chymotrypsin

[CHYM(E) + TRYPSIN.]

An enzyme involved in the digestion of proteins; secreted as the inactive precursor chymotrypsinogen in the pancreatic juice. It is activated by trypsin, and is an endopeptidase, with a different specificity from trypsin and pepsin.

An enzyme involved in protein digestion in the small intestine. Chymotrypsin has been used to accelerate the repair of soft-tissue sports injuries, such as sprains and internal bruising of muscles. However, the treatment has not always been successful, and chymotrypsin may be toxic to some hypersensitive people.

Description

Chymotrypsin is a digestive enzyme that breaks down proteins (i.e., it is a proteolytic enzyme; it can also be referred to as a protease). It is naturally produced by the pancreas in the human body. However, it can also be taken as an enzyme supplement to improve health and digestion and aid in the treatment of various diseases.

The pancreas, which produces chymotrypsin and other digestive enzymes, is a digestive organ in the abdomen that is located just below the stomach. Its primary job is to produce enzymes required for the digestion and absorption of food. Each day the pancreas secrets about 1.5 qt (1.4 L) of pancreatic juice, consisting of enzymes, water, and electrolytes (primarily bicarbonate) into the small intestine. The enzymes are secreted in an inactive form (as proenzymes) so that they will not digest the pancreas. The pancreas secretes an inhibitor to ensure that the enzymes are not activated too early. When the pancreatic juice reaches the small intestine, the enzymes become activated. The small intestine is not digested because it contains a protective mucous lining. However, self-digestion can occur if the pancreatic duct becomes blocked or if the pancreas is damaged. The proenzymes can overwhelm the inhibitor, causing the enzymes to become active while in the pancreas. This condition, called acute pancreatitis, can result in a lifetime of pancreatic insufficiency.

The enzymes secreted by the pancreas break down food by breaking the chemical bonds that hold food molecules together. Enzymes secreted include lipase, which, along with bile, digests fat; amylases, which break down starch molecules into smaller sugars; and protease, which breaks protein molecules into dipeptides and some single amino acids. In addition to chymotrypsin, other protease enzymes secreted by the pancreas include trypsin and carboxypeptidase.

Chymotrypsin, as a hydrolase type of enzyme (which means it adds a water molecule during the breakdown process) acts by catalyzing the hydrolysis of peptide bonds of proteins in the small intestine. It is selective for peptide bonds with aromatic or large hydrophobic side chains on the carboxyl side of this bond. Chymotrypsin also catalyzes the hydrolysis of ester bonds. Chymotrypsin does not digest blood proteins because of protective factors in the blood that block the enzyme.

General Use

Generally, the primary uses of chymotrypsin are as a digestive aid and as an anti-inflammatory agent. The presence and amount of chymotrypsin in a person's stool is sometimes measured for diagnostic purposes as a test of pancreatic function. Testing for fecal chymotrypsin is non-invasive, unlike some other tests of pancreatic function.

Chymotrypsin, along with the other pancreatic enzymes, is most often used in the treatment of pancreatic insufficiency. Pancreatic insufficiency is characterized by impaired digestion, malabsorption and passing of undigested food into the stool, nutrient deficiencies, gas, and abdominal bloating and discomfort. Pancreatic deficiency also occurs in persons with cystic fibrosis, a rare inherited disorder. It may also occur in those with chronic pancreatitis, as well as in the elderly. Other conditions that could result in chymotrypsin deficiency include physical injuries, chemotherapy, and chronic stress.

Starch and fat digestion can be accomplished without the help of pancreatic enzymes; however, the protease enzymes (i.e., chymotrypsin, trypsin, and carboxypeptidase) are required for proper protein digestion. Incomplete digestion of proteins may result in the development of allergies and the formation of toxic substances produced by putrefaction, the breakdown of protein materials by bacteria. Protease enzymes and other intestinal secretions are also required to keep the small intestine free from parasites such as bacteria, yeast, protozoa, and intestinal worms. A laboratory analysis of a stool sample along with physical symptoms are used to assess pancreatic function.

As an anti-inflammatory agent, the chymotrypsin and the other protease enzymes prevent tissue damage during inflammation and the formation of fibrin clots. Protease enzymes participate in the breakdown of fibrin in a process called fibrinolysis. Fibrin causes a wall to form around an area of inflammation, resulting in the blockage of blood and lymph vessels, which leads to swelling. Fibrin can also cause the development of blood clots. In autoimmune diseases, the protease enzymes aid in the breakdown of immune complexes, which are antibodies produced by the immune system associated with the compounds they bind to (antigens). High levels of immune complexes in the blood are associated with autoimmune diseases.

Specifically, chymotrypsin is used to:

• Aid in digestion.
• Treat inflammation and reduce swelling (i.e., soft tissue injuries, acute traumatic injuries, sprains, contusions, hematomas, ecchymoses, infections, edema of the eyelids and genitalia, muscle cramps, and sports injuries).
• Treat arthritis and such other autoimmune diseases as lupus, scleroderma, and multiple sclerosis.
• Treat ulcerations and abscesses.
• Liquefy mucus secretions.
• Treat enterozoic worms and other parasites in the digestive tract.
• Treat cancer (a controversial use that requires much more scientific study, though chymotrypsin may be helpful in alleviating effects of radiation treatment or chemotherapy).
• Treat shingles and acne.
• Decrease effects of sun damage and age spots.

Preparations

Chymotrypsin is produced from fresh hog, beef, or oxen pancreas. It can be taken orally, topically, or by injection (by injection only by a physician in severe life-threatening situations), but is commonly taken orally in tablet form. As a tablet, it may be uncoated, microencapsulated, or enterically coated (to prevent digestion in the stomach so that the enzyme will be released in the small intestine). Other forms include coated granules, powder, capsules, and liquids. Creams and ointments are used to break down proteins and debride dead tissue resulting from burns, wounds, and abscesses. The enzyme preparation should be stored in a tight container with a moisture-proof liner in a dry, cool place. An opened container stored properly should maintain enzyme activity for about two to three months.

Usually chymotrypsin is included in a combination with other enzymes. A typical formulation may include: chymotrypsin (0.5–1 mg), bromelain (a plant protease) (25–45 mg), pancreatin (a mixture of many pancreatic enzymes) (100 mg), papain (a plant protease similar in action to chymotrypsin) (25–60 mg), and trypsin (a pancreatic protease) (24 mg). Formulations may also include vitamins, herbs, phytochemicals, and other nutrients to enhance the activity of the enzyme supplement.

Enzyme activity should be considered when a supplement is selected. Activity is usually indicated in units; however there is no one standard for enzyme activity level. Recognized guidelines for measuring enzyme activity include Food Chemicals Codex (FCC), United States Pharmacopoeia (USP), Federation Internationale du Pharmaceutiques (FIP), British Pharmacopoeia (BP), and Japanese Pharmacopoeia (JP). For example, the United States Pharmacopoeia has set a strict definition for level of activity that must be reported in a enzyme supplement. A 1X chymotrypsin product must contain not less than 25 USP units for chymotrypsin activity. A preparation of higher potency is given a whole number multiple indicating its strength. For example, a full-strength undiluted extract that is 10 times stronger than the USP standard would be referred to as 10X USP. A consumer can compare enzyme activity levels among enzyme products within a single guideline system, but unfortunately the information is not interchangeable among guideline systems.

The dose required will vary on the quantity (amount in mg) and the quality (activity level) of the enzyme in the preparation, which is usually tablet form. The dose will also depend on the condition being treated. In most cases, for oral ingestion and for topical application, the directions on the bottle or tube label can be followed. Enterically coated tables should be swallowed and not chewed or ground up. Tablets should also be taken with at least 8 oz of water to help activate the enzyme. Chymotrypsin taken to enhance digestion is usually taken just before, during, or just after meals, or before going to bed at night. With proper dosages, improvements in digestion should be noted within a few hours.

For inflammatory or chronic conditions, chymotrypsin should be taken on an empty stomach, either one hour before meals or at least two hours after meals. When chymotrypsin is taken for an inflammatory condition, some improvement may be noted within three to seven days. Those with chronic conditions such as arthritis may require one to three months or more to notice a change in conditions.

Precautions

Chymotrypsin is generally well tolerated and not associated with any significant side effects. However, since a safe dose has not been established, it should only be used when there is apparent need.

People who should not use enzyme therapy include those with hereditary clotting disorders such as hemophilia, those suffering from coagulation disturbances, those who are just about to or have undergone surgery, those on anticoagulant therapy, anyone suffering from protein allergies, and pregnant women or those breast-feeding. Since there is not much known about the effects of enzyme therapy on children, it would be prudent to avoid giving enzyme supplements to children.

When protective mechanisms against self-digestion in the body break down, chymotrypsin should not be used. For example, if a patient has stomach ulcers, chymotrypsin therapy should be discontinued.

Side Effects

There do not appear to be any long-term side effects from chymotrypsin therapy if precautions for its use are followed. Studies have shown that at recommended doses, enzymes cannot be detected in blood analysis after 24–48 hours. Temporary side effects that may occur (but that should disappear when therapy is discontinued or dosage is reduced) include changes in the color, consistency, and odor of the stool. Some individuals may experience gastrointestinal disturbances, such as flatulence, a feeling of fullness, diarrhea, constipation, or nausea. With high doses, minor allergic reactions such as reddening of the skin may occur.

Interactions

Chymotrypsin is most often used in combination with other enzymes to enhance its treatment potential. In addition, a well-balanced diet or the use of vitamin and mineral supplements are recommended to stimulate chymotrypsin activity.

Some types of seeds, including jojoba and wild soja seeds, have been found to contain proteins that inhibit the activity of chymotrypsin. These proteins can be inactivated by boiling the seeds.

Chymotrypsin should not be used together with acetylcysteine, a drug used to thin mucus in the lungs. It should also not be used together with anticoagulant (blood thinning) drugs, as it increases their effects. Chloramphenicol, a medication used to treat eye infections, may counteract the effectiveness of chymotrypsin ophthalmic solutions.

Resources

Books

Bland, Jeffrey. Digestive Enzymes. New Canaan, CT: Keats Publishing, Inc., 1993.

Cichoke, Anthony J. The Complete Book of Enzyme Therapy. Garden City Park, NY: Avery Publishing Group, 1999.

Periodicals

Deshimaru, M., R. Hanamoto, C. Kusano, et al. "Purification and Characterization of Proteinase Inhibitors from Wild Soja (Glycine Soja) Seeds." Bioscience, Biotechnology, and Biochemistry 66 (September 2002): 1897-1903.

Fujino, H., T. Aoki, and H. Watabe. "A Highly Sensitive Assay for Proteases Using Staphylococcal Protein Fused with Enhanced Green Fluorescent Protein." Bioscience, Biotechnology, and Biochemistry 66 (July 2002): 1601-1604.

Shrestha, M. K., I. Peri, P. Smirnoff, et al. "Jojoba Seed Meal Proteins Associated with Proteolytic and Protease Inhibitory Activities." Journal of Agricultural and Food Chemistry 50 (September 25, 2002): 5670-5675.

Zintl, A., C. Westbrook, H. E. Skerrett, et al. "Chymotrypsin and Neuraminidase Treatment Inhibits Host Cell Invasion by Babesia divergens (Phylum Apicomplexa)." Parasitology 125 (July 2002): 45-50.

Organizations

American Dietetic Association (ADA). 216 West Jackson Blvd., Suite 800, Chicago, IL 60606. (312) 899-0040. .

Digestive Disease National Coalition (DDNC). 711 Second Street NE, Suite 200, Washington, DC 20002. (202) 544-7497. .

National Digestive Diseases Information Clearinghouse, National Institute of Diabetes and Digestive and Kidney Disease, and National Institutes of Health. 2 Information Way, Bethesda, MD 20892-3570. (310) 654-3810.

[Article by: Judith Sims; Rebecca J. Frey, PhD]

An endopeptidase with action similar to that of trypsin, produced in the intestine by activation of chymotrypsinogen from the exocrine pancreas; a product crystallized from an extract of the pancreas of the ox has been used clinically as an anti-inflammatory agent and for enzymatic zonulolysis and débridement.

• c. test — a test of pancreatic exocrine efficiency depending on the presence of chymotrypsin to split a peptide–para-aminobenzoic acid compound.

Tutor's tip: This word was used in the 2006 Scripps National Spelling Bee finals.

chymotrypsinogen B1
Identifiers
Symbol	CTRB1
Alt. Symbols	CTRB
Entrez	1504
HUGO	2521
OMIM	118890
RefSeq	NM_001906
UniProt	P17538
Other data
EC number	3.4.21.1
Locus	Chr. 16 q23.1

chymotrypsinogen B2
Identifiers
Symbol	CTRB2
Entrez	440387
HUGO	2522
RefSeq	NM_001025200
UniProt	Q6GPI1
Other data
Locus	Chr. 16 q22.3

chymotrypsin C (caldecrin)
Identifiers
Symbol	CTRC
Entrez	11330
HUGO	2523
OMIM	601405
RefSeq	NM_007272
UniProt	Q99895
Other data
Locus	Chr. 1 p36.21

Chymotrypsin (bovine γ chymotrypsin: PDB 1AB9, EC 3.4.21.1) is a digestive enzyme that can perform proteolysis. Chymotrypsin cleaves peptides at the carboxyl side of tyrosine, tryptophan, and phenylalanine because these three amino acids contain aromatic rings, which fit into a 'hydrophobic pocket' in the enzyme. Over time, chymotrypsin also hydrolyzes other amide bonds, particularly those with leucine-donated carboxyls.

Contents 1 Activation of chymotrypsin 2 Action and kinetics of chymotrypsin 3 References 4 External links

Activation of chymotrypsin

Chymotrypsin is synthesized in the pancreas by protein biosynthesis as a precursor called chymotrypsinogen that is enzymatically inactive. On cleavage by trypsin into two parts that are still connected via an S-S bond, cleaved chymotrypsinogen molecules can activate each other by removing two small peptides in a trans-proteolysis. The resulting molecule is active chymotrypsin, a three polypeptide molecule interconnected via disulfide bonds.

Action and kinetics of chymotrypsin

In vivo, chymotrypsin is a proteolytic enzyme acting in the digestive systems of mammals and other organisms. It facilitates the cleavage of peptide bonds by a hydrolysis reaction, a process which albeit thermodynamically favourable, occurs extremely slowly in the absence of a catalyst. The main substrates of chymotrypsin include tryptophan, tyrosine, phenylalanine, leucine, and methionine, which are cleaved at the carboxyl terminal. Like many proteases, chymotrypsin will also hydrolyse ester bonds in vitro, a virtue that enabled the use of substrate analogs such as N-acetyl-L-phenylalanine p-nitrophenyl ester for enzyme assays.

Mechanism of peptide bond cleavage in α-chymotrypsin

Chymotrypsin cleaves peptide bonds by attacking the unreactive carbonyl group with a powerful nucleophile, the serine 195 residue located in the active site of the enzyme, which briefly becomes covalently bonded to the substrate, forming an enzyme-substrate intermediate.

These findings rely on inhibition assays and the study of the kinetics of cleavage of the aforementioned substrate, exploiting the fact that the enzyme-substrate intermediate p-nitrophenolate has a yellow colour, enabling us to measure its concentration by measuring light absorbance at 405 nm.

It was found that the reaction of chymotrypsin with its substrate takes place in two stages, an initial “burst” phase at the beginning of the reaction and a steady-state phase following Michaelis-Menten kinetics.It is also called "ping-pong" mechanism. The mode of action of chymotrypsin explains this as hydrolysis takes place in two steps. First acylation of the substrate to form an acyl-enzyme intermediate and then deacylation in order to return the enzyme to its original state.

References

• Stryer et al. (2002). Biochemistry (5th ed.). New York: Freeman. ISBN 0716746840.
• Garrett & Grisham. (2004). Biochemistry (3rd ed.). Brooks Cole. ISBN 0534490336.

External links

• MeSH Chymotrypsin

v • d • e Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21) Digestive enzymes Enteropeptidase · Trypsin · Chymotrypsin · Elastase (Neutrophil, Pancreatic) Coagulation factors: Thrombin · Factor VIIa · Factor IXa · Factor Xa · Factor XIa · Factor XIIa · Kallikrein (PSA, KLK1, KLK2, KLK3, KLK4, KLK5, KLK6, KLK7, KLK8, KLK9, KLK10, KLK11, KLK12, KLK13, KLK14, KLK15) fibrinolysis: Plasmin · Plasminogen activator (Tissue plasminogen activator · Urinary plasminogen activator) Complement system Factor B · Factor D · Factor I · MASP (MASP1, MASP2) · C3-convertase Other immune system Chymase · Granzyme · Tryptase · Proteinase 3/Myeloblastin Venombin Ancrod · Batroxobin Other Acrosin · Prolyl endopeptidase · Pronase · Proprotein convertases (1, 2) · Reelin · Subtilisin/Furin · Streptokinase · S1P · Cathepsin (A, G)

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