A college professor, celebrating his 60th birthday, had too much foie gras and wine at his celebratory dinner. The next morning, he awakened with both a hangover and a severe pain in his right great toe, a condition he had experienced a number of times previously. Being somewhat absentminded, the professor then remembered that he had forgotten to take his maintenance medication for this condition for over 2 weeks. His maintenance medication most likely blocks which one of the following reactions?
The nucleotides that are produced in the liver are converted to nucleosides and bases, which travel in red blood cells to other tissues where they are reconverted to nucleotides and further metabolized.a. Purine synthesis (Figure I below)(1). The purine base is synthesized on the ribose moiety.(a). 5'-Phosphoribosyl-1'-pyrophosphate (PRPP), which provides the ribose moiety, reacts with glutamine to form phosphoribosyl amine.(b). This first step in purine biosynthesis produces N9 of the purine ring and is inhibited by AMP and guanosine monophosphate (GMP).(c). The entire glycine molecule is added to the growing purine precursor. Then, C8 is added by formyl-FH4 , N3 by glutamine, C6 by CO2 , N1 by aspartate, and C2 by formyl-FH4 (see Figure I-A).(d). IMP, which contains the base hypoxanthine, is generated.1. IMP is cleaved in the liver. Its free base, or nucleoside, travels to various tissues where it is reconverted to the nucleotide(2). IMP is the precursor of both AMP and GMP.(a). Each product, by feedback inhibition, regulates its own synthesis from the IMP branch point as well as inhibits the initial step in the pathway.(b). AMP and GMP can be phosphorylated to the triphosphate level.(c). The nucleotide triphosphates (ATP and guanosine triphosphate ) can be used for energy requiring processes or for RNA synthesis.(3). The reduction of the ribose moiety to deoxyribose occurs at the diphosphate level and is catalyzed by ribonucleotide reductase, which requires the protein thioredoxin.(a). After the diphosphates are phosphorylated, deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP) can be used for DNA synthesis.(4). Purine bases can be salvaged and converted between free bases, nucleotides, and nucleosides by a series of reactions, as indicated in Figure II.b. Purine degradation (Figure III)(1). In the degradation of the purine nucleotides, phosphate and ribose are removed first and then the nitrogenous base is oxidized.(a). The degradation of guanine produces xanthine.(b). The degradation of adenine produces hypoxanthine, which is oxidized to xanthine by xanthine oxidase; this enzyme requires molybdenum.(c). Xanthine is oxidized to uric acid by xanthine oxidase.(d). Uric acid, which is not very water soluble, is excreted by the kidneys.c. Pyrimidine synthesis (see Figure I)(1). The pyrimidine base is synthesized prior to the addition of the ribose moiety.(a). In the first reaction, glutamine reacts with CO2 and 2 ATP to form carbamoyl phosphate. This reaction is analogous to the first reaction of the urea cycle. However, for pyrimidine synthesis, glutamine provides the nitrogen, and the reaction occurs in the cytosol, where it is catalyzed by carbamoyl phosphate synthetase II, which is inhibited by UTP.(b). The entire aspartate molecule adds to carbamoyl phosphate. The molecule closes to yield a ring, which is oxidized, forming orotate.(c). Orotate reacts with PRPP, producing orotidine-5'-phosphate, which is decarboxylated to form UMP.(2). UMP is phosphorylated to UTP, which obtains an amino group from glutamine to form cytidine triphosphate (CTP). UTP and CTP are used in the synthesis of RNA.(3). The ribose moiety of cytidine diphosphate (CDP) is reduced to deoxyribose, forming deoxycytidine diphosphate (dCDP). Ribonucleotide reductase is the enzyme.(a). Deoxycytidine diphosphate (dCDP) is deaminated and dephosphorylated to form dUMP.(b). dUMP is converted to dTMP by methylene-FH4 .(c). Phosphorylations produce deoxycytidine triphosphate (dCTP) and deoxythymidine triphosphate, which are the precursors of DNA.d. Pyrimidine degradation(1). In pyrimidine degradation, the carbons produce CO2 , and the nitrogen produce urea.The professor is suffering from gout, caused by an accumulation of uric acid in the blood and precipitation of the uric acid in his big toe. Xanthine oxidase is involved in the conversion of the purine bases to uric acid. It catalyzes the oxidation of hypoxanthine to xanthine and of xanthine to uric acid. Allopurinol is used as a maintenance medication in the treatment of gout and acts as a suicide substrate that blocks xanthine oxidase activity. This results in lower concentrations of uric acid (so the uric acid in the blood will not precipitate) and higher concentrations of the more water-soluble compounds hypoxanthine (derived from adenine) and xanthine (derived from guanine).I. De novo synthesis of purines and pyrimidines. Ribonucleotide reductase (RR) catalyzes the reduction of the ribose moiety in ADP, GDP, and CDP to deoxyribose. The source of each of the atoms is indicated in part (A) of the figure. The biosynthetic pathways for purine and pyrimidine synthesis are outlined in part (B) of the figure. In hereditary orotic aciduria, the enzymes converting orotate to UMP are defective. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenine triphosphate; CDP, cytidine diphosphate; CPS, carbamoyl phosphate synthetase; CTP, cytidine triphosphate; dADP, deoxyadenosine diphosphate; dATP, deoxyadenosine triphosphate; dCDP, deoxycytidine diphosphate; dCMP, deoxycytidine monophosphate; dCTP, deoxycytidine triphosphate; dGDP, deoxyguanosine diphosphate; dGTP, deoxyguanosine triphosphate; dTDP, deoxythymidine diphosphate; dTMP, deoxythymidine monophosphate; dTTP, deoxythymidine triphosphate; FH2 , dihydrofolate; FH4 , tetrahydrofolate; GDP, guanosine diphosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; IMP, inosine monophosphate; Pi, inorganic phosphate; PRPP, 5'- phosphoribosyl-1'-pyrophosphate; RP, ribose 5-phosphate; R5P, ribose 5- phosphate; RR, ribonucleotide reductase; UDP, uridine diphosphate; UMP, uridine monophosphate; UTP, uridine triphosphate.II. The salvage of the purine bases. The key enzymes are the phosphoribosyltransferases, 5'-nucleotidase, adenosine deaminase, and purine nucleoside phosphorylase. ADP, adenosine diphosphate; AMP, adenosine monophosphate; APRT, adenine phosphoribosyltransferase; ATP, adenosine triphosphate; GMP, guanosine monophosphate; HGPRT, hypoxanthine guanine phosphoribosyltransferase; Pi, inorganic phosphate; PPi, pyrophosphate; PRPP, 5'-phosphoribosyl-1'-pyrophosphate.III. Purine degradation. Allopurinol, which inhibits xanthine oxidase, is used to treat gout. Gout occurs when uric acid crystals precipitate in joints because of an increased concentration in the blood. AMP, adenosine monophosphate; GMP, guanosine monophosphate; IMP, inosine monophosphate; Pi, inorganic phosphate.
IMP to GMP
Adenosine to inosine
Hypoxanthine to xanthine
dUMP to dTMP
Molecular Genetics