The Deoxyribonucleosides Of Uracil Cytosine Are Salvaged

While mammalian cells reutilize few free pyrimidines, "salvage reactions" convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2'-de-oxycytidine, 2'-deoxyguanosine, and 2'-deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP).

Methotrexate Blocks Reduction of Dihydrofolate

Reaction 12 of Figure 34-7 is the only reaction of pyrimidine nucleotide biosynthesis that requires a tetrahydrofo-late derivative. The methylene group of N5,N 10-methyl-ene-tetrahydrofolate is reduced to the methyl group that is transferred, and tetrahydrofolate is oxidized to dihydro-

PRPP

Adenine

ADENINE PHOSPHORIBOSYL TRANSFERASE

OH OH AMP

PRPP

^ -N N H Hypoxanthine

PRPP

^ -N N H Hypoxanthine

HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE

OH OH AMP

HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE

OH OH IMP

OH OH IMP

Guanine

2N "N PRPP PPi

OH OH GMP

Figure 34-4. Phosphoribosylation of adenine, hypoxanthine, and guanine to form AMP, IMP, and GMP, respectively.

folate. For further pyrimidine synthesis to occur, dihydro-folate must be reduced back to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. Dividing cells, which must generate TMP and dihydrofolate, thus are especially sensitive to inhibitors of dihydrofolate reductase such as the anticancer drug methotrexate.

Certain Pyrimidine Analogs Are Substrates for Enzymes of Pyrimidine Nucleotide Biosynthesis

Orotate phosphoribosyltransferase (reaction 5, Figure 34-7) converts the drug allopurinol (Figure 33-12) to

RIBONUCLEOTIDE REDUCTASE

Ribonucleoside ■ diphosphate

Reduced thioredoxin

• 2 '-Deoxyribonucleoside diphosphate

Oxidized thioredoxin

THIOREDOXIN REDUCTASE

Figure 34-5. Reduction of ribonucleoside diphosphates to 2'-deoxyribonucleoside diphosphates.

a nucleotide in which the ribosyl phosphate is attached to N-1 of the pyrimidine ring. The anticancer drug 5-fluorouracil (Figure 33-12) is also phosphoribosy-lated by orotate phosphoribosyl transferase.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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