Harpers

Metabolism of Purine &Pyrimidine Nucleotides 34Victor W. Rodwell, PhDBIOMEDICAL IMPORTANCEThe biosynthesis of purines and pyrimidines is stringentlyregulated and coordinated by feedback mechanismsthat ensure their production in quantities and attimes appropriate to varying physiologic demand. Geneticdiseases of purine metabolism include gout,Lesch-Nyhan syndrome, adenosine deaminase deficiency,and purine nucleoside phosphorylase deficiency.By contrast, apart from the orotic acidurias, there arefew clinically significant disorders of pyrimidine catabolism.PURINES & PYRIMIDINES AREDIETARILY NONESSENTIALHuman tissues can synthesize purines and pyrimidinesfrom amphibolic intermediates. Ingested nucleic acidsand nucleotides, which therefore are dietarily nonessential,are degraded in the intestinal tract to mononucleotides,which may be absorbed or converted topurine and pyrimidine bases. The purine bases are thenoxidized to uric acid, which may be absorbed and excretedin the urine. While little or no dietary purine orpyrimidine is incorporated into tissue nucleic acids, injectedcompounds are incorporated. The incorporationof injected [ 3 H]thymidine into newly synthesized DNAthus is used to measure the rate of DNA synthesis.BIOSYNTHESIS OF PURINE NUCLEOTIDESPurine and pyrimidine nucleotides are synthesized invivo at rates consistent with physiologic need. Intracellularmechanisms sense and regulate the pool sizes ofnucleotide triphosphates (NTPs), which rise duringgrowth or tissue regeneration when cells are rapidly dividing.Early investigations of nucleotide biosynthesisemployed birds, and later ones used Escherichia coli.Isotopic precursors fed to pigeons established the sourceof each atom of a purine base (Figure 34–1) and initiatedstudy of the intermediates of purine biosynthesis.Three processes contribute to purine nucleotidebiosynthesis. These are, in order of decreasing importance:(1) synthesis from amphibolic intermediates293(synthesis de novo), (2) phosphoribosylation of purines,and (3) phosphorylation of purine nucleosides.INOSINE MONOPHOSPHATE (IMP)IS SYNTHESIZED FROM AMPHIBOLICINTERMEDIATESFigure 34–2 illustrates the intermediates and reactionsfor conversion of α-D-ribose 5-phosphate to inosinemonophosphate (IMP). Separate branches then lead toAMP and GMP (Figure 34–3). Subsequent phosphoryltransfer from ATP converts AMP and GMP to ADPand GDP. Conversion of GDP to GTP involves a secondphosphoryl transfer from ATP, whereas conversionof ADP to ATP is achieved primarily by oxidativephosphorylation (see Chapter 12).Multifunctional Catalysts Participate inPurine Nucleotide BiosynthesisIn prokaryotes, each reaction of Figure 34–2 is catalyzedby a different polypeptide. By contrast, in eukaryotes,the enzymes are polypeptides with multiplecatalytic activities whose adjacent catalytic sites facilitatechanneling of intermediates between sites. Threedistinct multifunctional enzymes catalyze reactions 3,4, and 6, reactions 7 and 8, and reactions 10 and 11 ofFigure 34–2.Antifolate Drugs or Glutamine AnalogsBlock Purine Nucleotide BiosynthesisThe carbons added in reactions 4 and 5 of Figure 34–2are contributed by derivatives of tetrahydrofolate.Purine deficiency states, which are rare in humans, generallyreflect a deficiency of folic acid. Compounds thatinhibit formation of tetrahydrofolates and thereforeblock purine synthesis have been used in cancerchemotherapy. Inhibitory compounds and the reactionsthey inhibit include azaserine (reaction 5, Figure 34–2),diazanorleucine (reaction 2), 6-mercaptopurine (reactions13 and 14), and mycophenolic acid (reaction 14).