Question

Explain the importance of reduced glutathione to the mature red blood cell . Please include
a. what GSH does for the cell
b. how it does this (a)
c. what happens when one cannot make reduced glutathione.

Answer 1

a. Reduced glutathione or GSH scavenges the free oxygen radicals that may be present on membranes of red blood cells. Thus, it protects the RBC from oxidative damage by neutralizing the reactive oxygen species formed. GSH is a tripeptide that has a free sulfhydryl groups that can be oxidized or reduced and therefore can function as a redox buffer. RBCs are especially sensitive to oxidative damage as they carry oxygen to different part of the body via its interaction with hemoglobin. 3% hemoglobin is oxidized by human body to methemoglobin every day, which leads to superoxide radical formation. Oxidative stress causes damage to proteins within a cell and will also trigger apoptosis. RBCs cell membrane has polyunsaturated fatty acids, which are highly susceptible to oxidative damage as well. GSH prevents the oxidative stress and will therefore lead to increase survival of RBCs by maintaining normal structure of RBCs. GSH also maintains hemoglobin in its ferrous state. GSH also reacts with hydrogen peroxidase and thus, helps in detoxification.

b. GSH is present in reduced form in RBCs in very high amounts. NADPH synthesized in pentose phosphate pathway converts oxidized GSSG (oxidized glutathione) to reduced glutathione (GSH). GSSG is the oxidized form of glutathione. Thus, NADPH in red blood cells can reduce GSSG to GSH. by actions of the enzyme flavoprotein glutathione reductase. NADPH provides electrons, which are indirectly transferred to oxidized GSSG. In this indirect transfer of electrons, NADP transfers the electrons to first to FAD which is attached tightly to the enzyme. These electrons from FAD are then transferred to disulphide bridge formed between two cysteine residues of the enzyme. Finally, these enzymes will be transferred to GSSG to form GSH. GSH will then act as sulphydryl buffer. GSH will maintain the cysteine amino acids present in hemoglobin and other proteins present in RBCs.

c. When red blood cells have a deficiency that inhibits formation of GSH, the red blood cells will undergo hemolysis. This is due to increased susceptibility to reactive oxidative stress, which then forms H202 and other peroxides. GSH is known to eliminate peroxides as it is a reducing agent. Deficiency of GSH causes the sulphydryl groups that are present in hemoglobin to be oxidized. As a result, crosslinking of hemoglobin is observed, which results in formation of aggregates. Such aggregates of hemoglobin induced by GSH are known as Heinz bodies and are deposited on RBC cell membrane. As a result, the cell membrane will be damaged; causing lysis of RBCs. Hence, the individual is susceptible to develop hemolytic anemia. Deficiency of glucose-6 phosphate dehydrogenase is known to inhibit GSH production as its ingestion of fava beans.