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33-419: Aprotinin is a monomeric (single-chain) globular polypeptide derived from bovine lung tissue. It has a molecular weight of 6512 Da and consists of 16 different amino acid types arranged in a chain 58 residues long that folds into a stable, compact tertiary structure of the 'small SS-rich" type, containing 3 disulfides, a twisted β-hairpin and a C-terminal α-helix . The amino acid sequence for bovine BPTI

66-412: A meta-analysis performed in 2004, transfusion requirements decreased by 39% in coronary artery bypass graft (CABG) surgery. In orthopedic surgery, a decrease of blood transfusions was likewise confirmed. There have been concerns about the safety of aprotinin. Anaphylaxis (a severe allergic reaction) occurs at a rate of 1:200 in first-time use, but serology (measuring antibodies against aprotinin in

99-447: A Canadian study that showed it increased the risk of death when used to prevent bleeding during heart surgery. Two studies published in early 2008, both comparing aprotinin with aminocaproic acid , found that mortality was increased by 32 and 64%, respectively. One study found an increased risk in need for dialysis and revascularisation. No cases of bovine spongiform encephalopathy transmission by aprotinin have been reported, although

132-470: A biologically functional way, often bound to ligands such as coenzymes and cofactors , to another protein or other macromolecule such as DNA or RNA , or to complex macromolecular assemblies . Amino acids that have been incorporated into peptides are termed residues . A water molecule is released during formation of each amide bond. All peptides except cyclic peptides have an N-terminal (amine group) and C-terminal (carboxyl group) residue at

165-616: A concentration of about 125,000 IU/ml, and kallikrein at 300,000 IU/ml. Its action on kallikrein leads to the inhibition of the formation of factor XIIa . As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis. In cardiac surgery with a high risk of significant blood loss, aprotinin significantly reduced bleeding, mortality and hospital stay. Beneficial effects were also reported in high-risk orthopedic surgery. In liver transplantation , initial reports of benefit were overshadowed by concerns about toxicity. In

198-399: A diverse set of chemical manipulations on the developing product. These peptides are often cyclic and can have highly complex cyclic structures, although linear nonribosomal peptides are also common. Since the system is closely related to the machinery for building fatty acids and polyketides , hybrid compounds are often found. The presence of oxazoles or thiazoles often indicates that

231-403: A fluorescent histochemical reagent for staining glycoconjugates (mucosubstances) that are rich in uronic or sialic acids. Initially named "kallikrein inactivator", aprotinin was first isolated from cow parotid glands in 1930. and independently as a trypsin inhibitor from bovine pancreas in 1936. It was purified from bovine lung in 1964. As it inhibits pancreatic enzymes, it was initially used in

264-712: Is FDA-approved for use in the treatment of acute bleeding due to elevated fibrinolytic activity. It also carries an orphan drug designation from the FDA for the prevention of recurrent hemorrhage in patients with traumatic hyphema . In clinical practice, aminocaproic acid is frequently used off-label for control of bleeding in patients with severe thrombocytopenia, control of oral bleeding in patients with congenital and acquired coagulation disorders, control of perioperative bleeding associated with cardiac surgery, prevention of excessive bleeding in patients on anticoagulation therapy undergoing invasive dental procedures, and reduction of

297-416: Is RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA KRNNF KSAED CMRTC GGA. There are 10 positively charged lysine (K) and arginine (R) side chains and only 4 negative aspartate (D) and glutamates (E), making the protein strongly basic , which accounts for the basic in its name. (Because of the usual source organism, BPTI is sometimes referred to as bovine pancreatic trypsin inhibitor.) The high stability of

330-498: Is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins . Chains of fewer than twenty amino acids are called oligopeptides , and include dipeptides , tripeptides , and tetrapeptides . Peptides fall under the broad chemical classes of biological polymers and oligomers , alongside nucleic acids , oligosaccharides , polysaccharides , and others. Proteins consist of one or more polypeptides arranged in

363-481: Is cleaved into the mature sequence given above. BPTI is the classic member of the protein family of Kunitz-type serine protease inhibitors . Its physiological functions include the protective inhibition of the major digestive enzyme trypsin when small amounts are produced, by cleavage of the trypsinogen precursor during storage in the pancreas. Aprotinin is a competitive inhibitor of several serine proteases , specifically trypsin , chymotrypsin and plasmin at

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396-401: Is effective in treatment of certain bleeding disorders , and it is sold under the brand name Amicar . Aminocaproic acid is also an intermediate in the polymerization of Nylon-6 , where it is formed by ring-opening hydrolysis of caprolactam . The crystal structure determination showed that the 6-aminohexanoic acid is present as a salt, at least in the solid state. Aminocaproic acid (Amicar)

429-480: Is estimated that at least 10% of the pharmaceutical market is based on peptide products. The peptide families in this section are ribosomal peptides, usually with hormonal activity. All of these peptides are synthesized by cells as longer "propeptides" or "proproteins" and truncated prior to exiting the cell. They are released into the bloodstream where they perform their signaling functions. Several terms related to peptides have no strict length definitions, and there

462-491: Is often overlap in their usage: Peptides and proteins are often described by the number of amino acids in their chain, e.g. a protein with 158 amino acids may be described as a "158 amino-acid-long protein". Peptides of specific shorter lengths are named using IUPAC numerical multiplier prefixes: The same words are also used to describe a group of residues in a larger polypeptide ( e.g. , RGD motif ). (See Template:Leucine metabolism in humans – this diagram does not include

495-498: The "Blood conservation using antifibrinolytics" (BART) randomized trial in a cardiac surgery population. The preliminary findings suggest that, compared to other antifibrinolytic drugs (epsilon-aminocaproic acid and tranexamic acid) aprotinin may increase the risk of death. On October 29, 2006 the Food and Drug Administration issued a warning that aprotinin may have serious kidney and cardiovascular toxicity. The producer, Bayer, reported to

528-423: The FDA that additional observation studies showed that it may increase the chance for death, serious kidney damage, congestive heart failure and strokes. FDA warned clinicians to consider limiting use to those situations where the clinical benefit of reduced blood loss is essential to medical management and outweighs the potential risks. On November 5, 2007, Bayer announced that it was withdrawing Aprotinin because of

561-409: The blood) is not carried out in practice to predict anaphylaxis risk because the correct interpretation of these tests is difficult. Thrombosis , presumably from overactive inhibition of the fibrinolytic system, may occur at a higher rate, but until 2006 there was limited evidence for this association. Similarly, while biochemical measures of renal function were known to occasionally deteriorate, there

594-430: The compound was synthesized in this fashion. Peptones are derived from animal milk or meat digested by proteolysis . In addition to containing small peptides, the resulting material includes fats, metals, salts, vitamins, and many other biological compounds. Peptones are used in nutrient media for growing bacteria and fungi. Peptide fragments refer to fragments of proteins that are used to identify or quantify

627-416: The drug may benefit certain subpopulations of patients. In a Public Health Advisory Update dated October 3, 2006, the FDA recommended that "physicians consider limiting Trasylol use to those situations in which the clinical benefit of reduced blood loss is necessary to medical management and outweighs the potential risks" and carefully monitor patients. On October 25, 2007, the FDA issued a statement regarding

660-572: The drug was withdrawn in Italy due to fears of this. Small amounts of aprotinin can be added to tubes of drawn blood to enable laboratory measurement of certain rapidly degraded proteins such as glucagon . In cell biology aprotinin is used as an enzyme inhibitor to prevent protein degradation during lysis or homogenization of cells and tissues. Aprotinin can be labelled with fluorescein isothiocyanate. The conjugate retains its antiproteolytic and carbohydrate-binding properties and has been used as

693-1417: The end of the peptide (as shown for the tetrapeptide in the image). There are numerous types of peptides that have been classified according to their sources and functions. According to the Handbook of Biologically Active Peptides , some groups of peptides include plant peptides, bacterial/ antibiotic peptides , fungal peptides, invertebrate peptides, amphibian/skin peptides, venom peptides, cancer/anticancer peptides, vaccine peptides, immune/inflammatory peptides, brain peptides, endocrine peptides , ingestive peptides, gastrointestinal peptides, cardiovascular peptides, renal peptides, respiratory peptides, opioid peptides , neurotrophic peptides, and blood–brain peptides. Some ribosomal peptides are subject to proteolysis . These function, typically in higher organisms, as hormones and signaling molecules. Some microbes produce peptides as antibiotics , such as microcins and bacteriocins . Peptides frequently have post-translational modifications such as phosphorylation , hydroxylation , sulfonation , palmitoylation , glycosylation, and disulfide formation. In general, peptides are linear, although lariat structures have been observed. More exotic manipulations do occur, such as racemization of L-amino acids to D-amino acids in platypus venom . Nonribosomal peptides are assembled by enzymes , not

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726-412: The hydrogen exchange of individual peptide NH groups along the chain, ranging from too fast to measure on the most exposed surface to many months for the most buried hydrogen-bonded groups in the center of the β sheet, and those values also correlate fairly well with degree of motion seen in the dynamics simulations. BPTI was important in the development of knowledge about the process of protein folding ,

759-536: The laboratory of Robert Huber , and it's substrate-like interaction mode deciphered in the context of the bovine trypsin complex in 1974. It later also became famous being the first protein to have its structure determined by NMR spectroscopy , in the laboratory of Kurt Wuthrich at the ETH in Zurich in the early 1980s. Because it is a small, stable protein whose structure had been determined at high resolution by 1975, it

792-409: The molecule is due to the 3 disulfide bonds linking the 6 cysteine members of the chain (Cys5-Cys55, Cys14-Cys38 and Cys30-Cys51). The long, basic lysine 15 side chain on the exposed loop (at top left in the image) binds very tightly in the specificity pocket at the active site of trypsin and inhibits its enzymatic action. BPTI is synthesized as a longer, precursor sequence, which folds up and then

825-459: The pathway for β-leucine synthesis via leucine 2,3-aminomutase) Aminocaproic acid Aminocaproic acid (also known as ε-aminocaproic acid , ε-Ahx , or 6-aminohexanoic acid ) is a derivative and analogue of the amino acid lysine , which makes it an effective inhibitor for enzymes that bind that particular residue. Such enzymes include proteolytic enzymes like plasmin , the enzyme responsible for fibrinolysis . For this reason it

858-434: The ribosome. A common non-ribosomal peptide is glutathione , a component of the antioxidant defenses of most aerobic organisms. Other nonribosomal peptides are most common in unicellular organisms , plants , and fungi and are synthesized by modular enzyme complexes called nonribosomal peptide synthetases . These complexes are often laid out in a similar fashion, and they can contain many different modules to perform

891-471: The self-assembly of a polypeptide chain into a specific arrangement in 3D. The problem of achieving the correct pairings among the 6 Cys sidechains was shown to be especially difficult for the two buried, close-together SS near the BPTI chain termini, requiring a non-native intermediate for folding the mature sequence in vitro (it was later discovered that the precursor sequence folds more easily in vivo ). BPTI

924-562: The source protein. Often these are the products of enzymatic degradation performed in the laboratory on a controlled sample, but can also be forensic or paleontological samples that have been degraded by natural effects. Peptides can perform interactions with proteins and other macromolecules. They are responsible for numerous important functions in human cells, such as cell signaling, and act as immune modulators. Indeed, studies have reported that 15-40% of all protein-protein interactions in human cells are mediated by peptides. Additionally, it

957-422: The treatment for acute pancreatitis , in which destruction of the gland by its own enzymes is thought to be part of the pathogenesis. Its use in major surgery commenced in the 1960s. BPTI is one of the most thoroughly studied proteins in terms of structural biology , experimental and computational dynamics, mutagenesis, and folding pathway . It was one of the earliest protein crystal structures solved, in 1970 in

990-417: Was faulted by the FDA for not revealing during testimony the existence of a commissioned retrospective study of 67,000 patients, 30,000 of whom received aprotinin and the rest other anti-fibrinolytics. The study concluded aprotinin carried greater risks. The FDA was alerted to the study by one of the researchers involved. Although the FDA issued a statement of concern they did not change their recommendation that

1023-497: Was no evidence that this greatly influenced outcomes. A study performed in cardiac surgery patients reported in 2006 showed that there was indeed a risk of acute renal failure , myocardial infarction and heart failure , as well as stroke and encephalopathy . The study authors recommend older antifibrinolytics (such as tranexamic acid ) in which these risks were not documented. The same group updated their data in 2007 and demonstrated similar findings. In September 2006, Bayer A.G.

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1056-442: Was the cover image on a protein folding compendium volume by Thomas Creighton in 1992. One scientific study in rats reported that treatment with aprotinin prevents disruption of the blood–brain barrier during the C. neoformans infection. Another study in cell cultures suggests that the drug inhibits SARS-CoV-2 Replication. Polypeptide Peptides are short chains of amino acids linked by peptide bonds . A polypeptide

1089-551: Was the first macromolecule of scientific interest to be simulated using molecular dynamics computation, in 1977 by J. Andrew McCammon and Bruce Gelin, in the Karplus group at Harvard. That study confirmed the then-surprising fact found in the NMR work that even well-packed aromatic sidechains in the interior of a stable protein can flip over rather rapidly (microsecond to millisecond time scale). Rate constants were determined by NMR for

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