BCH 202 Purine Nucleotides PDF

BCH 202: NUCLEIC ACID CHEMISTRY METABOLISMS OF PURINES NUCLEOSIDES AND NUCLEOTIDES LECTURER: DR. DAVID C. OBASI DAVID UMAHI FEDERAL UNIVERSITY OF HEALTH SCIENCES  OBJECTIVES Overview of the purine bases, nucleosides and nucleotides Understan...

BCH 202: NUCLEIC ACID CHEMISTRY METABOLISMS OF PURINES NUCLEOSIDES AND NUCLEOTIDES LECTURER: DR. DAVID C. OBASI DAVID UMAHI FEDERAL UNIVERSITY OF HEALTH SCIENCES  OBJECTIVES Overview of the purine bases, nucleosides and nucleotides Understanding the sources of the various atoms of purine bases Synthesis of Inosine monophosphate as the initially synthesized derivative of purine bases Conversion of IMP to AMP and GMP Significance of IMP in B and T lymphocytes Synthesis of nucleotides diphosphates and triphosphates Regulation of purine nucleotide biosynthesis Purine Salvage Pathway Lesch-Nyhan syndrome Purine Degradation and Catabolism of Uric Acid Clinical disorders of purine catabolism OVERVIEW OF THE PURINE BASES, NUCLEOSIDES AND NUCLEOTIDES  INOSINE MONOPHOSPHATE (IMP)  The initially synthesized purine derivative is inosine monophosphate A. SYNTHESIS OF INOSINE MONOPHOSPHATE (IMP)  IMP is synthesized in a pathway composed of 11 reactions Elimination of fumarate Cyclization to form IMP B. IMP IS CONVERTED TO ADENINE AND GUANINE RIBONUCLEOTIDES  SIGNIFICANCE OF IMP IN B AND T LYMPHOCYTES  In B and T lymphocytes, which mediate the immune response, IMP dehydrogenase activity is high in order to supply the guanosine the cells need for proliferation. The fungal compound mycophenolic acid inhibits the enzyme and is used as an immunosuppressant following kidney transplants. SYNTHESIS OF NUCLEOTIDE DIPHOSPHATES AND TRIPHOSPHATES C. REGULATION OF PURINE NUCLEOTIDE BIOSYNTHESIS  The IMP pathway is regulated at its first two reactions: those catalyzing the synthesis of PRPP and 5-phosphoribosylamine.  Ribose phosphate pyrophosphokinase (Rxn 1) and amidophosphoribosyl transferase (Rxn 2 - first committed step of the IMP pathway) are inhibited by both ADP and GDP = feedback inhibition.  In this case, the enzyme binds ATP, ADP, and AMP at one inhibitory site and GTP, GDP, and GMP at another.  The rate of IMP production is therefore independently but synergistically controlled by the levels of adenine nucleotides and guanine nucleotides.  Moreover, amidophosphoribosyl transferase is allosterically stimulated by PRPP (feedforward activation).  AMP and GMP are each competitive inhibitors of IMP in their own synthesis, which prevents excessive buildup of the pathway products.  D. PURINE SALVAGE PATHWAYS In most cells, the turnover of nucleic acids, particularly some types of RNA, releases adenine, guanine, and hypoxanthine.  These free purines are reconverted to their corresponding nucleotides through salvage pathways; which are diverse in character and distribution. In mammals, purines are mostly salvaged by two different enzymes:  Adenine phosphoribosyl transferase (APRT) mediates AMP formation using PRPP:  Hypoxanthine–guanine phosphoribosyltransferase (HGPRT) catalyzes the analogous reaction for both hypoxanthine and guanine:  LESCH–NYHAN SYNDROME  Lesch–Nyhan Syndrome results from HGPRT deficiency.  It is a sex-linked congenital defect (it affects mostly males). The symptoms of Lesch–Nyhan syndrome, which is caused by a severe HGPRT deficiency, involve excessive uric acid production (uric acid is a purine degradation product) and neurological abnormalities such as spasticity, mental retardation, and highly aggressive and destructive behavior, including a bizarre compulsion toward self-mutilation. For example, many children with Lesch–Nyhan syndrome have such an irresistible urge to bite their lips and fingers that they must be restrained. If the restraints are removed, communicative patients will plead that the restraints be replaced, even as they attempt to injure themselves.  The excessive uric acid production in patients with Lesch–Nyhan syndrome is readily explained. The lack of HGPRT activity leads to an accumulation of the PRPP that would normally be used to salvage hypoxanthine and guanine. The excess PRPP activates amidophosphoribosyl transferase (which catalyzes Reaction 2 of the IMP biosynthetic pathway), thereby greatly accelerating the synthesis of purine nucleotides and thus the formation of their degradation product, uric acid.  Yet the physiological basis of the associated neurological abnormalities remains obscure. That a defect in a single enzyme can cause such profound but well-defined behavioral changes nevertheless has important neurophysiological implications.  PURINE DEGRADATION  Purine catabolism yields uric acid. The pathways in other organisms differ somewhat, but all the pathways lead to uric acid.  Many foodstuffs contain nucleic acids, since they are of cellular origin.  Dietary nucleic acids survive the acidic medium of the stomach; they are degraded to their component nucleotides, mainly in the intestine, by pancreatic nucleases and intestinal phosphodiesterases.  The ionic nucleotides, which cannot pass through cell membranes, are then hydrolyzed to nucleosides by a variety of group-specific nucleotidases and nonspecific phosphatases.  Nucleosides may be directly absorbed by the intestinal mucosa or further degraded to free bases and ribose or ribose-1-phosphate through the action of nucleosidases and nucleoside phosphorylases: PURINE DEGRADATION  CATABOLISM OF URIC ACID  In humans and other primates, the final product of purine degradation is uric acid, which is excreted in the urine. The same is true in birds, terrestrial reptiles, and many insects, but those organisms, which do not excrete urea, also catabolize their excess amino acid nitrogen to uric acid via purine biosynthesis.  In all other organisms, uric acid is further processed before excretion. Mammals other than primates oxidize and decarboxylate it to their excretory product, allantoin, in a reaction catalyzed by the hepatic Cu- containing enzyme urate oxidase/uricase.  A further degradation product, allantoic acid, is excreted by teleost (bony) fish. Cartilaginous fish and amphibia further degrade allantoic acid to urea prior to excretion. Finally, marine invertebrates decompose urea to NH4+.  Some fishes carry uricase as well as allantoinase. This converts allantoin into allantoic acid.  Amphibians and other such animals contain allantoinase which converts allantoic acid into ureidoglycolate. Ureidoglycolate is further cleaved by ureidoglycolase/allointoicase into urea and glyoxylate.  Urea is further converted to NH3 and CO2 in crustaceans by an enzyme urease found in their liver.  ASSIGNMENT Discuss the clinical disorders/diseases (and treatments) of purine catabolism.  THANKS FOR LISTENING ASK YOUR QUESTIONS