Nucleotide Metabolism Biochemistry by Lippincott pp

Transcription

1 Nucleotide Metabolism Biochemistry by Lippincott pp

2 Deoxyribonucleotides Synthesis 2'-deoxyribonucleotides: Nucleotides required for DNA synthesis Produced from ribonucleoside diphosphates by ribonucleotide reductase (RR). qribonucleotide Reductase (RR): Multisubunit enzyme with 2 identical B1 subunits and 2 identical B2 subunits. Acts in reducing nucleoside diphosphates (ADP, GDP, CDP, and UDP) to their deoxyforms (dadp, dgdp, dcdp, and dudp). Responsible for maintaining a balanced supply of the deoxyribonucleotides required for DNA synthesis The immediate donors of the hydrogen atoms needed for the reduction of the 2 -OH group are 2 sulfhydryl groups on the enzyme itself. Its regulation is complex.

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4 PURINE NUCLEOTIDE CATABOLISM Purine nucleotides are sequentially degraded by the removal of portions ofthe nucleotide. Successive oxidations of hypoxanthine and xanthine by xanthine oxidase leads to the formation ofuric acid (inhibited by allopurinol). (Uric Acid) Intermediaries formed in purine breakdown may be re-used in the salvage pathway; ribose-1-phosphate generated in the course of the reactions may beconverted to PRPP. AMP/Adenosine can not be degraded directly, but must be deaminated first by AMP deaminase or adenosine deaminase (ADA).

5 Amino group is removed from AMP to give IMP by AMP deaminase or from adenosine to inosine by adenosine deaminase. IMP and GMP are converted into nucleoside by 5 - nucleosidase Purine nucleoside phosphorylase converts inosine and guanosine to purine bases hypoxanthine and guanine Guanine is deaminated to xanthine Hypoxanthine is oxidized by xanthine oxidase to give xanthine which forms uric acid the final product of uric acid Uric acid is excreted out in urine PURINE CATABOLISM

6 HYPERURICEMIA Uric acid: Made in the liver Excreted by the kidneys. High levels of uric acid in the body hyperuricemia: Excessive production of uric acid Reduced excretion of uric acid Deposition of urate crystals in kidney causes stones and deposition in joints causes gout

7 Pyrimidines The pyrimidine ring is synthesized before being attached to ribose 5-phosphate donated by PRPP. First and committed step in synthesis of pyrimidine: Synthesis of Carbamoyl Phosphate: From glutamine and CO 2, and catalyzed by cytosolic carbamoyl phosphatesynthetase (CPS) II. Requires 2ATP and ultimately when pyrimidine has been formed it requires PRPP for obtained ribose 5-phosphate. Glutamine and PRPP are required for both purine and pyrimidine synthesis

8 dtmp Synthesis UMP undergoes reduction for removal of oxygen from the ribose sugar forming dump dump is converted to dtmp by thymidylate synthetase, using methylene tetrahydrofolate as the methyl groupdonor. Inhibitors of thymidylate synthetase such as 5-fluorouracil are used as antitumor drugs. By decreasing the supply ofthf, thesedrugs: lowers the cellular concentration of dttp.

9 Pyrimidine Catabolism Pyrimidines are ultimately degraded to CO 2, H 2 O, and urea. Cytosine can be broken down to uracil which can be further broken down to b-alanine Thymine is broken down into b- aminoisobutyrate.

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11 SALVAGE PATHWAY Two enzymes are involved in the salvage pathway, which utilize PRPP as the source of ribose 5-phosphate group. The enzymes are adenine phosphoribosyltransferase (APRT) which act on adenine whereas hypoxanthine-guanine phosphoribosyltransferase (HGPRT) acting of hypoxanthine and guanine. q A deficiency of HGPRT causes the Lesch-Nyhan syndrome. This results in decreased utilization of purines in making nucleotides by salvage pathway thus increases synthesis of purines nucleotides by de novo synthesis. The decreased utilization and increased synthesis of purines results in increased degradation of purines and the production of large amounts of uric acid causing hyperuricemia frequently resulting in formation of uric acid stones in kidneys and crystals in joints and soft tissues. Inaddition syndrome is characterized by mental disorders.