Dirty Medicine: Biochemistry Series - Part 2

Overview

• Continuation of the mini-series focused on the HMP Shunt and its connection to glutathione reductase.
• Part 1 discussed the generation of NADPH by the HMP shunt.
• Part 2 will complete the understanding by focusing on glutathione and free radicals.

Glutathione Reductase Pathway

• Purpose: To reduce glutathione, often referred to as the glutathione or free radical pathway.
• Objective: Reduce oxidized glutathione to process and detoxify free radicals and peroxides.

Key Concepts

• Reduced Glutathione: Essential for detoxifying free radicals and peroxides.
• NADPH from the HMP shunt is used in the glutathione reductase pathway to reduce glutathione.
• Cycle Interaction: Constant interaction between the HMP shunt and glutathione pathway.

Biochemical Process

• Starting Point: Oxidized glutathione.
• Enzyme: Glutathione reductase reduces oxidized glutathione to its reduced form.
• Function: Reduced glutathione detoxifies free radicals and converts peroxide into water.

Importance

• Inability to detoxify free radicals leads to cellular damage.
• NADPH is essential for reducing glutathione—sourced from the HMP shunt.
• Continuous Cycle: NADPH is turned back into NADP+ in the reduction process.

Pathway Connection

• Glucose 6-phosphate Dehydrogenase: Converts glucose 6-phosphate in glycolysis to generate NADPH.
• Glutathione Reductase: Uses NADPH to reduce glutathione.
• Continuous interaction between pathways ensures handling of oxidative stress.

Oxidative Stress and Deficiency

• Consequences of lacking NADPH:
  • Decrease in reduced glutathione.
  • Increase in oxidative stress and potential for disease.
• Causes of Oxidative Stress:
  • Sulfa drugs, primaquine, infections, nitrofuran antibiotics, favism (favabeans).
  • Mnemonic: SPIN F (Sulfa, Primaquine, Infections, Nitrofurantoin, Favism).

G6PD Deficiency

• X-linked recessive disorder.
• Results:
  • Lack of glucose 6-phosphate dehydrogenase means no NADPH is generated.
  • Leads to severe oxidative damage.
• Clinical Manifestations:
  • Heinz bodies: Denatured hemoglobin clumps in RBCs.
  • Bite cells: Result from macrophages removing Heinz bodies.

Mnemonic for G6PD Deficiency

• 6G PD: Imagine a "6G order pounder with Heinz ketchup".
  • Bite: Refers to bite cells.
  • Heinz: Refers to Heinz bodies.

Summary

• HMP Shunt and glutathione reductase pathway work in synergy to manage oxidative stress.
• Understanding this cycle is critical for biochemical studies, particularly for medical exams like USMLE and COMLEX.
• Revise and watch related material to solidify understanding.