Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration

DR (dietary restriction), or reduced food intake without malnutrition, is associated with extended longevity, improved metabolic fitness and increased stress resistance in a wide range of organisms. DR is often referred to as calorie restriction, implying that reduced energy intake is responsible for its widespread and evolutionarily conserved benefits. However, recent data indicate dietary amino acid restriction as a key mediator of DR benefits. In fruitflies, an imbalance in essential amino acid intake is thought to underlie longevity benefits of DR. In mammals, reduced dietary protein or essential amino acid intake can extend longevity, improve metabolic fitness and increase stress resistance. In the present paper we review two evolutionarily conserved signal transduction pathways responsible for sensing amino acid levels. The eIF2α (eukaryotic initiation factor 2α) kinase GCN2 (general amino acid control non-derepressible 2) senses the absence of one or more amino acids by virtue of direct binding to uncharged cognate tRNAs. The presence of certain amino acids, such as leucine, permits activation of the master growth regulating kinase TOR (target of rapamycin). These two signal transduction pathways react to amino acid deprivation by inhibiting general protein translation while at the same time increasing translation of specific mRNAs involved in restoring homoeostasis. Together, these pathways may contribute to the regulation of longevity, metabolic fitness and stress resistance.

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Acquisition of Certain Streptomycin-Resistant (str) Mutations Enhances Antibiotic Production in Bacteria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.8.2041 ◽

1998 ◽

Vol 42 (8) ◽

pp. 2041-2047 ◽

Cited By ~ 77

Author(s):

Yoshiko Hosoya ◽

Susumu Okamoto ◽

Hideyuki Muramatsu ◽

Kozo Ochi

Keyword(s):

Amino Acid ◽

Antibiotic Production ◽

Gene Replacement ◽

Rational Approach ◽

Increase In Productivity ◽

Adverse Environmental Conditions ◽

Ribosomal Protein S12 ◽

Acid Alteration ◽

Type Strains ◽

Amino Acid Alteration

ABSTRACT Physiological differentiation (including antibiotic production) in microorganisms usually starts when cells encounter adverse environmental conditions and is frequently accompanied by an increase in the accumulation of intracellular ppGpp. We have found that the acquisition of certain streptomycin-resistant (str) mutations enables cells to overproduce antibiotics, demonstrating an increase in productivity 5- to 50-fold greater than that of wild-type strains. The frequency of such antibiotic-overproducing strains among the str mutants was shown to range from 3 to 46%, as examined with several strains of the genera Streptomyces,Bacillus, and Pseudomonas. Analysis of str mutants from Bacillus subtilisMarburg 168 revealed that a point mutation occurred within therpsL gene, which encodes the ribosomal protein S12, changing Lys-56 (corresponding to Lys-43 in Escherichia coli) to Asn, Arg, Thr, or Gln. Antibiotic productivity increased in a hierarchical manner depending upon which amino acid residue replaced Lys at this position. The strA1 mutation, a genetic marker frequently used for mapping, had no effect on antibiotic productivity even though it was found to result in an amino acid alteration of Lys-56 to Ile. Gene replacement experiments with thestr alleles demonstrated unambiguously that thestr mutation is responsible for the antibiotic overproductivity observed. These results offer a rational approach for improving the production of antibiotic (secondary metabolism) from microorganisms.

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Ribosomal Mutations Conferring Resistance to Macrolides in Streptococcus pneumoniae Clinical Strains Isolated in Germany

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.7.2319-2322.2003 ◽

2003 ◽

Vol 47 (7) ◽

pp. 2319-2322 ◽

Cited By ~ 33

Author(s):

Ralf René Reinert ◽

Angela Wild ◽

Peter Appelbaum ◽

Rudolf Lütticken ◽

Murat Yücel Cil ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Amino Acid ◽

Ribosomal Protein ◽

Macrolide Resistance ◽

23S Rrna ◽

Resistance Phenotype ◽

Clinical Strains ◽

Acid Alteration ◽

Amino Acid Alteration

ABSTRACT Among a collection of 4,281 pneumococcal isolates, 7 strains isolated in Germany had an unusual macrolide resistance phenotype. The isolates were found to have multiple mutations in the 23S rRNA and alterations in the L4 ribosomal protein. One strain had an amino acid alteration in the L22 ribosomal protein.

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A Single Amino Acid Alteration in the Human Parainfluenza Virus Type 3 Hemagglutinin-Neuraminidase Glycoprotein Confers Resistance to the Inhibitory Effects of Zanamivir on Receptor Binding and Neuraminidase Activity

Journal of Virology ◽

10.1128/jvi.75.14.6310-6320.2001 ◽

2001 ◽

Vol 75 (14) ◽

pp. 6310-6320 ◽

Cited By ~ 15

Author(s):

Matthew T. Murrell ◽

Matteo Porotto ◽

Olga Greengard ◽

Natalia Poltoratskaia ◽

Anne Moscona

Keyword(s):

Sialic Acid ◽

Amino Acid ◽

Virus Type ◽

Parainfluenza Virus ◽

Single Amino Acid ◽

Plaque Morphology ◽

Human Parainfluenza Virus ◽

Type 3 ◽

Acid Alteration ◽

Amino Acid Alteration

ABSTRACT Entry and fusion of human parainfluenza virus type 3 (HPF3) requires interaction of the viral hemagglutinin-neuraminidase (HN) glycoprotein with its sialic acid receptor. 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-GU-DANA; zanamivir), a sialic acid transition-state analog designed to fit the influenza virus neuraminidase catalytic site, possesses antiviral activity at nanomolar concentrations in vitro. We have shown previously that 4-GU-DANA also inhibits both HN-mediated binding of HPF3 to host cell receptors and HN's neuraminidase activity. In the present study, a 4-GU-DANA-resistant HPF3 virus variant (ZM1) was generated by serial passage in the presence of 4-GU-DANA. ZM1 exhibited a markedly fusogenic plaque morphology and harbored two HN gene mutations resulting in two amino acid alterations, T193I and I567V. Another HPF3 variant studied in parallel, C-0, shared an alteration at T193 and exhibited similar plaque morphology but was not resistant to 4-GU-DANA. Neuraminidase assays revealed a 15-fold reduction in 4-GU-DANA sensitivity for ZM1 relative to the wild type (WT) and C-0. The ability of ZM1 to bind sialic acid receptors was inhibited 10-fold less than for both WT and C-0 in the presence of 1 mM 4-GU-DANA. ZM1 also retained infectivity at 15-fold-higher concentrations of 4-GU-DANA than WT and C-0. A single amino acid alteration at HN residue 567 confers these 4-GU-DANA-resistant properties. An understanding of ZM1 and other escape variants provides insight into the effects of this small molecule on HN function as well as the role of the HN glycoprotein in HPF3 pathogenesis.

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