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Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation.

ABSTRACT: One of the key questions in biology is how the metabolism of a cell responds to changes in the environment. In budding yeast, starvation causes a drop in intracellular pH, but the functional role of this pH change is not well understood. Here, we show that the enzyme glutamine synthetase (Gln1) forms filaments at low pH and that filament formation leads to enzymatic inactivation. Filament formation by Gln1 is a highly cooperative process, strongly dependent on macromolecular crowding, and involves back-to-back stacking of cylindrical homo-decamers into filaments that associate laterally to form higher order fibrils. Other metabolic enzymes also assemble into filaments at low pH. Hence, we propose that filament formation is a general mechanism to inactivate and store key metabolic enzymes during a state of advanced cellular starvation. These findings have broad implications for understanding the interplay between nutritional stress, the metabolism and the physical organization of a cell.

SUBMITTER: Petrovska I

PROVIDER: S-EPMC4011332 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation.

Petrovska Ivana I Nüske Elisabeth E Munder Matthias C MC Kulasegaran Gayathrie G Malinovska Liliana L Kroschwald Sonja S Richter Doris D Fahmy Karim K Gibson Kimberley K Verbavatz Jean-Marc JM Alberti Simon S

eLife 20140425

One of the key questions in biology is how the metabolism of a cell responds to changes in the environment. In budding yeast, starvation causes a drop in intracellular pH, but the functional role of this pH change is not well understood. Here, we show that the enzyme glutamine synthetase (Gln1) forms filaments at low pH and that filament formation leads to enzymatic inactivation. Filament formation by Gln1 is a highly cooperative process, strongly dependent on macromolecular crowding, and involv ...[more]

PMID: 24771766

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Project description:Metabolic syndrome typically includes Type 2 diabetes associated with hyperglycemia, central obesity, dyslipidemia and hypertension. It is highly related to oxidative stress, formation of advanced glycated end products (AGEs) and key enzymes, such as carbohydrate digesting enzymes like pancreatic ?-amylase and intestinal ?-glucosidase, pancreatic lipase and angiotensin I-converting enzyme (ACE). This study used an in vitro approach to assess the potential of four extracts of Siegesbeckia orientalis linne on key enzymes relevant to metabolic syndrome. In this research, S. orientailis was firstly extracted by ethanol. The ethanol extract (SE) was then partitioned sequentially with hexane, ethyl acetate and methanol, and these extracts were named SE-Hex, SE-EA and SE-MeOH, respectively. The experimental results showed that SE-EA had the highest total phenolic content (TPC, 76.9 ± 1.8 mg/g) and the total flavonoids content (TFC, 5.3 ± 0.3 mg/g). This extract exhibited the most significant antioxidant activities, including DPPH radical-scavenging capacity (IC50 = 161.8 ± 2.4 ?g/mL), ABTS radical-scavenging capacity (IC50 = 13.9 ± 1.5 ?g/mL) and reducing power. For anti-glycation activities, SE-EA showed the best results in the inhibition of AGEs, as well as inhibitory activities against ?-glucosidase (IC50 = 362.3 ± 9.2 ?g/mL) and ?-amylase (IC50 = 119.0 ± 17.7 ?g/mL). For anti-obesity activities, SE-EA indicated the highest suppression effect on pancreatic lipase (IC50 = 3.67 ± 0.52 mg/mL). Finally, for anti-hypertension activity, SE-EA also demonstrated the strongest inhibitory activity on ACE (IC50 = 626.6 ± 15.0 ?g/mL). Close relationships were observed among the parameters of TPC, antioxidant activities, inhibitory activities on ?-amylase, ?-glucosidase, lipase and ACE (R > 0.9). Moderate correlations were found among the parameters of TFC, antioxidant activities, and suppression of dicarbonyl compounds formation (R = 0.5-0.9). Taken together these in vitro studies reveal the therapeutic potential of SE-EA extract in the prevention and treatment of metabolic disorders.

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Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation.

Publications

Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation.

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