scholarly journals Glucose restriction drives spatial reorganization of mevalonate metabolism

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sean M Rogers ◽  
Hanaa Hariri ◽  
N Ezgi M Wood ◽  
Natalie Ortiz Speer ◽  
W Mike Henne
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Mevalonate Pathway ◽  
Dependent Manner ◽  
Metabolic Remodeling ◽  
Spatial Reorganization ◽  
Glucose Restriction ◽  
Rate Limiting ◽  
Pathway Flux

Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high molecular weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.

scholarly journals Glucose restriction drives spatial re-organization of mevalonate metabolism and liquid-crystalline lipid droplet biogenesis

2020 ◽  
Author(s):  
Sean Rogers ◽  
Hanaa Hariri ◽  
Long Gui ◽  
N. Ezgi Wood ◽  
Natalie Speer ◽  
...  
Keyword(s):  
Liquid Crystalline ◽  
Mevalonate Pathway ◽  
Dependent Manner ◽  
Metabolic Remodeling ◽  
Ester Biosynthesis ◽  
Metabolic Reactions ◽  
Glucose Restriction ◽  
Rate Limiting ◽  
Pathway Flux

AbstractEukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. AGR-induced HMGCR compartmentalization enhances mevalonate metabolism and sterol-ester biosynthesis that generates lipid droplets (LDs) with liquid-crystalline sub-architecture. Loss of NVJ-dependent HMGCR partitioning affects yeast growth, but can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting HMGCR inter-enzyme associations. We propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes, and reveal that AGR creates LDs with remarkable phase transition properties.One Sentence SummarySpatial compartmentalization of HMG-CoA Reductases at ER-lysosome contacts modulates mevalonate pathway flux

Role of proteolysis in apoptosis: involvement of serine proteases in internucleosomal DNA fragmentation in immature thymocytes

1993 ◽  
Vol 71 (9-10) ◽  
pp. 488-500 ◽  
Author(s):  
Valerie M. Weaver ◽  
Boleslaw Lach ◽  
P. Roy Walker ◽  
Marianna Sikorska
Keyword(s):  
Molecular Weight ◽  
Serine Protease ◽  
High Molecular Weight ◽  
Protease Inhibitors ◽  
Dna Fragmentation ◽  
Dna Cleavage ◽  
Apoptotic Cell ◽  
Dependent Manner ◽  
Serine Protease Inhibitors ◽  
High Molecular Weight Dna

Three chemically distinct serine, but not cysteine, protease inhibitors (phenylmethylsulphonyl fluoride, N-tosyl-L-phenylalanylchloromethyl ketone and 3,4-dichloroisocoumarin) prevented, in a dose-dependent manner, the characteristic apoptotic internucleosomal DNA cleavage (DNA ladder) typically observed in thymocytes in response to dexamethasone and teniposide VM-26. This effect was not the result of a direct inhibition of the Ca2+, Mg2+-dependent endonuclease, since oligonucleosomal DNA cleavage occurred in the presence of these inhibitors in isolated nuclei. The proteolytic step occurred at a very early stage of apoptosis, and preincubation of thymocytes with the inhibitors before dexamethasone or teniposide VM-26 were added irreversibly suppressed ladder formation. This implied that the cellular effector(s) of these compounds preexisted and were not resynthesized in response to the inducers of apoptosis. Serine protease inhibitors also suppressed apoptotic cell shrinkage and complete nuclear collapse, suggesting that these morphological changes were directly related to internucleosomal fragmentation of DNA. However, the serine protease inhibitors did not prevent high molecular weight DNA cleavage (> 50 kilobases) that preceded the ladder formation and thymocytes still died by apoptosis. This supported the view that internucleosomal DNA cleavage, considered to be the biochemical marker of apoptosis, might in fact be a late and dispensable step and that the newly described high molecular weight DNA cleavage might be a better indicator of apoptosis.Key words: serine protease, apoptosis, internucleosomal DNA fragmentation, high molecular weight DNA cleavage, protease inhibitors.

scholarly journals The Role of High Molecular Weight Kininogen and Prothrombin as Cofactors in the Binding of Factor XI A3 Domain to the Platelet Surface

2000 ◽  
Vol 275 (33) ◽  
pp. 25139-25145 ◽  
Author(s):  
David H. Ho ◽  
Karen Badellino ◽  
Frank A. Baglia ◽  
Mao-Fu Sun ◽  
Ming-Ming Zhao ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Platelet Surface

scholarly journals Role of Sintering Temperature in Production of Nepheline Ceramics-Based Geopolymer with Addition of Ultra-High Molecular Weight Polyethylene

Materials ◽  
2021 ◽  
Vol 14 (5) ◽  
pp. 1077
Author(s):  
Romisuhani Ahmad ◽  
Mohd Mustafa Al Bakri Abdullah ◽  
Wan Mastura Wan Ibrahim ◽  
Kamarudin Hussin ◽  
Fakhryna Hannanee Ahmad Zaidi ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Sintering Temperature ◽  
Ceramic Materials ◽  
Microstructural Properties ◽  
Sintering Process ◽  
Final Microstructure ◽  
Change Of Microstructure ◽  
Ultra High Molecular Weight

The primary motivation of developing ceramic materials using geopolymer method is to minimize the reliance on high sintering temperatures. The ultra-high molecular weight polyethylene (UHMWPE) was added as binder and reinforces the nepheline ceramics based geopolymer. The samples were sintered at 900 °C, 1000 °C, 1100 °C, and 1200 °C to elucidate the influence of sintering on the physical and microstructural properties. The results indicated that a maximum flexural strength of 92 MPa is attainable once the samples are used to be sintered at 1200 °C. It was also determined that the density, porosity, volumetric shrinkage, and water absorption of the samples also affected by the sintering due to the change of microstructure and crystallinity. The IR spectra reveal that the band at around 1400 cm−1 becomes weak, indicating that sodium carbonate decomposed and began to react with the silica and alumina released from gels to form nepheline phases. The sintering process influence in the development of the final microstructure thus improving the properties of the ceramic materials.

scholarly journals Actinobacteria challenge the paradigm: A unique protein architecture for a well-known, central metabolic complex

2021 ◽  
Vol 118 (48) ◽  
pp. e2112107118
Author(s):  
Eduardo M. Bruch ◽  
Pierre Vilela ◽  
Lu Yang ◽  
Alexandra Boyko ◽  
Norik Lexa-Sapart ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Metabolic Engineering ◽  
High Molecular Weight ◽  
Protein Oligomerization ◽  
Central Metabolism ◽  
Hollow Core ◽  
Protein Architecture ◽  
Unique Protein ◽  
Gene Coding

α-oxoacid dehydrogenase complexes are large, tripartite enzymatic machineries carrying out key reactions in central metabolism. Extremely conserved across the tree of life, they have been, so far, all considered to be structured around a high–molecular weight hollow core, consisting of up to 60 subunits of the acyltransferase component. We provide here evidence that Actinobacteria break the rule by possessing an acetyltranferase component reduced to its minimally active, trimeric unit, characterized by a unique C-terminal helix bearing an actinobacterial specific insertion that precludes larger protein oligomerization. This particular feature, together with the presence of an odhA gene coding for both the decarboxylase and the acyltransferase domains on the same polypetide, is spread over Actinobacteria and reflects the association of PDH and ODH into a single physical complex. Considering the central role of the pyruvate and 2-oxoglutarate nodes in central metabolism, our findings pave the way to both therapeutic and metabolic engineering applications.

Role of nano-fillers on tribological behaviour of ultra high molecular weight polyethylene composites

2020 ◽  
Vol 27 ◽  
pp. 2169-2173
Author(s):  
B. Suresha ◽  
B. Harshavardhan ◽  
Ashwij M. Rao ◽  
U.R. Koushik ◽  
R. Hemanth
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Tribological Behaviour ◽  
Ultra High Molecular Weight ◽  
Polyethylene Composites

scholarly journals Potential role of high molecular weight hyaluronan in the anti-Candidaactivity of human oral epithelial cells

2007 ◽  
Vol 45 (1) ◽  
pp. 73-79 ◽  
Author(s):  
Akiyoshi Sakai ◽  
Sumio Akifusa ◽  
Naoki Itano ◽  
Koji Kimata ◽  
Taro Kawamura ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Epithelial Cells ◽  
High Molecular Weight ◽  
Potential Role ◽  
Oral Epithelial Cells ◽  
Oral Epithelial

Altering potato isoprenoid metabolism increases biomass and induces early flowering

2020 ◽  
Vol 71 (14) ◽  
pp. 4109-4124
Author(s):  
Moehninsi ◽  
Iris Lange ◽  
B Markus Lange ◽  
Duroy A Navarre
Keyword(s):  
Metabolic Regulation ◽  
Transcriptional Control ◽  
Mevalonate Pathway ◽  
Early Flowering ◽  
Bioenergy Crops ◽  
Isoprenoid Metabolism ◽  
Transgenic Lines ◽  
Coa Reductase ◽  
Rate Limiting

Abstract Isoprenoids constitute the largest class of plant natural products and have diverse biological functions including in plant growth and development. In potato (Solanum tuberosum), the regulatory mechanism underlying the biosynthesis of isoprenoids through the mevalonate pathway is unclear. We assessed the role of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) homologs in potato development and in the metabolic regulation of isoprenoid biosynthesis by generating transgenic lines with down-regulated expression (RNAi-hmgr) or overexpression (OE) of one (StHMGR1 or StHMGR3) or two genes, HMGR and farnesyl diphosphate synthase (FPS; StHMGR1/StFPS1 or StHMGR3/StFPS1). Levels of sterols, steroidal glycoalkaloids (SGAs), and plastidial isoprenoids were elevated in the OE-HMGR1, OE-HMGR1/FPS1, and OE-HMGR3/FPS1 lines, and these plants exhibited early flowering, increased stem height, increased biomass, and increased total tuber weight. However, OE-HMGR3 lines showed dwarfism and had the highest sterol amounts, but without an increase in SGA levels, supporting a rate-limiting role for HMGR3 in the accumulation of sterols. Potato RNAi-hmgr lines showed inhibited growth and reduced cytosolic isoprenoid levels. We also determined the relative importance of transcriptional control at regulatory points of isoprenoid precursor biosynthesis by assessing gene–metabolite correlations. These findings provide novel insights into specific end-products of the sterol pathway and could be important for crop yield and bioenergy crops.

scholarly journals Oligomerization and Dissociation of AP-1 Adaptors Are Regulated by Cargo Signals and by ArfGAP1-induced GTP Hydrolysis

2005 ◽  
Vol 16 (10) ◽  
pp. 4745-4754 ◽  
Author(s):  
Daniel M. Meyer ◽  
Pascal Crottet ◽  
Bohumil Maco ◽  
Elena Degtyar ◽  
Dan Cassel ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Adaptor Proteins ◽  
Gtpase Activity ◽  
Gtpase Activating Protein ◽  
Gtp Hydrolysis ◽  
Sorting Signals ◽  
Initial Assembly ◽  
Cargo Sorting

The mechanism of AP-1/clathrin coat formation was analyzed using purified adaptor proteins and synthetic liposomes presenting tyrosine sorting signals. AP-1 adaptors recruited in the presence of Arf1·GTP and sorting signals were found to oligomerize to high-molecular-weight complexes even in the absence of clathrin. The appendage domains of the AP-1 adaptins were not required for oligomerization. On GTP hydrolysis induced by the GTPase-activating protein ArfGAP1, the complexes were disassembled and AP-1 dissociated from the membrane. AP-1 stimulated ArfGAP1 activity, suggesting a role of AP-1 in the regulation of the Arf1 “GTPase timer.” In the presence of cytosol, AP-1 could be recruited to liposomes without sorting signals, consistent with the existence of docking factors in the cytosol. Under these conditions, however, AP-1 remained monomeric, and recruitment in the presence of GTP was short-lived. Sorting signals allowed stable recruitment and oligomerization also in the presence of cytosol. These results suggest a mechanism whereby initial assembly of AP-1 with Arf1·GTP and ArfGAP1 on the membrane stimulates Arf1 GTPase activity, whereas interaction with cargo induces oligomerization and reduces the rate of GTP hydrolysis, thus contributing to efficient cargo sorting.

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