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Granzymes (lymphocyte serine proteases): characterization with natural and synthetic substrates and inhibitors.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2000 Mar 07; Vol. 1477 (1-2), pp. 307-23. - Publication Year :
- 2000
-
Abstract
- Natural killer (NK) and cytotoxic T-lymphocytes (CTLs) kill cells within an organism to defend it against viral infections and the growth of tumors. One mechanism of killing involves exocytosis of lymphocyte granules which causes pores to form in the membranes of the attacked cells, fragments nuclear DNA and leads to cell death. The cytotoxic granules contain perforin, a pore-forming protein, and a family of at least 11 serine proteases termed granzymes. Both perforin and granzymes are involved in the lytic activity. Although the biological functions of most granzymes remain to be resolved, granzyme B clearly promotes DNA fragmentation and is directly involved in cell death. Potential natural substrates for Gr B include procaspases and other proteins involved in cell death. Activated caspases are involved in apoptosis. The search continues for natural substrates for the other granzymes. The first granzyme crystal structure remains to be resolved, but in the interim, molecular models of granzymes have provided valuable structural information about their substrate binding sites. The information has been useful to predict the amino acid sequences that immediately flank each side of the scissile peptide bond of peptide and protein substrates. Synthetic substrates, such as peptide thioesters, nitroanilides and aminomethylcoumarins, have also been used to study the substrate specificity of granzymes. The different granzymes have one of four primary substrate specificities: tryptase (cleaving after Arg or Lys), Asp-ase (cleaving after Asp), Met-ase (cleaving after Met or Leu), and chymase (cleaving after Phe, Tyr, or Trp). Natural serpins and synthetic inhibitors (including isocoumarins, peptide chloromethyl ketones, and peptide phosphonates) inhibit granzymes. Studies of substrate and inhibitor kinetics are providing valuable information to identify the most likely natural granzyme substrates and provide tools for the study of key reactions in the cytolytic mechanism.
- Subjects :
- Animals
Apoptosis
Binding Sites
Chymases
Cytoplasmic Granules enzymology
Deoxyribonucleases
Enzyme Activation
Granzymes
Humans
Kinetics
Membrane Glycoproteins
Models, Molecular
Perforin
Pore Forming Cytotoxic Proteins
Serine Endopeptidases chemistry
Serine Endopeptidases genetics
Serine Proteinase Inhibitors chemical synthesis
Serpins chemistry
Serpins metabolism
Substrate Specificity
Tryptases
Killer Cells, Natural enzymology
Serine Endopeptidases metabolism
Serine Proteinase Inhibitors metabolism
T-Lymphocytes, Cytotoxic enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1477
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 10708866
- Full Text :
- https://doi.org/10.1016/s0167-4838(99)00282-4