Lysozyme

Lysozymes, also known as muramidase or N-acetylmuramide glycanhydrolase, are is_associated_with::glycoside hydrolases. These are is_associated_with::enzymes that damage bacterial cell walls by catalyzing is_associated_with::hydrolysis of 1,4-beta-linkages between is_associated_with::N-acetylmuramic acid and is_associated_with::N-acetyl-D-glucosamine residues in a is_associated_with::peptidoglycan and between is_associated_with::N-acetyl-D-glucosamine residues in chitodextrins. Lysozyme is abundant in a number of is_associated_with::secretions, such as is_associated_with::tears, is_associated_with::saliva, is_associated_with::human milk, and is_associated_with::mucus. It is also present in is_associated_with::cytoplasmic granules of the is_associated_with::macrophages and the is_associated_with::polymorphonuclear neutrophils (PMNs). Large amounts of lysozyme can be found in egg white. C-type lysozymes are closely related to is_associated_with::alpha-lactalbumin in sequence and structure, making them part of the same family. In humans, the lysozyme enzyme is encoded by the LYZ gene.

Function
The is_associated_with::enzyme functions by attacking is_associated_with::peptidoglycans (found in the cell walls of bacteria, especially is_associated_with::Gram-positive bacteria) and hydrolyzing the glycosidic bond that connects N-acetylmuramic acid with the fourth carbon atom of is_associated_with::N-acetylglucosamine. It does this by binding to the is_associated_with::peptidoglycan molecule in the binding site within the prominent cleft between its two domains. This causes the substrate molecule to adopt a strained conformation similar to that of the transition state. According to Phillips-Mechanism, the lysozyme binds to a hexasaccharide. The lysozyme then distorts the fourth sugar in hexasaccharide (the D ring) into a half-chair conformation. In this stressed state, the glycosidic bond is easily broken.



The amino acid side-chains glutamic acid 35 (Glu35) and aspartate 52 (Asp52) have been found to be critical to the activity of this enzyme. Glu35 acts as a proton donor to the glycosidic bond, cleaving the C-O bond in the substrate, whereas Asp52 acts as a nucleophile to generate a glycosyl enzyme intermediate. The glycosyl enzyme intermediate then reacts with a water molecule, to give the product of hydrolysis and leaving the enzyme unchanged.



Role in disease
Lysozyme is part of the innate immune system. Reduced lysozyme levels have been associated with is_associated_with::bronchopulmonary dysplasia in newborns. Children fed infant formula lacking lysozyme in their diet have three times the rate of diarrheal disease. Since lysozyme is a natural form of protection from gram-positive pathogens like is_associated_with::Bacillus and is_associated_with::Streptococcus, a deficiency due to infant formula feeding can lead to increased incidence of disease. Whereas the skin is a protective barrier due to its dryness and acidity, the is_associated_with::conjunctiva (membrane covering the eye) is, instead, protected by secreted enzymes, mainly lysozyme and is_associated_with::defensin. However, when these protective barriers fail, is_associated_with::conjunctivitis results.

In certain cancers (especially myelomonocytic leukemia) excessive production of lysozyme by cancer cells can lead to toxic levels of lysozyme in the blood. High lysozyme blood levels can lead to kidney failure and low blood potassium, conditions that may improve or resolve with treatment of the primary malignancy.

History
The antibacterial property of hen egg white, due to the lysozyme it contains, was first observed by is_associated_with::Laschtschenko in 1909, although it was not until 1922 that the name 'lysozyme' was coined, by is_associated_with::Alexander Fleming (1881–1955), the discoverer of is_associated_with::penicillin. Fleming first observed the antibacterial action of lysozyme when he treated bacterial cultures with nasal mucus from a patient suffering from a is_associated_with::head cold.

The three-dimensional structure of hen egg white lysozyme was described by is_associated_with::David Chilton Phillips (1924–1999) in 1965, when he obtained the first 2-is_associated_with::ångström (200 pm) resolution model via X-ray crystallography. The structure was publicly presented at a Royal Institution lecture in 1965. Lysozyme was the second protein structure and the first enzyme structure to be solved via X-ray diffraction methods, and the first enzyme to be fully sequenced that contains all twenty common amino acids. As a result of Phillips' elucidation of the structure of lysozyme, it was also the first enzyme to have a detailed, specific mechanism suggested for its method of catalytic action. This work led Phillips to provide an explanation for how is_associated_with::enzymes speed up a chemical reaction in terms of its physical structures. The original mechanism proposed by Phillips was more recently revised.

Chemical synthesis
The first chemical synthesis of a lysozyme protein was attempted by Prof. George W. Kenner and his group at the University of Liverpool in England. This was finally achieved in 2007 by Steve Kent at the University of Chicago who made synthetic functional lysozyme molecule.