BIOCHEMISTRY TRANS 10b Nucleotide metabolism.pdf

1A BIOCHEMISTRY NUCLEOTIDE METABOLISM (Part 2) DR. BRENDO JANDOC M.D....

1A BIOCHEMISTRY NUCLEOTIDE METABOLISM (Part 2) DR. BRENDO JANDOC M.D.  X-linked PRPP synthetase mutation OUTLINE  Increased PRPP  increases purine production  elevated I. Degradation of Purine nucleotides (cont.) levels of plasma uric acid  Diseases associated  Increased Vmax for the production of PRPP  Gout  Lower Km for ribose 5-phosphate  ADA deficiency  Decreased sensitivity to purine nucleotides II. Pyrimidine synthesis and degradation  allosteric inhibitors  Synthesis of carbamoyl phosphate  Lesch-Nyhan syndrome  Synthesis of orotic acid  Hyperuricemia due to:  Formation of a pyrimidine nucleotide  Decreased salvage of hypoxanthine and guanine  Synthesis of UTP and CTP  Increased PRPP availability  Synthesis of TMP from dUMP  Secondary Hyperuricemia  Salvage of pyrimidines  Increased availability of purine  Degradation of pyrimidine nucleotides  Myeloproliferative disorders  Chemotherapy  High rate of cell turnover DEGRADATION OF PURINE NUCLEOTIDES  Seemingly unrelated metabolic diseases A. Diseases associated with purine degradation  Von Gierke 1. GOUT  Fructose intolerance  Characterized by high levels of uric acid (hyperuricemia)  Increased risk of gout  End product of purine catabolism  Diet rich in meat and seafood  Either the overproduction or underexcretion of uric acid.  Decreased risk  Deposition of monosodium urate crystals in the:  Diet rich in low-fat dairy  joints  inflammatory response  acute gout  chronic C. Treatment of gout gouty arthritis  Anti-inflammatory agents  soft tissues  Colchicine  resulting in chronic tophaceous gout  Prevent microtubule formation  decrease  Kidneys movement of neutrophil to affected area  Urolithiasis  Steroidal drugs (prednisone)  Typically asymptomatic and does not lead to gout, but gout  Nonsteroidal drugs (indomethacin) is preceded by hyperuricemia  Uricosuric agent  DIAGNOSIS:  Lowering uric acid below its saturation point  prevent  Aspiration and examination deposition of synovial fluid from an  UNDEREXCRETORS affected joint (or material  Promote renal excretion from a tophus)  Probenecid  Polarized light microscopy  Sulfinpyrazone show needle-shaped  OVEREXCRETORS monosodium urate crystals  Inhibit uric acid synthesis  Allopurinol A. Underexcretion of uric acid  Converted to oxypurinol  Inhibit xanthine oxidase  Primary = due to as-yet-unidentified inherent excretory defects  Secondary to known disease processes that affect how the  hypoxanthine and xanthine accumulation kidney handles urate  more soluble  Lactic acidosis  less likely to initiate inflammation  lactate and urate compete for the same renal  normal HGPRT level transporter)  hypoxanthine salvage  de novo synthesis  Environmental factors  Febuxostat  Use of drugs  Non-purine inhibitor of XO  thiazide diuretics  exposure to lead (saturnine gout) 2. ADENOSINE DEAMINASE (ADA) DEFICIENCY  ADA B. Overproduction of uric acid  Highest in lymphocytes  Less common cause of gout is hyperuricemia  ADA deficiency  Primary hyperuricemia  Accumulation of adenosine  Idiopathic (having no known cause)  ADA  ribonucleotide or deoxyribonucleotide  Via kinases Trans FINALS 10b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 1 of 4  BIOCHEMISTRY NUCLEOTIDE METABOLISM (Part 2)  Rise in dATP  inhibit ribonucleotide reductase C. Formation of a pyrimidine nucleotide  Prevent production of deoxyribose-containing nucleotides  completed pyrimidine ring is converted to orotidine 5’-  Cells cannot make DNA nor divide monophosphate (OMP)  Developmental arrest and apoptosis of lymphocytes  orotate phosphoribosyltransferase  Severe combined immunodeficiency disease  releases pyrophosphate  Most severe form  PRPP as ribose-5-phosphate donor  Autosomal recessive  OMP  uridine monophosphate  Decrease in T, B and NK cells  Orotidylate decarboxylase  Treatment  Removes acidic carboxyl group  Bone marrow transplant  UMP synthetase domains  Enzyme replacement therapy  Orotate phosphoribosyltransferase  No treatment  Orotidylate decarboxylase  Death at age 2  Orotic aciduria  Purine nucleoside phosphorylase deficiency  Rare genetic defect  Less severe  Deficiency of one or both activity of UMP synthase  Primarily involves T cells  UMP  UDP  UTP PYRIMIDINE SYNTHESIS AND DEGRADATION UDP  PYRIMIDINE RING  Synthesized before being attached to ribose-5-phosphate Ribonucleotide reductase donated by PRPP  SOURCES dUMP  Glutamine  Aspartic acid phosphorylation  CO2 dUDP A. Synthesis of carbamoyl phosphate  Regulated step UTP diphosphatase  Glutamine and CO2  carbamoyl phosphate dUTP  carbamoyl phosphate synthetase (CPS) II  Inhibited by UTP  Activated by PRPP  Also synthesized by CPS I  Precursor of urea  Defect in ornithine transcarbamylase  Promote pyrimidine synthesis B. Synthesis of orotic acid  Second step  formation of carbamoylaspartate  Aspartate transcarbamoylase  Closed hydrolytically  Dihydroorotase  Oxidation of dihydroorotate  orotic acid D. Synthesis of UTP and cytidine triphosphate (CTP)  Dihydroorotate dehydrogenase  CTP  Inner mitochondrial membrane only  Amination of UTP by CTP  Multifunctional or multicatalytic peptide domain = CAD synthetase  CPS II  Glutamine provides Nitrogen  Aspartate transcarbamoylase  Dephosphorylated to CDP  dihydroorotase  Substrate of ribonucleotide reductase  dCDP  dCTP  for DNA synthesis Trans FINALS 10b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 2 of 4  BIOCHEMISTRY NUCLEOTIDE METABOLISM (Part 2) E. Synthesis of thymidine monophosphate (TMP) from dUMP  dUMP  dTMP  thymidylate synthase  inhibited by thymine analogs (5-fluorouracil)  antitumor agents  5-fluorouracil  5-FdUMP  Permanently bound to inactivated thymidylate synthase  Suicide inhibitor  N5,N10-methylene tetrahydrofolate as the source of the methyl group  THF contribute one-carbon unit, 2 hydrogen atoms  Oxidized to DHF  Can be reduced by dihydrofolate reductase  Inhibited by Methotrexate  Decrease THF supply  Inhibit purine synthesis, prevent methylation of dUMP to dTMP  DNA synthesis is inhibited and slows cell growth  Trimethoprim  Folate analogs  Potent antibacterial activity  Selective inhibition of bacterial dihydrofolate reductase F. Salvage of pyrimidines  Nucleotide kinases  Utilizes ATP in the phosphorylation of nucleoside to nucleotide  Basis for using URIDINE in the treatment of hereditary orotic aciduria G. Degradation of pyrimidine nucleotides  Opened and degraded to highly soluble products  Β-alanine  Β-aminoisobutyrate  NH3 and CO2 Trans FINALS 10b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 3 of 4  BIOCHEMISTRY NUCLEOTIDE METABOLISM (Part 2) Trans FINALS 10b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 4 of 4