Angiostatin is a naturally occurring protein found in several animal species, including humans. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl It is an endogenous angiogenesis inhibitor (i. An angiogenesis inhibitor is a substance that inhibits Angiogenesis (the growth of new blood vessels e. , it blocks the growth of new blood vessels), and it is currently undergoing clinical trials for its use in anticancer therapy. The blood vessels are part of the Circulatory system and function to transport Blood throughout the body In health care clinical trials are conducted to allow safety and Efficacy data to be collected for new drugs or devices [1]
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Structure
Angiostatin is a 38 kDa fragment of a larger protein, plasmin (itself a fragment of plasminogen) enclosing three to five contiguous Kringle modules. Plasmin is an important Enzyme ( present in Blood that degrades many Blood plasma proteins most notable Fibrin clots The degradation Plasmin is an important Enzyme ( present in Blood that degrades many Blood plasma proteins most notable Fibrin clots The degradation Kringle is a Pastry developed in Scandinavia although some claim its roots are in Germany Each module contains two small beta sheets and three disulfide bonds. The β sheet (also β-pleated sheet) is the second form of regular Secondary structure in Proteins consisting of beta strands connected laterally In Chemistry, a disulfide bond is a single Covalent bond derived from the coupling of Thiol groups [2] [3]
Generation
Angiostatin is produced, for example, by autoproteolytic cleavage of plasminogen, involving extracellular disulfide bond reduction by phosphoglycerate kinase. Redox (shorthand for reduction-oxidation reaction describes all Chemical reactions in which atoms have their Oxidation number ( Oxidation state Furthermore angiostatin can be cleaved from plasminogen by different metalloproteinases (MMPs), elastase, prostata-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase. Metalloproteinases (or metalloproteases constitute a family of Enzymes from the group of Proteinases classified by the nature of the most prominent Functional In Molecular biology, elastase is an Enzyme from the class of Proteases (peptidases, that break down Proteins Forms and An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response Serine proteases or serine endopeptidases (newer name are Proteases ( Enzymes that cut Peptide bonds in Proteins in which one of Endopeptidase or endoproteinase are proteolytic Peptidases that break Peptide bonds of nonterminal Amino acids (i
Biological activity
Angiostatin is known to bind many proteins, especially to angiomotin and endothelial cell surface ATP synthase but also integrins, annexin II, C-met receptor, NG2-proteoglycans, tissue-type plasminogen activator, chondroitin sulfate proteoglycans, and CD26. Angiomotin is a 675-residue protein that increases the random migration of endothelial cells as well as the migration of endothelial cells toward Growth factors. An ATP synthase ( is a general term for an Enzyme that can synthesize Adenosine triphosphate (ATP from Adenosine diphosphate (ADP and inorganic Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. Annexin is a common name for a group of cellular Proteins The annexins are a family of proteins first described in the 1980s that bind Phospholipid membrane Additionally, smaller fragments of angiostatin may bind several other proteins. There is still considerable uncertainty on its mechanism of action, but it seems to involve inhibition of endothelial cell migration,[4] proliferation and induction of apoptosis. It has been proposed that angiostatin activity is related, among other things, to the coupling of its mechanical and redox properties [5]
References
- ^ Safety and Efficacy Study of rhAngiostatin Administered in Combination With Paclitaxel and Carboplatin to Patients With Non-Small-Cell Lung Cancer - Full Text View - ClinicalTrials.gov
- ^ Kringle Domains of Human Angiostatin; Journal of Biological Chemistry, Volume 271, Number 46, Issue of November 15, 1996 pp. The Journal of Biological Chemistry (often abbreviated JBC) is a Scientific journal founded in 1905 and published since 1925 by the American Society 29461-29467
- ^ Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma; Cell, Vol 79, 315-328, 21 October 1994
- ^ Alexander Redlitz, Guenter Daum, E. Helene Sage; Angiostatin Diminishes Activation of the Mitogen-Activated Protein Kinases ERK-1 and ERK-2 in Human Dermal Microvascular Endothelial Cells; Journal of Vascular Research 1999;36:28-34 (DOI: 10. 1159/000025623)
- ^ Fabio Grandi, Massimo Sandal, Giovanni Guarguaglini, Emidio Capriotti, Rita Casadio, Bruno Samorì Hierarchical Mechanochemical Switches in Angiostatin; ChemBioChem 2006;7(11):1774-1782
External links
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