Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of Amino Acids and Nucleotides
Ribonucleotides serve as precursors for deoxyribonucleotides

The Building Blocks of DNA, deoxynucleotides, are formed from the corresponding ribonucleotides through reactions in which the D-ribose moiety of the ribonucleotide is reduced at the 2' carbon atom to yield a 2'-deoxy derivative. In this manner, for example, adenosine diphosphate (ADP) is reduced to 2'-deoxyadenosine diphosphate (dADP), and GDP to dGDP. The reduction of the D-ribose portion of ribonucleoside diphosphate molecules to 2'-deoxy-D-ribose requires a pair of hydrogen atoms. These hydrogen atoms ultimately originate from NADPH, but a specialized hydrogen-carrier protein, thioredoxin, participates in their transfer. The thioredoxin molecule contains two SH groups, which facilitate The transfer of hydrogen atoms from NADPH to the ribonucleoside diphosphate. The oxidized, or disulfide, form of thioredoxin is reduced by NADPH in a reaction catalyzed by thioredoxin reductase. Subsequently, the reduced thioredoxin reduces the nucleoside diphosphate (NDP) to deoxyribonucleoside diphosphate (dNDP) in a reaction catalyzed by Ribonucleotide reductase (Fig. 22-22)

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DNA contains thymidylate (dTMP) residues instead of the uridylate (UMP) residues found in RNA (Section 14.18). These are generated as follows: first, deoxyuridine diphosphate (dUDP), derived from uridine diphosphate (UDP), is hydrolyzed to form dUMP

dUDP + Н₂О → dUMP + Р_і,

and then dUMP is converted into deoxythymidylate (dTMP) via methylation by N⁵, N¹⁰-methylenetetrahydrofolate in a reaction catalyzed by thymidylate synthase

dUMP + N⁵,N¹⁰-methylenetetrahydrofolate → dTMP + Dihydrofolate.

dTMP is phosphorylated to yield dTDP

dTMP + ATP → dTDP + ADP,

while tetrahydrofolate is regenerated from dihydrofolate through the action of tetrahydrofolate dehydrogenase

Dihydrofolate + NADPH + Н⁺ →

→Tetrahydrofolate + NADP⁺.

The synthesis of deoxyribonucleoside 5'-triphosphates, which serve as the direct precursors for DNA (Chapter 28), is completed through the following Reactions Catalyzed by the corresponding Kinases:

Fig. 22-22. Conversion of ADP into dADP. Other ribonucleoside 5'-diphosphates (NDPs) are converted into their respective 2'-deoxy forms (dDNPs) via an identical reaction.