Amino Sugars
Description
Amino sugars are essential components of all body tissues, being integral parts of cell membranes and their surface structures, and of interstitual tissue which holds cells together. About half of the interstitual tissue components are derived from amino sugars.
An amino sugar is made up of a sugar and an amino acid. While most sugars come from dietary sources and are burned for energy, amino sugars are mainly formed in the body and used in manufacturing tissue components. Normal wear and tear during body functions means that tissues are constantly broken down and rebuilt or restructured, thus amino sugars are steadily recycled. Loss during such turnover will be made by synthesis from glucose, since dietary supplies of amino sugars are usually low.
Tissues Containing Amino Sugars
Tissues cells are arranged in patterns and held in place by the ubiquitous interstitium which is a fine network of collagen fibres in which giant molecules of Proteoglycans (PG) are interspersed. This gives a neatly packed gel-like structure which resists compression and regulates movement of molecules like nutrients and waste products among cells. PG structures vary according to the type of tissues, and are manufactured locally as required.
Basement membranes (BM) are ultrathin sheets enveloping blood vessels and tissues; their PG component affects their permeability and hence controls molecular traffic between blood vessels and tissue cells.
Glycocalyx is a third important product containing amino sugars. It is a very thin layer of glycoprotein covering the mucous membrane lining of the digestive and urinary tracts and air tubes, and is indeed fused into the cell membrane, so it functions as the ultimate barrier and filter between the mucosal cells and the contents of the tracts concerned (e.g. food, urine, etc).
A wide variety of other tissues contain PG and glycoproteins. Chitin, found in the hard shells of insects and shell fish and hair in mammals, is a special example of polymer formation (a number of similar molecules strung up together). It is made up almost entirely of N-acetyl-glucosamine (NAG), just as cellulose is a polymer exclusively of glucose. In fact, cellulose is the most abundant organic matter in the biosphere (accounting for more than half of the total carbon there), while chitin is not far behind.
Amino sugars and disease
There is suggestive evidence certain disease processes are related to PG abnormalities. Thus in diabetes mellitus, the basement membranes are thickened and poorly formed and deficient in sialic acid (a PG). This narrows and weakens the wall of small arteries and capillaries, thereby impairing blood circulation. Depending on the tissues involved, this may cause cold and painful limbs, poor vision, or nerve degeneration (neuropathy). Furthermore, the kidneys lack adequate glomerular polyanion which is rich in sialic acid; this affects the "pore size" of the filtering mechanism, so that in diabetic nephropathy large molecules like proteins may "leak through" into the urine. The kidneys in patients with Nephrotic Syndrome (a primary kidney disease) are also deficient in glomerular polyanion, and there is heavy protein loss in the urine. However, this conditon is unrelated to diabetes mellitus and the BM is normal.
In Cystic Fibrosis, thick and sticky mucus tends to block smaller tubes lined by mucous membrane, such as the pancreatic duct and the smaller brances of the respiratory tract. Such obstructon encourages infecton and cystic formation of the passages behind the block.
Normally, the lining mucosal cells of the digestive tract have a high turnover rate, so the whole layer of surface cells may be renewed in 3-4 days. In patients with chronic inflammatory bowel disease (IBS) like ulcerative colitis and Crohn's disease, this renewal rate is even faster, and much amino sugars are required in this rapid cell growth. However, under these circumstances, a supply of NAG is taken up and made use of at a speed three times that of plain glucosamine. This suggests that in IBS, rates of glucosamine conversion into NAG within the intestinal cells cannot keep pace with the excessive demand, and pre-formed NAG may serve better.
Infants born 6 weeks or more prematurely have a 50% chance of developing brain hemorrhage from capillaries weakened by poorly formed basement membrane and supporting tissues. These structures, as mentioned earlier, are rich in hyaluronate and PG. So are heart valves, which are also not uncommonly deformed in preterm babies. 17-alpha-hydroxyprogesterone, a placental product, stimulates producton of hyaluronate and PG.
Unlike essential amino acids which are needed by all cells, amino sugars are more specific to tissues. Thus any deficiency (due, for example, to a missing enzyme in a particular sequence) may affect only a few types of cells.
Method of Action
Glucose is first combined with glutamine with help of a key enzyme (glucosamine synthetase) which regulates the whole production line. An acetyl group is next added, and the final product is trimmed into N-acetyl-glucosamine (NAG).
Amino sugars have asymmetrical molecules, so those with the same constituent atomes (called epimers) may have different shapes, functions and names. Thus NAG, N-acetyl-galactosamine and N-acetyl-mannosamine are epimers. One epimer may be changed into another through enzyme action, and NAG is the cheif precursor of the whole family of amino sugars.
Amino sugars variously combine with proteins, lipids (fats) or long chains of other sugar units to form huge molecules (macromolecules) which become part of basic tissue components.
Glycoproteins are proteins with one or more oligosaccharide chains, each comprising about a dozen sugar units, which significantly modify the properties of these proteins. Such chains are attached onto newly formed proteins through an NAG or N-acetyl-galactosamine linkage. Some glyco-proteins are important components of many enzymes and hormones; others remain on cell surfaces where their "antennae" of oligosaccaride chains perform special functons, e.g. as binding sites for circulating hormones and for recognition between cells. The grouping of different cells to form a tissue depends on proper recognition of one cell surface by another. The sugar chains may also determine the antigenic property of the glycoprotein so that the immune system can identify the body's own cells from foreign ones. Mucus is a special glycoprotein with a high sugar content which accounts for its very viscous nature.
Glycolipids, the sugar-containing lipids, are essential components of cell membranes, where once again the oligosaccaride chains are always on the outer surface of the cell; the number of such chains varies with different cells.
Hyaluronic acid (hyaluronate) is a string of alternate molecules of glucuronic acid (made from oxidation of glucose) and NAG. It forms long straight chains which attract water to produce a gel-like structure.
Glycosaminoglycans (GAG), also called mucopolysaccharide, each has an extended protein "backbone" to which different types of oligosaccaride chains are attached like the bristles to the wire core of a bottle brush. The sugar chains are made up largely of molecules of NAG or N-acetyl galactosamine alternating with molecules of glucuronic acid or its epimer. GAG's also swell up greatly in water.
Proteoglycans (PG) are huge molecular complexes in each of which the core protein of multiple GAG molecules are themselves attached to a long strand of hyaluronate along its length (much like the bottle brush analogy except the GAG molecules themselves are now the bristles). The whole structure has a molecular weight of millions, and makes up much of the tissues between cells. Some 95% of a PG molecule is carbohydrate.
Therapeutic Approaches
Cells from different tissues have their own normal life spans and turnover rates, and there are maximum rates which cannot be exceeded without peril. Tissues damaged by disease need repair. This poses extra demands on biosynthetic processes as well as supply of raw material, and may lead to defective manufacture of both cell structures and the matrix supporting them, allowing leakage of proteins from cells (to where they are considered "foreign") and formation of antibodies against them. A kind of "civil war" follows.
Ways of correction include slowing down the cell machinery to manageable levels, or increasing the supply of raw material. Lowering the cell turnover rate is artificial; it is in a sense contrary to nature and the real need of the circumstances (where more cells are needed for repair processes), and may involve the use of efficient but potentially toxic substances like immunosuppressive drugs (such as certain anti-cancer agents) or corticosteroids. Increasing the supply of ready-made building material, for example using a N-acetyl glucosamine (NAG) supplement, may help to some extent and is entirely harmless. NAG is readily absorbed from the intestines, stays in the blood for several hours, and is exclusively used for cell structures, thus it is a potentially useful supplement.
References
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