Enzyme Responsible for Ribonucleotide Reduction and Source of Reducing Equivalents
Ribonucleotide reductase (RNR) is the enzyme directly responsible for reducing ribonucleotides to deoxyribonucleotides, and NADPH serves as the ultimate source of reducing equivalents (hydrogen atoms) for this reaction. 1, 2
Enzyme Identity and Function
Ribonucleotide reductase is the unique enzyme exclusively responsible for converting ribonucleotides into their corresponding deoxyribonucleotides, which are essential building blocks for DNA synthesis and repair. 1, 2, 3, 4
- RNR is a multisubunit enzyme composed of two dimeric proteins (R1 and R2 subunits), both of which are necessary for catalytic activity. 4, 5
- This enzyme catalyzes the rate-limiting reaction that provides precursors for DNA replication, making it essential for cell proliferation. 5
- RNR is classified as an iron-containing, non-heme, non-iron-sulfur protein involved in DNA synthesis and repair at the cellular level. 6
Electron Transfer Chain for Reduction
The reduction of ribonucleotides to deoxyribonucleotides involves a specific electron transfer pathway:
- NADPH provides the reducing equivalents (hydrogen atoms) that are ultimately transferred to the ribonucleotide substrate. 6
- The electron transfer occurs through an intermediate carrier system, typically involving thioredoxin or glutaredoxin as electron donors to RNR. 1
- These intermediate proteins receive electrons from NADPH through their respective reductases (thioredoxin reductase or glutathione reductase). 1
Clinical and Biological Significance
RNR represents a critical target for cancer therapy because dysregulated RNR activity is associated with genomic instability, malignant transformation, and tumor cell growth. 1, 2
- Increased RNR activity has been directly linked to malignant transformation and enhanced tumor cell proliferation. 1
- Multiple RNR inhibitors including Triapine, Gemcitabine, and GTI-2040 have entered clinical trials or received approval for cancer treatment. 1
- The enzyme's essential role in DNA synthesis makes it an attractive chemotherapeutic target, with inhibitors showing efficacy against non-small cell lung cancer, pancreatic adenocarcinoma, bladder cancer, leukemia, and various solid tumors. 4
Regulatory Mechanisms
RNR activity is tightly controlled through multiple mechanisms:
- Transcriptional activation of gene expression regulates RNR subunit production. 5
- Post-transcriptional mechanisms alter mRNA stability through sequences in the 3'-untranslated region of R1 and R2 messages. 5
- Growth factors, cytokines, and tumor promoters can modulate mRNA message stability, thereby influencing RNR expression levels. 5