondrial Dynamics ◽  
Clinical Importance ◽  
Malignant Cells ◽  
Malignant Growth ◽  
New Paradigm ◽  
Pancreatic Cancer Cells

: The term Mitophagy has been newly concerned in reforming metabolic landscape inside cancerous cells in addition to interface between malignant cells as well as other major constituents of tumor microenvironment. Several profoundly interrelated systems, comprising mitochondrial dynamics and mitophagy, function in mammalian cells as vital mitochondrial regulator process, and their consequence in neoplastic development has newly illuminated clinically. In specific instance of cancer cells, mitochondrialprotected metabolic paths are revamped to meet expanded bioenergetics along with biosynthetic necessities of malignant cells in addition to deal with oxidative stress. It is an exhausting task to foresee the role that mitophagy has on malignant growth cells since it relies upon various elements like cancer variability, malignant growth phase, genetic background and harmony between cell demand and accessibility. As per condition, mitophagy may have a double role as cancer suppressor for example Atg5 (autophagy related 5) or Atg7 (autophagy related 7) or execute promoter like function for instance FUNDC1 (FUN14 domain-containing protein 1), BNIP3 (BCL2/adenovirus E1B 19-kDa-interacting protein 3), PINK1 (PTEN-instigated kinase 1) etc. Tumor suppressive function of Parkin (E3 ubiquitin ligase) is likewise distinguished in mammary gland carcinoma where obstruction of mitophagy impacts tumor progression. In pancreatic cancer cells and in hepatocellular carcinoma hypermethylation of the BNIP3, promoter occurs that prevent HIF-1 (HypoxiaInducible Factor 1) binding besides ensuing initiation of mitophagy. Since the double role mitophagy has in malignant growth relying upon various circumstances and cell varieties, a range of studies have been going on mitophagy and its role in cancer progression and development is opening up a new paradigm with immense clinical importance.

scholarly journals Pathway Analysis of a Transcriptome and Metabolite Profile to Elucidate a Compensatory Mechanism for Taurine Deficiency in the Heart of Taurine Transporter Knockout Mice

J ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 57-70
Author(s):  
Takashi Ito ◽  
Shigeru Murakami ◽  
Stephen Schaffer
Keyword(s):  
Pathway Analysis ◽  
Knockout Mice ◽  
Metabolite Profile ◽  
Integrated Analysis ◽  
Compensatory Mechanism ◽  
Compensatory Mechanisms ◽  
Taurine Transporter ◽  
Kegg Pathway Database ◽  
Taurine Deficiency ◽  
Pathway Analyses

Taurine, which is abundant in mammalian tissues, especially in the heart, is essential for cellular osmoregulation. We previously reported that taurine deficiency leads to changes in the levels of several metabolites, suggesting that alterations in those metabolites might compensate in part for tissue taurine loss, a process that would be important in maintaining cardiac homeostasis. In this study, we investigated the molecular basis for changes in the metabolite profile of a taurine-deficient heart using pathway analysis based on the transcriptome and metabolome profile in the hearts of taurine transporter knockout mice (TauTKO mice), which have been reported by us. First, the genes associated with transport activity, such as the solute carrier (SLC) family, are increased in TauTKO mice, while the established transporters for metabolites that are elevated in the TauTKO heart, such as betaine and carnitine, are not altered by taurine deficiency. Second, the integrated analysis using transcriptome and metabolome data revealed significant increases and/or decreases in the genes involved in Arginine metabolism, Ketone body degradation, Glycerophospholipid metabolism, and Fatty acid metabolism in the KEGG pathway database. In conclusion, these pathway analyses revealed genetic compensatory mechanisms involved in the control of the metabolome profile of the taurine-deficient heart.

A new compensatory mechanism for having only one feeding claw in male Uca rosea (Tweedie, 1937)

Crustaceana ◽  
2016 ◽  
Vol 89 (13) ◽  
pp. 1551-1558 ◽  
Author(s):  
Fahmida Wazed Tina ◽  
Mullica Jaroensutasinee ◽  
Krisanadej Jaroensutasinee
Keyword(s):  
Feeding Rate ◽  
Compensatory Mechanism ◽  
Fiddler Crabs ◽  
Compensatory Mechanisms

We investigated how male Uca rosea (Tweedie, 1937) have behaviourally or morphologically compensated for having only one functional feeding claw while females have two. We found that male U. rosea used four compensatory mechanisms: (1) larger feeding claws (dactyl length and width), (2) higher feeding rate/claw per min, (3) higher numbers of pinches/feeding claw per min than similar sized females, and (4) higher numbers of pinches/feeding claw lift than females of similar feeding rate/feeding claw per min. This study is the first one to demonstrate that taking higher numbers of pinches/feeding claw per min than comparable sized females, and taking higher numbers of pinches/feeding claw lift than females of similar feeding rate/claw per min are used as additional compensatory mechanisms for male fiddler crabs to compensate for having only one feeding claw.

scholarly journals Distribution and paralogue specificity of mammalian deSUMOylating enzymes

2010 ◽  
Vol 430 (2) ◽  
pp. 335-344 ◽  
Author(s):  
Nagamalleswari Kolli ◽  
Jowita Mikolajczyk ◽  
Marcin Drag ◽  
Debaditya Mukhopadhyay ◽  
Nela Moffatt ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Catalytic Efficiency ◽  
Covalent Attachment ◽  
Kinetic Properties ◽  
Kinetic Measurements ◽  
Systematic Analysis ◽  
Catalytic Domains ◽  
Irreversible Inhibitors ◽  
Marked Preference ◽  
Relative Selectivity

The covalent attachment of SUMO (small ubiquitin-like protein modifier) to target proteins results in modifications in their activity, binding interactions, localization or half-life. The reversal of this modification is catalysed by SENPs (SUMO-specific processing proteases). Mammals contain four SUMO paralogues and six SENP enzymes. In the present paper, we describe a systematic analysis of human SENPs, integrating estimates of relative selectivity for SUMO1 and SUMO2, and kinetic measurements of recombinant C-terminal cSENPs (SENP catalytic domains). We first characterized the reaction of each endogenous SENP and cSENPs with HA–SUMO-VS [HA (haemagglutinin)-tagged SUMO-vinyl sulfones], active-site-directed irreversible inhibitors of SENPs. We found that all cSENPs and endogenous SENP1 react with both SUMO paralogues, whereas all other endogeneous SENPs in mammalian cells and tissues display high selectivity for SUMO2-VS. To obtain more quantitative data, the kinetic properties of purified cSENPs were determined using SUMO1- or SUMO2-AMC (7-amino-4-methylcoumarin) as substrate. All enzymes bind their respective substrates with high affinity. cSENP1 and cSENP2 process either SUMO substrate with similar affinity and catalytic efficiency; cSENP5 and cSENP6 show marked catalytic specificity for SUMO2 as measured by Km and kcat, whereas cSENP7 works only on SUMO2. Compared with cSENPs, recombinant full-length SENP1 and SENP2 show differences in SUMO selectivity, indicating that paralogue specificity is influenced by the presence of the variable N-terminal domain of each SENP. Our data suggest that SUMO2 metabolism is more dynamic than that of SUMO1 since most SENPs display a marked preference for SUMO2.

scholarly journals NAD(P)H-dependent aldose reductase from the xylose-assimilating yeast Candida tenuis: Isolation, characterization and biochemical properties of the enzyme

1997 ◽  
Vol 326 (3) ◽  
pp. 683-692 ◽  
Author(s):  
Wilfried NEUHAUSER ◽  
Dietmar HALTRICH ◽  
Klaus D. KULBE ◽  
Bernd NIDETZKY
Keyword(s):  
Aldose Reductase ◽  
Binding Constants ◽  
Catalytic Efficiency ◽  
Anion Exchange Chromatography ◽  
Competitive Inhibitor ◽  
Biochemical Properties ◽  
Product Inhibition ◽  
Exchange Chromatography ◽  
Binding Studies ◽  
Coenzyme Binding

During growth on D-xylose the yeast Candida tenuis produces one aldose reductase that is active with both NADPH and NADH as coenzyme. This enzyme has been isolated by dye ligand and anion-exchange chromatography in yields of 76%. Aldose reductase consists of a single 43 kDa polypeptide with an isoelectric point of 4.70. Initial velocity, product inhibition and binding studies are consistent with a compulsory-ordered, ternary-complex mechanism with coenzyme binding first and leaving last. The catalytic efficiency (kcat/Km) in D-xylose reduction at pH 7 is more than 60-fold higher than that in xylitol oxidation and reflects significant differences in the corresponding catalytic centre activities as well as apparent substrate-binding constants. The enzyme prefers NADP(H) approx. 2-fold to NAD(H), which is largely due to better apparent binding of the phosphorylated form of the coenzyme. NADP+ is a potent competitive inhibitor of the NADH-linked aldehyde reduction (Ki 1.5 μM), whereas NAD+ is not. Unlike mammalian aldose reductase, the enzyme from C. tenuisis not subject to oxidation-induced activation. Evidence of an essential lysine residue located in or near the coenzyme binding site has been obtained from chemical modification of aldose reductase with pyridoxal 5′-phosphate. The results are discussed in the context of a comparison of the enzymic properties of yeast and mammalian aldose reductase.

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