MCQ on Metabolism of Red Blood Cells: Biochemistry, Microbiology

Q) Which of the following is a FALSE statement about the fate of the glycolytic pathway in erythrocytes?
a) Glycolysis is the sole source of ATP (adenosine triphosphate) in erythrocytes.
b) Deficiency of pyruvate kinase leads to hemolytic anemia.
c) Pyruvate generated during glycolysis is converted to lactate.
d) Pyruvate generated during glycolysis is converted to acetyl CoA and enters the TCA cycle (tricarboxylic acid cycle) in mitochondria.

(Correct Answer: Please find it at the end of this text)

The objective of the MCQ above is to discuss
- Shape and morphology of Red blood cell
- The fate of glucose in red blood cells
- Metabolic control of glucose metabolism

• Red blood cells are bone marrow-derived non-dividing cells that contain hemoglobin (95% of intracellular protein) and help to transport oxygen from the lungs to peripheral tissue. 
• The RBCs help in the disposal of carbon dioxide and a proton from the peripheral tissue, they are biconcave in the structure, this type of structure increases the surface-to-volume ratio and facilitates gas exchange. 
• Morphologically, red blood cells are anucleate and lack organelles such as mitochondria, lysosomes, or Golgi apparatus thus relying solely on glycolysis for ATP (adenosine triphosphate) production. 

Although biosynthetic pathways do not occur in RBC, ATP and NADPH are required for the maintenance of cellular structure. The energy is utilized by anion-exchange proteins, NA+ K+ ATPase, other transporter proteins to maintain cellular homeostasis. 

The glycolytic pathway occurs in cytosol and pyruvate, it can be converted to lactate and regenerate the NAD required for the continuation of the glycolytic pathway. These characteristics of the glycolytic pathway makes glucose which is a suitable source of energy in red blood cells.

In red blood cells, glucose can enter into two different pathways;

• Glycolysis
• Pentose phosphate pathway

Glycolysis (Embden-Meyerhof Pathway) :

It is the main pathway for glucose metabolism in glycolysis. Glucose is converted into pyruvate with the generation of net two molecules of ATP (adenosine triphosphate) and two molecules of NADH (nicotinamide adenine dinucleotide phosphate). The glycolytic pathway is activated when the cellular ATP level is decreased. These ATPs are utilized by various ion transporter to maintain the integrity of the cells. 

The hemoglobin in red blood cells binds to oxygen and deliver to the target tissues. Auto-oxidation of iron-containing hemoglobin and propagation of electrons leads to a generation of free radicals that are toxic to the tissues. The red blood cell consists of enzymes such as catalase, superoxide dismutase. 

Superoxide dismutase, glutathione requiring enzyme, converts superoxide to hydrogen peroxide and catalase converts hydrogen peroxide into water and oxygen. Superoxide dismutase enzyme activity depends on the availability of reduced glutathione. 

The glutathione peroxidase catalyzes the cycling of reduced glutathione at an expense of NADPH. 

The pentose phosphate pathway (Hexose monophosphate shunt):

This pathway is a alternative metabolic pathway for glucose metabolism in red blood cells. It generates NADPH that is utilized by RBC for converting toxic superoxide radicals to non-toxic oxygen and water. An essential step for maintaining the redox balance within the cell and protecting against oxidative stress.

The pentose phosphate pathway has two distinct phases: the oxidative phase and the non-oxidative phase. In the oxidative phase, glucose-6-phosphate is converted into ribulose-5-phosphate, generating NADPH and releasing carbon dioxide. The non-oxidative phase involves a series of reversible reactions that interconvert various sugar phosphates, which can be used for nucleotide synthesis or fed back into the glycolytic pathway.


                         
               Figure1: The fate of glucose in red blood cells



Figure 2: Glutathione NADPH cycle in RBC.
SOD- Superoxide dismutase, GSH- Glutathione, GPX-Glutathione peroxidase, G6PD-Glucose-6-phosphate dehydrogenase, CAT- Catalase

Glycolysis and the pentose phosphate pathway, play important roles in red blood cell metabolism, providing energy in the form of ATP and generating NADPH for redox reactions and oxidative stress defense.

Results of defective enzymes of the pathways:

Defective enzymes in glycolytic pathway or pentose phosphate pathway can adversely affect the cellular integrity of red blood cells by two distinct mechanisms. 

When enzymes in the glycolytic pathway are defective, it can result to reduced ATP production, a decrease in the activity of ATP-dependent ions channels, dysregulation of ions, and cellular lysis. 

On the other hand, the defect in the enzyme of the pentose phosphate pathway (e.g. glucose-6-phosphate dehydrogenase) leads to decreased NADPH, decreased activity of NADPH dependent enzymes, the accumulation of toxic free radicals ultimately leading to hemolytic anemia.

Answer D is the correct answer ( Red blood cells lack mitochondria which is required for the conversion of pyruvate to acetyl CoA)