UNIT IV: Nitrogen Metabolism Nucleotide Metabolism Part 2 A. Degradation of dietary nucleic acids in the small intestine 2
Ribonucleases and deoxyribonucleases, secreted by the pancreas, hydrolyze RNA and DNA primarily to oligonucleotides. Oligonucleotides are further hydrolyzed by pancreatic phosphodiesterases, producing a mixture of 3- and 5-mononucleotides. A family of nucleotidases removes the phosphate groups hydrolytically, releasing nucleosides that may be absorbed by the intestinal mucosal cells, or be further degraded to free bases before uptake. Dietary purines and pyrimidines are not used to a large extent for the synthesis of tissue
nucleic acids. Instead, the dietary purines are generally converted to uric acid by intestinal mucosal cells. 3 B. Formation of uric acid 4  An amino group is removed from AMP to produce IMP, or from adenosine to produce inosine (hypoxanthine-ribose) by AMP deaminase or adenosine deaminase.
 IMP and GMP are converted into their nucleoside formsinosine and guanosine by the action of 5-nucleotidase.  Purine nucleoside phosphorylase converts inosine and guanosine into their respective purine bases, hypoxanthine and guanine.  Guanine is deaminated to form xanthine.  Hypoxanthine is oxidized by xanthine oxidase to xanthine, which is further oxidized by xanthine oxidase to uric acid, ADA is expressed in a
variety of tissues, but, in humans, lymphocytes have the highest activity of this cytoplasmic enzyme 5 C. Diseases associated with purine degradation
6 1.Gout: Gout is a disorder characterized by high levels of uric acidthe end product of purine catabolismin blood (hyperuricemia), as a result of either the overproduction or underexcretion of uric acid. The hyperuricemia leads to the deposition of monosodium urate crystals in the joints, and an inflammatory response to the crystals, causing first acute and then to chronic gouty
arthritis. C. Diseases associated with purine degradation Formation of uric acid stones in the 7 kidney may also be seen. Hyperuricemia is typically asymptomatic and does not lead to gout, but gout is preceded by hyperuricemia The definitive diagnosis of gout
requires aspiration and examination of synovial fluid from an affected joint (or material from a tophus) using polarized light microscopy to confirm the presence of needle-shaped 8 9 Analysis of joint fluid can help to define causes of joint swelling or arthritis, such as infection, gout, and rheumatoid disease
10 C. Treatment of gout Acute attacks of gout are treated with anti- inflammatory agents. Colchicine, steroidal drugs such as prednisone, and nonsteroidal drugs such as indomethacin are used Colchicine depolymerizes microtubules, thus
decreasing the movement of neutrophils into the affected area. Like the other anti-inflammatory drugs, it has no effect on uric acid levels. Long-term therapeutic strategies for gout 11 involve lowering the uric acid level below the saturation point, thereby preventing the deposition of urate crystals. C. Treatment of gout
Uricosuric agents, such as probenecid or 12 sulfinpyrazone, that increase renal excretion of uric acid, are used in patients who are underexcretors of uric acid. Allopurinol, an inhibitor of uric acid synthesis, is used in patients who are overproducers of uric acid Allopurinol is converted in the body to oxypurinol, which inhibits xanthine oxidase, resulting in an accumulation of hypoxanthine and xanthine compounds more soluble
than uric acid and, therefore, less likely to initiate an inflammatory response In patients with normal levels of HGPRT, the hypoxanthine can be salvaged, thus reducing the levels of PRPP and, therefore, de novo VI. Pyrimidine Synthesis and Degradation Unlike the synthesis of the purine ring, which is constructed on a preexisting ribose 5-phosphate, the pyrimidine ring is synthesized before being attached to ribose 5-phosphate, which is donated by
PRPP. The sources of the atoms in the pyrimidine ring are glutamine, CO2, and aspartic acid Therefore, Glutamine and aspartic acid are 13 thus required for both purine and pyrimidine synthesis 14 A. Synthesis of carbamoyl phosphate The regulated step of this pathway in
mammalian cells is the synthesis of carbamoyl phosphate from glutamine and CO2, catalyzed by carbamoyl phosphate synthetase (CPS) II. CPS II is inhibited by UTP (the end product of this pathway, which can be converted into the other pyrimidine nucleotides), and is activated by ATP and PRPP. 15 B. Synthesis of orotic acid The second step in pyrimidine synthesis is
16 the formation of carbamoylaspartate, catalyzed by aspartate transcarbamoylase. The pyrimidine ring is then closed hydrolytically by dihydroorotase. The resulting dihydroorotate is oxidized to produce orotic acid (orotate). The enzyme that produces orotate, dihydroorotate dehydrogenase, is associated with the inner mitochondrial membrane.
17 C. Formation of a pyrimidine nucleotide The completed pyrimidine ring is converted to the nucleotide orotidine 5monophosphate (OMP) in the second stage of pyrimidine nucleotide synthesis. PRPP is again the ribose 5-phosphate donor. The enzyme orotate phosphoribosyltransferase produces OMP and releases pyrophosphate, thereby
making the reaction biologically irreversible. 18 C. Formation of a pyrimidine nucleotide OMP, the parent pyrimidine mononucleotide, is converted to uridine monophosphate (UMP) by orotidylate decarboxylase, which removes the acidic carboxyl group. Orotate phosphoribosyltransferase and orotidylate decarboxylase are also catalytic
domains of a single polypeptide chain called UMP synthase. Orotic aciduriaa rare genetic defectis 19 caused by a deficiency of this bifunctional enzyme, resulting in orotic acid in the urine (see D. Synthesis of UTP and cytidine triphosphate (CTP) CTP is produced by amination of UTP by CTP synthetase. [Note: The nitrogen is provided by
glutamine] 20 E. Synthesis of thymidine monophosphate (TMP) from dUMP dUMP is converted to dTMP by thymidylate 21 synthase, which uses N5,N10-methylene tetrahydrofolate as the source of the methyl
group. This is an unusual reaction in that tetrahydrofolate (THF) contributes not only a one-carbon unit but also two hydrogen atoms from the pteridine ring, resulting in the oxidation of THF to dihydrofolate (DHF). Inhibitors of thymidylate synthase include thymine analogs such as 5-fluorouracil, which serves as successful antitumor agents. 5-Fluorouracil is metabolically converted to 5- 22 E. Synthesis of thymidine
monophosphate (TMP) from dUMP DHF can be reduced to THF by 23 dihydrofolate reductase, an enzyme that is inhibited in the presence of drugs such as methotrexate. By decreasing the supply of THF, these folate analogs not only inhibit purine synthesis, but, by preventing methylation of dUMP to dTMP, they also lower the cellular concentration of this essential
component of DNA. DNA synthesis is inhibited and cell growth slowed. Drugs such as those described above, 24 F. Salvage of pyrimidines Few pyrimidine bases are salvaged in human cells. However, the pyrimidine nucleosides can be salvaged by nucleoside kinases that utilize ATP in the
phosphorylation of the nucleosides to nucleotides. Note: The salvage of pyrimidine nucleosides 25 is the basis for using uridine in the G. Degradation of pyrimidine nucleotides Unlike the purine ring, which is not cleaved by human cells, the pyrimidine ring is opened and degraded to highly
of acetyl CoA and succinyl CoA, soluble products:precursors respectively), with the production of NH -alanine and and CO2. -aminoisobutyrate 26 3 7. Chapter summary Nucleotides are composed of a
27 nitrogenous base (adenine = A, guanine = G, cytosine = C, uracil = U, and thymine = T), a pentose, and one, two, or three phosphate groups (Figure 22.24). A and G are purines; C, U, and T are pyrimidines. If the sugar is ribose, the nucleotide is a ribonucleoside phosphate (for example, AMP), and it can have several functions in the cell, including being a component of RNA.
7. Chapter summary The committed step in purine synthesis uses: 5-phosphoribosyl-1-pyrophosphate (PRPP, an activated pentose that provides the ribosephosphate group for de novo purine and pyrimidine synthesis and purine salvage) and nitrogen from glutamine to produce phosphoribosyl amine. The enzyme is glutamine:PRPP 28
amidotransferase, and is inhibited by AMP and GMP (the end products of the pathway) and activated by PRPP. Purine nucleotides can also be produced from preformed purine bases by using salvage 7. Chapter summary A near total deficiency of HGPRT causes 29 Lesch-Nyhan syndromea severe, heritable form of hyperuricemia
accompanied by compulsive self-mutilation. All deoxyribonucleotides are synthesized from ribonucleotides by the enzyme ribonucleotide reductase. This enzyme is highly regulated, for example, it is strongly inhibited by dATP a compound that is overproduced in bone marrow cells in individuals with adenosine deaminase deficiency. This syndrome causes severe combined 7. Chapter summary The end product of purine degradation is
30 uric acida compound whose overproduction or under-secretion causes hyperuricemia that, if accompanied by the deposition of urate crystals in joints and soft tissues, and an inflammatory response to those crystals, results in gout. The first step in pyrimidine synthesis the production of carbamoyl phosphate by carbamoyl phosphate synthetase IIis the regulated step in this pathway (it is
7. Chapter summary The UTP produced by this pathway can be converted to CTP. dUMP can be converted to dTMP using thymidylate synthasean enzyme targeted by anticancer drugs such as 5fluorouracil. The regeneration of THF from DHF produced in the thymidylate synthase reaction requires dihydrofolate reductasean enzyme targeted by the drug, methotrexate. 31
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