Protein synthesis Initiation, Proteolytic

Poliovirus is an RNA-RNA virus that redirects the host-cell protein synthesis machinery toward translation of its own RNA genome. The poliovirus polypeptide is cleaved into active subunits by the proteolytic action of virally encoded proteases. Poliovirus RNA replication utilizes a novel protein-uridine primer to initiate RNA synthesis using its own RNA-dependent RNA polymerase. 

The data available suggests that poliovirus induces the synthesis of some inhibitor which causes the slow inactivation of initiation factor eIE-4B. While it appears that there may be a break-through in the problem of protein synthesis shut-off, many questions still remain unanswered. For example, the nature of the eIF-4B inhibitor is unknown. Is it a viral product, or is it a cellular factor induced by the virus Is the eIF-4B inactivated by proteolytic digestion or is it inactivated by modification ... 

It has long been known that peptides of bacterial origin, such as N-formylat-ed oligopeptides, are potent activators of neutrophils. Bacterial protein biosynthesis is initiated by the codon AUG, which codes for polypeptide chains at the NH2 terminus to start with N-formylmethionine. However, very few mature bacterial proteins actually have this amino acid at the NH2 terminus because Af-formylmethionine is cleaved off by proteolytic processing. Sometimes just this amino acid is cleaved, but often several adjacent residues are also removed with it. These observations formed the basis for the chemical synthesis of a variety of N-formylated oligopeptides and an assessment of their ability to activate neutrophils in vitro. The most potent of these formylated peptides is TV-formylmethionyl-leucyl-phenylalanine (fMet-Leu-Phe). 

The chemotactic peptides are also active in the stimulation of release of O and in the release of lysosomal contents Directed locomotion by PMNs is stimulated by a family of tri-, tetra-, and dipeptides which have in common formylated methionine as the first amino acid. Since formylated methionine is the initiator to which other amino acids are added in the synthesis of bacterial protein, small peptides which commence with formylated methionine are likely to be liberated proteolytically at sites of bacterial infection, possibly explaining their great potency as chematoxins. Using superoxide-dependent chemiluminescence (see below) as a measure of synthesis of O , Hatch et al. showed a hierarchy of potency of FMLP > FMP > FMV > FMA. Becker et al. measured the formation of O in suspensions of rabbit PMNs and found that the hierarchy of potency was the same for stimulation of the formation of O7 as it was for stimulation of release of lysosomal enzymes, namely... 

A pro-drug is a substance that has no special biological activity per se but can be converted into an active drug by enzymic action in the body. Thus, all the initial proteins formed by ribosomal synthesis that contain a peptide hormone structure locked within their amino-acid sequence are analogous to pro-drugs. The hormones are released by the action of proteolytic enzymes. Usually, however, the term prodrug is restricted to artificially synthesised molecules that are acted upon by the... 

Proteolysis makes the length of the amino acid chain in proteins shorter. In all proteins, the N-terminal amino acid methionine occurring as the initiation amino acid is removed as soon as or even before the synthesis of a protein is over. In addition, many proteins are originally synthesized as a longer chain but later are shortened by proteolytic cleavage to a much shorter active form of the protein or enzyme. The common examples of this class of proteins are insulin and zymogen. These proteins are synthesized as pre-pro-proteins and undergo proteolysis first to yield as pro-proteins and then to proteins, which are the active form of these pre-pro-proteins. 

To our surprise, however, we have not been able to identify free VPg in extracts of infected cells (Golini and Wimmer, unpublished results). This paradox may be explained if VPg is generated by proteolytic cleavage from a larger precursor protein only at the moment of initiation of MA synthesis, and is then covalently linked to the MA and if cleavage of VPg from newly synthesized plus strands results in the concomitant rapid degradation of the protein. A more radical hypothesis is that VPg is sjmthesized as part of a precursor protein distinct from polyprotein NCVP 00, and that this precursor protein for VPg is translated at much lower frequency than polyprotein NCVP 00 (see E. Ehrenfeld, this voliime, chapter 11). 

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