Target type: molecularfunction
Catalysis of the reaction: 2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O = ribonucleoside diphosphate + thioredoxin. Thioredoxin disulfide is the oxidized form of thioredoxin. [EC:1.17.4.1]
Ribonucleoside-diphosphate reductase (RNR) activity with thioredoxin disulfide as acceptor is a crucial step in the synthesis of deoxyribonucleotides, the building blocks of DNA. RNR catalyzes the reduction of ribonucleoside diphosphates (RDPs) to deoxyribonucleoside diphosphates (dRDPs) by transferring a hydrogen atom from a reducing agent to the 2'-hydroxyl group of the ribose moiety. This reaction is essential for DNA replication and repair.
In this specific reaction, thioredoxin disulfide acts as the direct electron donor to the RNR active site. Thioredoxin is a small, ubiquitous protein that exists in a reduced (dithiol) and oxidized (disulfide) form. In its reduced form, thioredoxin binds to the RNR enzyme and delivers electrons from NADPH, a reducing agent generated by the pentose phosphate pathway. This electron transfer reduces a cysteine residue in the RNR active site, initiating the catalytic cycle.
The reduction of RDPs to dRDPs involves a complex series of steps, including radical generation, substrate binding, and hydrogen atom transfer. The RNR active site contains a tyrosine radical, which is generated by a unique mechanism involving a diiron center and a complex network of electron transfers. The tyrosine radical then initiates a chain reaction that ultimately leads to the reduction of the RDP substrate.
The thioredoxin-dependent RNR activity is highly regulated to ensure proper DNA synthesis and prevent uncontrolled cell proliferation. The enzyme activity is regulated by factors such as substrate availability, redox potential, and protein phosphorylation. Dysregulation of RNR activity can lead to DNA replication errors and cell cycle dysregulation, potentially contributing to cancer development.
Overall, ribonucleoside-diphosphate reductase activity with thioredoxin disulfide as acceptor plays a vital role in DNA synthesis, ensuring the accurate replication of genetic information and maintaining genome integrity.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| Ribonucleoside-diphosphate reductase subunit M2 B | A ribonucleoside-diphosphate reductase subunit M2 B that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q7LG56] | Homo sapiens (human) |
| Ribonucleoside-diphosphate reductase subunit M2 | A ribonucleoside-diphosphate reductase subunit M2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P31350] | Homo sapiens (human) |
| Ribonucleoside-diphosphate reductase large subunit | A ribonucleoside-diphosphate reductase large subunit that is encoded in the genome of human. [PRO:DNx, UniProtKB:P23921] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| hydroxyurea | one-carbon compound; ureas | antimetabolite; antimitotic; antineoplastic agent; DNA synthesis inhibitor; EC 1.17.4.1 (ribonucleoside-diphosphate reductase) inhibitor; genotoxin; immunomodulator; radical scavenger; teratogenic agent | |
| uridine diphosphate | Uridine Diphosphate: A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. | pyrimidine ribonucleoside 5'-diphosphate; uridine 5'-phosphate | Escherichia coli metabolite; mouse metabolite |
| cytidine diphosphate | Cytidine Diphosphate: Cytidine 5'-(trihydrogen diphosphate). A cytosine nucleotide containing two phosphate groups esterified to the sugar moiety. Synonyms: CRPP; cytidine pyrophosphate. | cytidine 5'-phosphate; pyrimidine ribonucleoside 5'-diphosphate | Escherichia coli metabolite; mouse metabolite |
| 1-aminoadenosine | 1-aminoadenosine: structure | ||
| 3-aminopyridine-2-carboxaldehyde thiosemicarbazone | 3-aminopyridine-2-carboxaldehyde thiosemicarbazone: a neuroprotective agent; structure given in first source |