Ligandin

Apart from their catalytic function, at least one form of glutathione-5-trans-ferases has the function of simply binding xenobiotics and transporting them, without metabolism. In effect, this is an example of storage (see Section 2.3.3). The form in question is termed ligandin, and binding is associated with one particular subunit. Binding is not associated with catalytic activity. 

Ligandin A form of glutathione-5-transferase with a marked capacity for binding certain lipophilic xenobiotics. 

Le Trong I, Stenkamp RE, Ibarra C, Atkins WM, Adman ET. 1.3-A resolution structure of human glutathione N-transferase with N-hexyl glutathione bound reveals possible extended ligandin binding site. Proteins 2002 48 618-27. 

Once bilirubin enters the hepatocytes, it can bind to certain cytosolic proteins, which help to keep it solubilized prior to conjugation. Ligandin (a family of glutathione S-transferases) and protein Y are the involved proteins. They may also help to prevent efflux of bilirubin back into the blood stream. 

Figure 32-15. Diagrammatic representation of the three major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins of hepatocytes, such as ligandin (a family of glutathione S-transferase) and Y protein, bind intracellular bilirubin and may prevent its efflux into the blood stream. The process affected in a number of conditions causing jaundice is also shown.

Litwack G, Ketterer B, Arias IM (1971) Ligandin a hepatic protein which binds steroids, bilirubin, carcinogens and a number of exogenous organic anions. Nature 234 466 167 Lubchenco J, Gaines SD (1981) A unified approach to marine plant-herbivore interactions. 

Unconjugated bilirubin is taken into the hepatocytes by binding to membrane transport proteins and transported through the liver cells to the SER by proteins called ligandins. The SER is the location of a specific bilirubin-UDP-glucuronosyl transferase... 

Thus some of the compounds bound to ligandin are not substrates for the transferase activity (GSTA1, GSTA2). 

Z Uptake of bilirubin by the liven Bilirubin is only slightly soluble in plasma and, therefore, is transported to the liver by binding non-covalently to albumin. [Note Certain anionic drugs, such as salicylates and sulfonamides,1 can displace bilirubin from abu-min, permitting bilirubin to enter the central nervous system (CNS). This causes the potential for neural damage in infants.] Bilirubin dissociates from the carrier albumin molecule and enters a hepatocyte, where it binds to intracellular proteins, particularly the protein ligandin. 

Tipping, E., Ketterer, B., and Christodoulides, L. (1979). Interactions of small molecules with phospholipid bilayers. Binding to egg phosphatidylcholine of some organic anions (bromosulphophthalein, oestrone sulphate, haem and bilirubin) that bind to ligandin and aminoazo-dye-binding prot [Pg.414]

In about 90% of all neonates, jaundice occurs after the first 2-5 days of life and rarely exceeds 6 mg/dl serum bilirubin. In premature infants, bilirubin levels can rise to 10-12 mg/dl. The cause is related to a number of factors .) reinforced degradation of haemoglobin as a result of the short erythrocyte survival span of 70-90 days (120 days in adults), (2.) reduction in cellular transport proteins, above all ligandin, (i.) deficiency of uri-dyltransferase and glucuronosyltransferase, and (4.) increasing intestinal absorption of meconium bilirubin. 

The affinity of liver and kidney for a number of chemicals is also considerable. A protein in the liver, ligandin, has a remarkable degree of affinity for organic acids it plays a role in the transfer of these chemicals from blood into liver. Both liver and kidney may become storage depots for metals, like cadmium and zinc, due to the presence of small binding proteins called metallothioneins. When the binding capacity of these proteins is exceeded, local toxicity may appear, as is the case for cadmium in the kidney. 

In addition to their catalytic role GSH-S-transferases also serve a binding function in the cell, having a relatively high affinity for several endogenous materials as well as potentially harmful foreign compounds. This is typically referred to as ligandin activity and undoubtedly results in part from the non-specificity of the hydrophobic binding site of the enzyme. 

The primary blocks to bilirubin metabolism are low activity of bilirubin glucuronyltransferase and low concentration of ligandin in the liver at birth. Secretion of conjugated bilirubin into the bile is also reduced. 

Glutathione transferases catalyze a substitution reaction at electrophilic centers of molecules. They are also binding proteins in analogy with the E4 esterase a mammalian form, called ligandin, binds with high affinity to a broad spectrum of compounds but does not catalyze the subsequent substitution reaction (38). The role of the transferases in the catalytic reaction is thought to be to provide close proximity between the xenobiotic and the reduced glutathione anion, GS-. 

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