Q.98 2-Deoxyglucose (2-DG) inhibits the proliferation of cells and hence finds use as an
anti-cancer agent. It is also used in COVID therapy, where it blocks
hyperproliferation of virus-infected cells. Mechanistically, 2-DG blocks glycolysis
by inhibiting the activities of which of the following enzyme/s?
(A) Hexokinase
(B) Glucose 6-phosphate isomerase
(C) Glucose-6 phosphate dehydrogenase
(D) Phosphofructokinase
2-Deoxyglucose (2-DG) primarily inhibits glycolysis by targeting hexokinase and glucose-6-phosphate isomerase through competitive mechanisms and product accumulation. This makes option (A) and (B) correct for the question on enzymes blocked by 2-DG in anti-cancer and COVID therapy contexts. Understanding these interactions is key for CSIR NET Life Sciences preparation.
Glycolysis Pathway Overview
Glycolysis converts glucose to pyruvate in 10 enzymatic steps, generating ATP and NADH. Key early enzymes include hexokinase (step 1: glucose to glucose-6-phosphate), glucose-6-phosphate isomerase (step 2: glucose-6-phosphate to fructose-6-phosphate), and phosphofructokinase (step 3: fructose-6-phosphate to fructose-1,6-bisphosphate). Glucose-6-phosphate dehydrogenase initiates the pentose phosphate pathway, not core glycolysis. 2-DG, a glucose analog lacking the 2-hydroxyl group, enters cells via GLUT transporters and disrupts this pathway.
Option Analysis
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(A) Hexokinase: Correct. 2-DG is phosphorylated by hexokinase to 2-deoxyglucose-6-phosphate (2-DG6P), which accumulates and competitively inhibits hexokinase, blocking further glucose phosphorylation.
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(B) Glucose 6-phosphate isomerase: Correct. 2-DG6P cannot be isomerized to the fructose form due to the missing 2-OH group, directly inhibiting this enzyme and halting glycolysis progression.
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(C) Glucose-6-phosphate dehydrogenase: Incorrect. This enzyme acts in the pentose phosphate pathway; 2-DG primarily affects glycolysis, not this branch.
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(D) Phosphofructokinase: Incorrect. No direct inhibition by 2-DG or 2-DG6P; upstream blocks prevent substrate reach.
Mechanism Details
2-DG mimics glucose, undergoing phosphorylation by hexokinase II (prevalent in cancer cells) to form 2-DG6P. This traps the charged molecule intracellularly, depleting phosphate and ATP while inhibiting hexokinase allosterically and competitively. 2-DG6P also binds poorly to glucose-6-phosphate isomerase (phosphoglucoisomerase), causing backlog and energy starvation, which is amplified in glycolytic cancer or virus-infected cells. This explains its anti-proliferative effects without broad toxicity to normal cells.
2-Deoxyglucose (2-DG) serves as a potent glycolysis inhibitor, primarily blocking 2-deoxyglucose glycolysis inhibition through hexokinase and glucose-6-phosphate isomerase in cancer cells and virus-infected cells during COVID therapy. This glucose analog exploits the Warburg effect in tumors, reducing ATP and proliferation.
Therapeutic Applications
Cancer cells rely on aerobic glycolysis for rapid growth, making 2-deoxyglucose glycolysis inhibition ideal for anti-cancer use. 2-DG curbs hyperproliferation in solid tumors like glioblastoma and was approved in India for COVID-19 as an adjunct, alleviating oxygen needs by starving infected cells. Preclinical data show synergy with radiotherapy and chemotherapeutics .
Biochemical Inhibition Steps
2-DG enters via GLUT1/4, gets phosphorylated by hexokinase to 2-DG6P, which inhibits hexokinase via feedback and stalls glucose-6-phosphate isomerase, preventing fructose-6-phosphate formation. Downstream enzymes like phosphofructokinase remain unaffected directly.
| Enzyme | Role in Glycolysis | 2-DG Effect |
|---|---|---|
| Hexokinase | Glucose → G6P | Phosphorylates 2-DG; 2-DG6P inhibits competitively |
| Glucose-6-P Isomerase | G6P → F6P | 2-DG6P poor substrate; direct block |
| G6P Dehydrogenase | PPP entry | No significant inhibition |
| Phosphofructokinase | F6P → F1,6BP | Upstream block prevents activation |
Exam Relevance
For CSIR NET Life Sciences, recognize dual inhibition (A & B) as the mechanism; single options mislead. Cancer’s glycolytic dependence amplifies 2-DG’s selectivity.
