RNR

• RNR = ribonucleotide reductase; enzyme that takes ribonucleotides and converts them to deoxyribonucleotides
• all de novo DNA comes from RNA, since RNR is what creates the deoxyribonucleotides (note though that dUDP and must be converted to TDP)
• RNR uses radical chemistry, where an initial cysteine thiyl radical starts the whole process
• Cys radical -> 3' radical on the nucleotide -> protonate the 2' OH using a hydrogen from one of the enzyme's cysteines -> water leaves, forming a carbon cation on the 2' that is stabilized by the 3' radical -> then using the other cysteine in the pair on the enzyme, the 2' gets reduced by hydride transfer
• the three classes of RNR differ in the way that they generate the cysteine radical; otherwise they use the same catalytic method
• RNR Classes and their radical sources:

  1. RNR Class I: uses a tyrosine radical in the beta subunit that hops through a series of events to form cysteine thiyl radical in active site of alpha subunit
  2. RNR Class II: uses adenosylcobalamin (vitamin B12) to generate an Ado radical that directly makes the cysteine thiyl radical
  3. RNR Class III: uses a partner enzyme GRE (glycyl radical enzyme) that has a glycyl radical to transfer to cysteine; the glycyl radical comes from a SAM radical enzyme, so ultimately the radical comes from Ado radical
• how regenerate the reduced cysteines on the RNR enzyme?

  they get re-reduced by thioredoxin, which gets re-reduced by thioredoxin reductase, which ultimately gets reduced by NADPH (through FADH2)