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Nucleotide metabolism – Part 1 (purine biosynthesis). By Henry Wormser, Ph.D Professor of Medicinal Chemistry. Biological significance of nucleotide metabolism. Nucleotides make up nucleic acids (DNA and RNA) Nucleotide triphosphates are the “energy carriers” in cells (primarily ATP)

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Nucleotide metabolism part 1 purine biosynthesis l.jpg

Nucleotide metabolism – Part 1(purine biosynthesis)

By

Henry Wormser, Ph.D

Professor of Medicinal Chemistry


Biological significance of nucleotide metabolism l.jpg
Biological significance of nucleotide metabolism

  • Nucleotides make up nucleic acids (DNA and RNA)

  • Nucleotide triphosphates are the “energy carriers” in cells (primarily ATP)

  • Many metabolic pathways are regulated by the level of the individual nucleotides

    • Example: cAMP regulation of glucose release

  • Adenine nucleotides are components of many of the coenzymes

    • Examples: NAD+, NADP+, FAD, FMN, coenzyme A


Dietary nucleotides l.jpg
Dietary nucleotides

  • do not contribute energy as do carbs, proteins and fats

  • are not incorporated into RNA or DNA unless given I.V.

  • normally metabolized to individual components (bases, sugar and phosphate)

  • purines are converted to uric acid which is then excreted


Medical significance of nucleotide metabolism l.jpg
Medical significance of nucleotide metabolism

  • Anticancer agents:

    • Rapidly dividing cells biosynthesize lots of purines and pyrimidines, but other cells reuse them. Cancer cells are rapidly dividing, so inhibitor of nucleotide metabolism kill them

  • Antiviral agents

    • Zidovudine (Retrovir)

    • Lamivudine (Epivir)

    • Valacyclovir (Valtrex)



  • Structures of nucleotide building blocks and nucleotides7 l.jpg
    Structures of nucleotide buildingblocks and nucleotides

    guanine: comes from guano; thymine –thymus gland




    Synthesis of inosine monophosphate l.jpg
    Synthesis of Inosine Monophosphate

    • Basic pathway for biosynthesis of purine ribonucleotides

    • Starts from ribose-5-phosphate which is derived from the pentose phosphate pathway

    • Requires 11 steps overall

    • occurs primarily in the liver



    Steps 1 thru 3 l.jpg
    Steps 1 thru 3

    • Step 1:Activation of ribose-5-phosphate

      • enzyme: ribose phosphate pyrophosphokinase

      • product: 5-phosphoribosyl-a-pyrophosphate (PRPP)

      • PRPP is also a precursor in the biosynthesis of pyrimidine nucleotides and the amino acids histidine and tryptophan



    Steps 1 thru 314 l.jpg
    Steps 1 thru 3

    • Step 2: acquisition of purine atom 9

      • enzyme: amidophosphoribosyl transferase

      • displacement of pyrophosphate group by glutamine amide nitrogen (inversion of configuration – a to b

      • product: b-5-phosphoribosylamine

    Steps 1 and 2 are tightly regulated by feedback inhibition



    Steps 1 thru 316 l.jpg
    Steps 1 thru 3

    • Step 3: acquisition of purine atoms C4, C5, and N7

      • enzyme: glycinamide synthetase

      • b-phosphoribosylamine reacts with ATP and glycine

      • product: glycinamide ribotide (GAR)



    Steps 4 thru 6 l.jpg
    Steps 4 thru 6

    • Step 4: acquisition of purine atom C8

      • formylation of free a-amino group of GAR

      • enzyme: GAR transformylase

      • co-factor of enzyme is N10-formyl THF

    • Step 5: acquisition of purine atom N3

      • The amide amino group of a second glutamine is transferred to form formylglycinamidine ribotide (FGAM)

    • Step 6: closing of the imidazole ring or formation of 5-aminoimidazole ribotide



    Step 7 l.jpg
    Step 7

    • Step 7: acquisition of C6

      • C6 is introduced as HCO3-

      • enzyme: AIR carboxylase (aminoimidazole ribotide carboxylase)

      • product: CAIR (carboxyaminoimidazole ribotide)

      • enzyme composed of 2 proteins: PurE and PurK (synergistic proteins)



    Steps 8 thru 11 l.jpg
    Steps 8 thru 11

    • Step 8: acquisition of N1

      • N1 is acquired from aspartate in an amide condensation reaction

      • enzyme: SAICAR synthetase

      • product: 5-aminoimidazole-4-(N-succinylocarboxamide)ribotide (SAICAR)

      • reaction is driven by hydrolysis of ATP



    Steps 8 thru 1125 l.jpg
    Steps 8 thru 11

    • Step 9: elimination of fumarate

      • Enzyme: adenylosuccinate lyase

      • Product: 5-aminoimidazole-4-carboxamide ribotide (AICAR)

    • Step 10: acquisition of C2

      • Another formylation reaction catalyzed by AICAR transformylase

      • Product: 5-formaminoimidazole-4-carboxamide ribotide (FAICAR)




    Step 11 l.jpg
    Step 11

    • cyclization or ring closure to form IMP

    • water is eliminated

    • in contrast to step 6 (closure of the imidazole ring), this reaction does not require ATP hydrolysis

    • once formed, IMP is rapidly converted to AMP and GMP (it does not accumulate in cells



    Slide31 l.jpg

    Synthesis of adenine

    and guanine nucleotides


    Slide32 l.jpg

    Purine nucleoside diphosphates and triphosphates:

    - to be incorporated into DNA and RNA, nucleoside

    monophosphates (NMP’s) must be converted into

    nucleoside triphosphates (NTP’s)

    - nucleoside monophosphate kinases (adenylate & guanylate kinases)

    - nucleoside diphosphate kinase



    The purine salvage pathway l.jpg
    The purine salvage pathway

    • Purine bases created by degradation of RNA or DNA and intermediate of purine synthesis were costly for the cell to make, so there are pathways to recover these bases in the form of nucleotides

    • Two phosphoribosyl transferases are involved:

      • APRT (adenine phosphoribosyl transferase) for adenine

      • HGPRT (hypoxanthine guanine phosphoribosyl transferase) for guanine or hypoxanthine


    Salvage of purines l.jpg
    Salvage of purines

    Adenine phosphoribosyltransferase (APRT)


    Salvage of purines37 l.jpg

    Salvage is needed to maintain the purine pool (biosynthesis is not completely adequate, especially in neural tissue)

    Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

    Hypoxanthine + PRPP IMP + Ppi

    Guanine + PRPP GMP + Ppi

    Lack of HGPRT leads to Lesch-Nyhan syndrome. Lack of enzyme leads to overproduction of purines which are metabolized to uric acid, which damages cells

    Salvage of purines


    Lesch nyhan syndrome l.jpg
    Lesch-Nyhan syndrome is not completely adequate, especially in neural tissue)

    • there is a defect or lack in the HGPRT enzyme

    • the rate of purine synthesis is increased about 200X

    • uric acid level rises and there is gout

    • in addition there are mental aberrations

    • patients will self-mutilate by biting lips and fingers off


    Lesch nyhan syndrome39 l.jpg
    Lesch-Nyhan syndrome is not completely adequate, especially in neural tissue)


    Slide40 l.jpg

    Salvage of purine bases is not completely adequate, especially in neural tissue)


    Slide41 l.jpg

    Next: Part 2 - biosynthesis of pyrimidine is not completely adequate, especially in neural tissue)

    nucleotides


    Nucleotide metabolism part 2 pyrimidine biosynthesis l.jpg

    Nucleotide metabolism – Part 2 is not completely adequate, especially in neural tissue)(pyrimidine biosynthesis)

    By

    Henry Wormser, Ph.D

    Professor of Medicinal Chemistry


    Synthesis of pyrimidine ribonucleotides l.jpg
    Synthesis of pyrimidine ribonucleotides is not completely adequate, especially in neural tissue)

    • shorter pathway than for purines

    • base is made first, then attached to ribose-P (unlike purine biosynthesis)

    • only 2 precursors (aspartate and glutamine, plus HCO3-) contribute to the 6-membered ring

    • requires 6 steps (instead of 11 for purine)

    • the product is UMP (uridine monophosphate)


    Origin of atoms in pyrimidine ring l.jpg
    Origin of atoms in pyrimidine ring is not completely adequate, especially in neural tissue)


    Slide45 l.jpg

    The big picture is not completely adequate, especially in neural tissue)


    Step 1 synthesis of carbamoyl phosphate l.jpg
    Step 1: synthesis of carbamoyl phosphate is not completely adequate, especially in neural tissue)

    • Condensation of glutamine, bicarbonate in the presence of ATP

    • Carbamoyl phosphate synthetase exists in 2 types: CPS-I which is a mitochondrial enzyme and is dedicated to the urea cycle and arginine biosynthesis) and CPS-II, a cytosolic enzyme used here


    Step 1 pyrimidine synthesis l.jpg
    Step 1: pyrimidine synthesis is not completely adequate, especially in neural tissue)

    CPS-II is the major site of regulation in animals: UDP and

    UTP inhibit the enzyme and ATP and PRPP activate it

    It is the committed step in animals


    Step 2 synthesis of carbamoyl aspartate l.jpg
    Step 2: synthesis of carbamoyl aspartate is not completely adequate, especially in neural tissue)

    • enzyme is aspartate transcarbamoylase (ATCase)

    • catalyzes the condensation of carbamoyl phosphate with aspartate with the release of Pi

    • ATCase is the major site of regulation in bacteria; it is activated by ATP and inhibited by CTP

    • carbamoyl phosphate is an “activated” compound, so no energy input is needed at this step


    Step 2 pyrimidine synthesis l.jpg
    Step 2: pyrimidine synthesis is not completely adequate, especially in neural tissue)


    Step 3 ring closure to form dihydroorotate l.jpg
    Step 3: ring closure to form dihydroorotate is not completely adequate, especially in neural tissue)

    • enzyme: dihydroorotase

    • forms a pyrimidine from carbamoyl aspartate

    • water is released in this process


    Step 3 pyrimidine synthesis l.jpg
    Step 3: pyrimidine synthesis is not completely adequate, especially in neural tissue)


    Slide52 l.jpg

    • the first 3 enzymatic reactions are catalyzed by 3 separate proteins/enzymes in E. coli

    • in animals, all 3 steps are found in a multifunctional enzyme (210 kD). This allows “channeling” of the substrates and products between active sites without releasing them to the medium where they could be degraded.

    • The acronym CAD is used as a name for the multienzyme: carbamoyl phosphate synthetase, aspartate transcarbamoylase and dihydroorotase

    • channeling also increases the overall rate of multistep processes


    Step 4 oxidation of dihydroorotate to orotate l.jpg
    Step 4: oxidation of dihydroorotate to orotate proteins/enzymes in E. coli

    • an irreversible reaction

    • enzyme: dihydroorotate dehydrogenase

    • oxidizing power is derived from quinones (thru coenzyme Q)


    Step 4 pyrimidine synthesis l.jpg
    Step 4: pyrimidine synthesis proteins/enzymes in E. coli


    Step 5 acquisition of ribose phosphate moiety l.jpg
    Step 5: acquisition of ribose phosphate moiety proteins/enzymes in E. coli

    • enzyme: orotate phosphoribosyl transferase

    • ribose phosphate originates from PRPP

    • product is orotidine-5’-monophosphate (OMP)

    • orotate phosphoribosyl transferase is also used in salvage of uracil and cytosine to their corresponding nucleotide


    Step 5 pyrimidine synthesis l.jpg
    Step 5: pyrimidine synthesis proteins/enzymes in E. coli


    Step 6 decarboxylation of omp l.jpg
    Step 6: decarboxylation of OMP proteins/enzymes in E. coli

    • enzyme: OMP decarboxylase

    • product: uridine monophosphate (UMP)

    • in animals, steps 5 and 6 are catalyzed by a single polypeptide with 2 active sites


    Step 6 pyrimidine synthesis l.jpg
    Step 6: pyrimidine synthesis proteins/enzymes in E. coli


    Slide60 l.jpg

    The big picture again proteins/enzymes in E. coli


    Orotic aciduria l.jpg
    Orotic aciduria proteins/enzymes in E. coli

    • an inherited human disease caused by a deficiency in the multifunctional enzyme that catalyzes the last 2 steps in the pyrimidine synthesis

    • large amounts of orotic acid in urine

    • retarded growth and severe anemia

    • treat by administration (injection) of uridine and/or cytidine


    Leflunomide arava l.jpg
    Leflunomide (Arava) proteins/enzymes in E. coli

    • Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.

    • It is currently used as a DMARD in patients with serious rheumatoid arthritis


    Leflunomide arava63 l.jpg
    Leflunomide (Arava) proteins/enzymes in E. coli


    Activation of leflunomide l.jpg
    Activation of leflunomide proteins/enzymes in E. coli

    Opening of the isoxazole yields a reactive compound which

    can then inhibit the enzyme dihydroorotate dehydrogenase


    Synthesis of uridine and cytidine triphosphate l.jpg
    Synthesis of uridine and cytidine triphosphate proteins/enzymes in E. coli

    (in bacteria, ammonia donates the amino group)


    Regulation of pyrimidine nucleotide biosynthesis l.jpg
    Regulation of pyrimidine nucleotide biosynthesis proteins/enzymes in E. coli

    UTP and CTP are feeback inhibitors of CPS II


    Formation of deoxyribonucleotides l.jpg
    Formation of deoxyribonucleotides proteins/enzymes in E. coli

    All pathways shown previously led to synthesis of ribonucleotides

    dADP, dGDP, dUDP and dCDP are all synthesized by the same enzyme

    Synthesized from nucleoside diphosphate (not mono or triphosphate) by

    ribonucleotide reductase


    Synthesis of dtmp l.jpg
    Synthesis of dTMP proteins/enzymes in E. coli

    • Methylation of d-UMP via N5,N10-methylene THF

    • Reaction inhibited by 5-fluorouracil (Efudex)


    Slide72 l.jpg

    Activation of 5-fluorouracil proteins/enzymes in E. coli


    Dihydrofolate reductase l.jpg
    Dihydrofolate reductase proteins/enzymes in E. coli


    Slide76 l.jpg

    Next - Part 3: catabolism proteins/enzymes in E. coli


    Nucleotide metabolism part 3 nucleotide degradation l.jpg

    Nucleotide metabolism – Part 3 proteins/enzymes in E. coli(nucleotide degradation)

    By

    Henry Wormser, Ph.D

    Professor of Medicinal Chemistry


    Nucleotide degradation l.jpg
    Nucleotide degradation proteins/enzymes in E. coli


    Slide79 l.jpg

    Degradation proteins/enzymes in E. coli

    of AMP


    Pentostatin l.jpg
    PENTOSTATIN proteins/enzymes in E. coli

    previously called deoxycoformycin (DCF)

    a purine analog with a 7-membered-ring

    potent inhibitor of adenosine deaminase

    ADA is a key enzyme which regulates

    adenosine levels in cells

    indicated for refractory hairy cell leukemia

    other uses: chronic lymphocytic leukemia

    and lymphomas


    Adenosine deaminase l.jpg
    Adenosine deaminase proteins/enzymes in E. coli


    Ada deficiency l.jpg
    ADA deficiency proteins/enzymes in E. coli

    • In the absence of ADA lymphocytes are destroyed

    • deoxyadenosine is not destroyed, is converted to dAMP and then into dATP

    • dATP is a potent feedback inhibitor of deoxynucleotide biosynthesis

    • this leads to SCID (severe combined immunodeficiency disease)

    • Infants with this deficiency have a high fatality rate due to infections


    Ada deficiency84 l.jpg
    ADA deficiency proteins/enzymes in E. coli

    • treatment consists of administering pegylated ADA which can remain in the blood for 1 – 2 weeks

    • more efficient is gene therapy: replacing the gene that is missing or defective

    • gene therapy has been performed on selected patients


    Slide85 l.jpg

    Degradation of proteins/enzymes in E. coli

    GMP and XMP


    Catabolism of purines l.jpg
    CATABOLISM OF PURINES proteins/enzymes in E. coli


    Slide89 l.jpg
    GOUT proteins/enzymes in E. coli

    • a disorder associated with abnormal amounts of urates in the body

    • early stage: recurring acute non-articular arthritis

    • late stage: chronic deforming polyarthritis and eventual renal complication

    • disease with rich history dating back to ancient Greece


    Slide90 l.jpg
    GOUT proteins/enzymes in E. coli

    • once fashionable to associate gout with intelligence

    • people with gout:

      • Isaac Newton

      • Benjamin Frankin

      • Martin Luther

      • Charles Darwin

      • Samuel Johnson


    Slide91 l.jpg
    Gout proteins/enzymes in E. coli

    • prevails mainly in adult males

    • rarely encountered in premenopausal women

    • symptoms are cause by deposition of crystals of monosodium urate monohydrate (can be seen under polarized light)

    • usually affect joints in the lower extremities (the big toe is the classic site)


    Slide92 l.jpg
    Gout proteins/enzymes in E. coli


    Four stages of gout l.jpg
    Four Stages of Gout proteins/enzymes in E. coli

    1. asymptomatic hyperuricemia

    2. acute gouty arthritic attacks

    3. asymptomatic intercritical period

    4. tophaceous gout (characterized by the formation of tophi in joints)

    • podagra (big toe)

    • cheiagra (wrist) according to Hippocrates

    • gonadra (knee)


    Diagnostic features l.jpg
    Diagnostic features proteins/enzymes in E. coli

    • usually affect joints in the lower extremities ( 95%)

    • onset is fast and sudden

    • pain is usually severe; joint may be swollen, red and hot

    • attack may be accompanied by fever, leukocytosis and an elevated ESR


    Drugs which may induce hyperuricemia l.jpg
    Drugs which may induce hyperuricemia proteins/enzymes in E. coli

    • niacin

    • thiazides and other diuretics

    • low dose aspirin

    • pyrazinamide

    • ethambutol

    • cyclosporine

    • cytotoxic drugs


    Non pharmacological approaches l.jpg
    Non-pharmacological approaches proteins/enzymes in E. coli

    • Avoid purine rich foods:

      • red meat and organ meat (liver, kidneys)

      • shellfish, anchovies, mackerel, herring

      • meat extracts and gravies

      • peas and beans, aspargus, lentils

      • beer, lager, other alcoholic beverages

    • Weight loss

    • Control alcohol (binge drinking)


    Pharmacological management of gout l.jpg
    Pharmacological management of gout proteins/enzymes in E. coli

    • based on the premise that the hyperuricemia is due to both overproduction and underexcretion of uric acid

    • symptomatic relief of pain is also achieved with analgesics (i.e. indomethacin)

    • drugs used:

      • analgesics (NSAIDs)

      • uricosuric agents

      • xanthine oxidase inhibitors


    Therapy of acute gout l.jpg
    Therapy of acute gout proteins/enzymes in E. coli

    • treat with colchicine or NSAIDs

    • avoid aspirin

    • do not treat with allopurinol or uricosuric drugs

    • uric acid lowering agents should never be started or stopped during acute attack

    • pain resolution occurs within 48-72 hrs


    Colchicine l.jpg
    Colchicine proteins/enzymes in E. coli

    a non-basic alkaloid from the seeds and corms of Colchicum autumnale

    (Meadow Safron)


    Colchicine100 l.jpg
    COLCHICINE proteins/enzymes in E. coli

    • used in the symptomatic treatment of acute attacks of gout

    • decreases leukocyte motility, decreases phagocytosis and lactic acid production

    • not used in other forms of arthritis

    • a very potent drug

    • can cause severe GI distress and abdominal pain


    Probenecid benemid l.jpg
    Probenecid (Benemid) proteins/enzymes in E. coli

    A uricosuric agent


    Probenecid benemid102 l.jpg
    Probenecid (Benemid) proteins/enzymes in E. coli

    • inhibits the tubular reabsorption of uric acid

    • it can also inhibit the tubular excretion of certain organic acid via the transporter

    • used in gout to promote the elimination of uric acid (not effective in acute attack)

    • also used to enhance plasma concentration of certain antiinfectives (beta lactams)


    Allopurinol zyloprim l.jpg
    ALLOPURINOL (Zyloprim) proteins/enzymes in E. coli

    • prevention of attacks of gouty arthitis and nephropathy

    • also used during chemotherapy of cancer and to prevent recurrent calcium oxalate calculi

    • metabolized to oxypurinol (also an inhibitor of xanthine oxidase)

    • inhibits the metabolism of certain anticancer drugs (6-MP, azathioprine)


    Allopurinol zyloprim104 l.jpg
    Allopurinol (Zyloprim) proteins/enzymes in E. coli

    An inhibitor of xanthine oxidase; prevents the formation of uric acid from

    precursorial purines


    Fate of uric acid l.jpg
    Fate of uric acid proteins/enzymes in E. coli

    • in human and other primates uric acid is the final product of purine degradation and is excreted in the urine

    • the same is true in bird, reptiles and many insects

    • in other mammals uric acid is oxidized to allantoin (urate oxidase)

    • teleost (bony) fish convert allantoin to allantoic acid

    • cartilaginous fish and amphibian further degrade allantoic acid to urea

    • and finally marine invertebrates decompose urea to ammonia


    Rasburicase elitek l.jpg
    Rasburicase (Elitek) proteins/enzymes in E. coli

    A recombinant form of uric

    acid oxidase. Used for initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.


    Slide109 l.jpg

    Catabolism of a pyrimidine proteins/enzymes in E. coli


    Formation of deoxyribonucleotides112 l.jpg
    Formation of deoxyribonucleotides proteins/enzymes in E. coli

    • ribonucleotide reductase studied by JoAnne Stubbe (Wisconsin, then MIT)

    • very complex enzyme; contains:

      • Tyrosine radical

      • 2 non-heme irons

      • Two catalytically active cysteine residues

      • Cys are reduced by other proteins – thioredoxin

      • Ribo. Reductase is the therapeutic target of the anticancer drug hydroxyurea


    Mechanism of ribonucleotide reductase l.jpg
    Mechanism of ribonucleotide reductase proteins/enzymes in E. coli

    • Free radical mechanism involving tyrosyl residues and cysteine residues on the enzyme

    • The enzyme is a dimer of dimers:

      • R1 – a dimer of identical a subunits (85 kD each)

      • R2 – a dimer of identical b subunits (45 kD each)


    Reduction of the disulfide bond in ribonucleotide reductase l.jpg
    Reduction of the disulfide bond in ribonucleotide reductase proteins/enzymes in E. coli

    • 2 proteins can perform this reductive reaction:

      • Thioredoxin (ubiquitous 12 kD monomer)

      • Glutaredoxin which functions similarly to thioredoxin. Oxidized glutredoxin is reduced by glutathione (g-glutamylcysteinylglycine)



    Hydroxyurea hydrea l.jpg
    HYDROXYUREA (Hydrea) proteins/enzymes in E. coli

    • inhibits the enzyme ribonucleotide reductase

      • this enzyme causes ribonucleotides to be converted to deoxyribonucleotides

      • DNA synthesis cannot occur

      • cell are killed in the S phase

      • drug holds other cells in the G1 phase

    • primarily used to treat chronic myelogenous leukemia

    • cancer cell develop resistance by:

      • increasing quantity of inhibited enzyme

      • decreasing sensitivity of enzyme for inhibitor

    • used orally

    • major side effect is leukopenia


    Gemcitabine gemzar l.jpg
    GEMCITABINE (Gemzar) proteins/enzymes in E. coli

    Another inhibitor of ribonucleotide reductase:indicated for non-small cell lung cancer (usually with cisplatin) also first line treatment for non-resectable pancreatic cancer


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    The purine nucleotide cycle for anaplerotic replenishment of citric acid cycle intermediates in skeletal muscle


    For quiz review check out this website l.jpg
    For quiz review: check out this of citric acid cycle intermediates in skeletal musclewebsite

    http://www.wiley.com/college/fob/quiz/quiz22/quizzer22.html


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    The end of citric acid cycle intermediates in skeletal muscle


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