Harpers

METABOLISM OF PURINE & PYRIMIDINE NUCLEOTIDES / 299regulation. Carbamoyl phosphate synthase II (reaction1, Figure 34–7) is inhibited by UTP and purine nucleotidesbut activated by PRPP. Aspartate transcarbamoylase(reaction 2, Figure 34–7) is inhibited byCTP but activated by ATP. In addition, the first threeand the last two enzymes of the pathway are regulatedby coordinate repression and derepression.Purine & Pyrimidine NucleotideBiosynthesis Are Coordinately RegulatedPurine and pyrimidine biosynthesis parallel one anothermole for mole, suggesting coordinated control oftheir biosynthesis. Several sites of cross-regulation characterizepurine and pyrimidine nucleotide biosynthesis.The PRPP synthase reaction (reaction 1, Figure 34–2),which forms a precursor essential for both processes, isfeedback-inhibited by both purine and pyrimidine nucleotides.HUMANS CATABOLIZE PURINESTO URIC ACIDHumans convert adenosine and guanosine to uric acid(Figure 34–8). Adenosine is first converted to inosineby adenosine deaminase. In mammals other thanhigher primates, uricase converts uric acid to the watersolubleproduct allantoin. However, since humans lackuricase, the end product of purine catabolism in humansis uric acid.GOUT IS A METABOLIC DISORDEROF PURINE CATABOLISMVarious genetic defects in PRPP synthetase (reaction 1,Figure 34–2) present clinically as gout. Each defect—eg, an elevated V max , increased affinity for ribose 5-phosphate, or resistance to feedback inhibition—resultsin overproduction and overexcretion of purine catabolites.When serum urate levels exceed the solubilitylimit, sodium urate crystalizes in soft tissues and jointsand causes an inflammatory reaction, gouty arthritis.However, most cases of gout reflect abnormalities inrenal handling of uric acid.NNH 2NHO H2CONNOHH HH HOHHO H2 AdenosineH 2 ONH + 4OHNNN NOH HH HOH OHInosineHNP iONN NHHypoxanthineH 2 NHOHNRibose 1-phosphateH 2 NHNH 2 O + O 2H O2 O 2NHNO NH NHXanthineH 2 O + O 2ONH2 COONNH HH HOH OHGuanosineNP iN NHGuanineHN 3Figure 34–8. Formation of uric acid from purine nucleosidesby way of the purine bases hypoxanthine, xanthine, and guanine.Purine deoxyribonucleosides are degraded by the samecatabolic pathway and enzymes, all of which exist in the mucosaof the mammalian gastrointestinal tract.H 2 O 2OHNHN179O 3NHNHUric acidO