Amino acid starvation

Complex metabolic processes carbon and amino acid starvation viral infection... 

The complex that RNA polymerase forms at the promoter site just prior to initiation. Some bacterial promoters require high NTP concentrations to initiate efficient transcription, because this represents a status report on the stores of ATP, UTP, GTP, and CTP needed for RNA synthesis. Nature has evolved a kinetic control device high initiating ATP and GTP concentrations must be present to stabilize an otherwise short-lived polymerase-promoter complex. The reader may also recall that bacterial translation is also tightly controlled, and amino acid starvation leads to ppGpp synthesis, the so-called stringent-response agent that also potently inhibits RNA polymerase. Such kinetic control ensures that NTP and amino acid concentrations are adequate before transcription and translation occur. 

Another regulatory nucleotide, ppGpp (Fig. 8-42), is produced in bacteria in response to a slowdown in protein synthesis during amino acid starvation. This nucleotide inhibits the synthesis of the rRNA and tRNA molecules (see Fig. 28-24) needed for protein synthesis, preventing the unnecessary production of nucleic acids. 

Guanosine tetraphosphate (ppGpp) concentration under normal conditions, after amino acid starvation, and after readdition of amino acids ( = wild-type cells A = relA cells and = spoT cells). 

Some of the PolyP complexes with proteins are very important in cell regulatory processes. RNA polymerase isolated from the stationary-phase cells of E. coli was found to be closely bound with PolyP (Kusano and Ishihama, 1997). The ATP-dependent protease Lon formed a complex with PolyPs under degradation of ribosomal proteins at amino acids starvation (Kuroda et al, 2001). PolyP is able to compete with DNA for the DNA binding sites at histones (Schroder et al., 1999), while PolyPs can interact with non-histone proteins in the nucleus (Offenbacher and Kline, 1984). 

One example of the adaptation of bacteria to an unfavourable environment is their response to amino acid starvation. In an environment rich in amino acids, cells do not produce enzymes of amino acid synthesis. However, in the case of a nutritional downshift in the environment, cells must use their own proteins as sources of amino acids for building enzymes required for amino acid biosynthesis pathways (Gottesman and Maurizi, 2001). 

Convincing evidence was obtained that protein degradation in E. coli during amino acid starvation depends on the ATP-dependent proteases Lon and Clp (Kuroda et al, 2001). Mutations in Lon and Clp proteases produced the same phenotype as ppkl mutation - the... 

Figure 8.5 PolyP accumulation, and polyphosphate kinase (PPK) and exopolyphosphatase (PPX) activities, under stringent conditions. E. coli MG1655 was grown on a MOPS medium containing 0.4 mM P . At A540 near 0.2, serine hydroxamate (SHX) was added (0.5 mg mO1) for induction of amino acid starvation and accumulation of (p)ppGpp. Symbols represent with ( ) and without (<0>) serine hydroxamate units of PPK and PPX in (b) are 1 nmol P muT1 (Kuroda et al., 1997). Reproduced with permission from Kuroda, A., Murphy, H., Cashel, M. and Kornberg, A., J. Biol. Chem., 272(34), 21240-21243 (1997). Copyright (1997) American Society for Biochemistry and Molecular Biology.

A. Kuroda, S. Tanaka, T. Ikeda, J. Kato, N. Takiguchi and H. Ohtake (1999). Inorganic polyphosphate kinase is required to stimulate protein degradation and for adaptation to amino acid starvation in Escherichia coli. Proc. Natl. Acad. Sci. USA, 96, 14264-14269. 

Translation can be inhibited through the phosphorylation of eukaryote initiation factor 2 (eIF2) by dsRNA-dependent PK (activated by viral dsRNA as a consequence of viral infection), by hemin-inhibited PK (activated in the absence of hemin in reticulocytes) and by GCN2 kinase (general control non-derepressible kinase) (activated by amino acid starvation and excess free tRNA). Phosphorylation of RNA polymerase II is a key process in the regulation of transcription (Chapter 9). 

Gaccioli F, Huang CC, Wang C, Bevilacqua E, Franchi-Gazzola R, et al. 2006. Amino acid starvation induces the SNAT2 neutral amino acid transporter by a mechanism that involves eukaryotic initiation factor 2a phosphorylation and cap-independent translation. J Biol Chem 281 17929-17940. 

Global regulation of protein synthesis occurs most commonly at the level of initiation as exemplified by studies carried out on protein-synthetic rates during the cell cycle, differentiation, embryonic development, and by altered physiological conditions such as serum starvation, amino acid starvation, glucose starvation, hypertonic conditions, ionic changes, heat shock, and other stresses. 

The third eIF2a kinase, PERK participates in the endoplasmatic reticulum stress response. The fourth eIF2a kinase, GCN2, is activated under conditions of amino acid starvation. 

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