Nucleotides – Purine and Pyramidine Synthesis and degradation | Anatomy2Medicine
Nucleotides - Purine and Pyrimidine Synthesis and degradation

Nucleotides – Purine and Pyramidine Synthesis and degradation

Nucleotides

    • PURines (A, G)—2 rings. (PURe As God)
    • PYrimidines (C, T, U)—1 ring. (CUT the PY (pie))
    • Thymine has a methyl group .

 

  • Deamination of cytosinemakes uracil.

 

    • Uracil found in RNA; thymine in DNA.
    • G-C bond (3 H bonds) stronger than A-T bond (2 H bonds).
    • G-C content →↑ melting temperature of DNA.
    • GAG—Amino acids necessary for purine synthesis:

 

  • Glycine
  • Aspartate
  • Glutamine

 

    • NucleoSide= base + (deoxy)ribose (Sugar).

 

  • NucleoTides = base + (deoxy)ribose + phosphaTe; linked by 3′-5′phosphodiesterbond.

 

 

Exam MCQ

A Pentose with a 5′ phosphate group, a 2′ OH group and 1′ pyrimidine group describes which of the following structures ?

  1. a) Cytosine
  2. b) Thymidine
  3. c) Thymidylate
  4. d) Cytidylate
  5. e) Guanosine

Ans  d

 

Ans C

Exam MCQ

Ans D

 

  • De novo pyrimidine and purine synthesis
  • Purines :

 

        • Start with sugar + phosphate (PRPP)

 

  • Add base
  • Pyrimidines :
  • Make temporary base (orotic acid)
  • Add sugar + phosphate (PRPP)
  • Modify base
  • Ribonucleotides are synthesized first and are converted to deoxyribonucleotides by ribonucleotidereductase.

 

      • Carbamoyl phosphate is involved in 2 metabolic pathways: de novo pyrimidine synthesis and the urea cycle

 

Exam MCQ

Feedback inhibition of pyrimidine nucleotide synthesis can occur by which of the following ?

  1. a) Increased activity of Carbamoyl phosphate synthetase b) Increased activity of Aspartate transcarbamoylase
    c) CTP allosteric effects
    d) UMP competitive inhibition
  2. e) TTP allosteric effects

Ans C

Exam MCQ

In tissues that do not carry out active de novo synthesis, maintenance of an adequate supply of adenine nucleotides:

  1. occurs primarily by adenine salvage using A-PRT.
  2. requires ATP uptake from the blood.
  3. depends upon the action of nucleoside phosphorylase
  4. is accomplished entirely by the action of adenylate kinase.
  5. involves hypoxanthine salvage using HG-PRT.

Ans E

  1. A-PRT is not considered to be the major enzyme because we produce very little free adenine.
  2. Phosphorylated compounds generally don’t cross the plasma membrane.
  3. This enzyme is primarily for the salvage of pyrimidines.
  4. Adenylate kinase equilibrates ATP, AMP and ADP
  5. Correct. The IMP formed is converted to AMP by amination with aspartate.

 

Exam MCQ

Orotic acid would be an intermediate

  1. Catabolism of guanine
  2. Catabolism of uracil
  3. A only
  4. B only
  5. Both A and B
  6. Neither A or B

The correct answer is (D).

Orotic acid is an intermediate in the synthesis of the pyrimidines

 

Exam MCQ

The major control of de novo pyrimidine nucleotide synthesis in man is:

  1. feedback inhibition of glutamine-PRPP amidotransferase.
  2. feedback inhibition of aspartate transcarbamylase.<
  3. availability of N-acetyl glutamate.
  4. substrate availability.
  5. competitive inhibition of carbamoyl phosphate synthetase II.

The correct answer is (E).

Comments:

  1. This is the control for purine nucleotide synthesis.
  2. This is true in bacteria but not in man.
  3. This is the control of CPS I which leads to urea synthesis but NAG is not an activator of CPS II.
  4. Although this is true for some pathways, eg. degradation of purines, it is not true for this one.
  5. Correct. UTP is competitive with ATP in this reaction.

Exam MCQ

Direct sources of purine ring atoms in the de novo synthesis of IMP include:

  1. glutamine.
  2. a component of the tetrahydrofolate one-carbon pool.
  3. aspartate.
  4. glycine.
  5. 1, 2 and 3
  6. 1 and 3
  7. 2 and 4
  8. 4 only
  9. All four

The correct answer is (E).

Comments:

  1. Nitrogens 3 and 9
  2. Carbons 2 and 8
  3. Nitrogen 1
  4. Atoms 4, 5, and 7

Exam MCQ

Which of the following would NOT be expected to contribute to hyperuricemia (gout)?

  1. Unusually high levels of PRPP
  2. Inhibition of xanthine oxidase
  3. Unusually high turnover of nucleic acids
  4. High activity of adenosine deaminase
  5. Deficiency of HG-PRT

The correct answer is (B).

Comments:

    • Since the only control on uric acid synthesis is the availablility of substrates, anything which contributes to an increase in substrate concentration could lead to hyperuricemia.
    • PRPP overcomes the normal feedback inhibition of synthesis. Both C and D would lead to more substrates.

 

  • Since HG-PRT is an active consumer of PRPP and also the main salvage mechanism for both the guanine and adenine nucleotides, a deficiency would lead to high synthesis of nucleotides and, therefore, uric acid. An inhibitor of xanthine oxidase would specifically lower uric acid levels.

 

Exam MCQ

A nucleoside phosphorylase:

  1. cleaves a nucleoside with the production of ribose 1-phosphate.
  2. is necessary for the major salvage pathway for pyrimidines.
  3. is used in the degradation of purine nucleotides.
  4. is responsible for the equilibration of nucleoside monophosphates and nucleoside diphosphate.
  5. 1, 2 and 3
  6. 1 and 3
  7. 2 and 4
  8. 4 only
  9. All four

The correct answer is (A).

Comments:

  1. As the name implies, the reaction is a phosphorolysis.
  2. The pyrimidine salvage is a two-step pathway. The next step is catalyzed by a kinase.
  3. This is true for the degradation of both purine and pyrimidine nucleosides
  4. This equilibration is catalyzed by nucleoside monophosphate kinases.

Exam MCQ

If a cell has an adequate supply of adenine nucleotides byt requires more guanine nucleotides for protein synthesis:

  1. Glutamine-PRPP amidotransferase will not be fully inhibited.
  2. AMP will be a feedback inhibitor of the condensation of IMP with aspartate.
  3. ATP will stimulate the production of GMP from IMP.
  4. ATP will inhibit nucleoside diphosphatereductase..
  5. 1, 2 and 3
  6. 1 and 3
  7. 2 and 4
  8. 4 only
  9. All four

The correct answer is (A).

Comments:

  1. The synergistic effect of both AMP and GMP is needed for complete inhibition.
  2. This assures that the limited amount of IMP formed will be channeled to the production of the guanine nucleotides.
  3. ATP provides the energy for this branch.
  4. The formation of dATP is not applicable in this situation.

@ Major controls of de novo AMP synthesis include:

  1. allosteric inhibition by GMP.
  2. allosteric inhibition by AMP.
  3. availability of PRPP.
  4. stimulation by GTP..
  5. 1, 2 and 3
  6. 1 and 3
  7. 2 and 4
  8. 4 only
  9. All four

The correct answer is (E).

Comments:

 

allosteric inhibition by GMP , AMP – Both of these are inhibitors of gln-PRPP amidotransferase and their effect is synergistic.

  1. Since the kinetics of gln-PRPP amidotransferasearesIgmoidal with respect to PRPP, and the concentrations are in the steep part of the curve, [PRPP] can significantly influence the rate.
  2. GTP provides the energy for the branch from IMP to AMP.

Exam MCQ

Aspartate plays a role in all of the following EXCEPT:

  1. conversion of UTP to CTP.
  2. de novo synthesis of AMP.
  3. de novo synthesis of orotic acid
  4. maintenance of the adenine nucleotide pool by a salvage mechanism.
  5. the synthesis of most proteins.

 

The correct answer is (A).

Comments:

  1. UTP to CTP does involve an amination but the amino group used is the amide of glutamine.
  2. Aspartate provides nitrogen 1 of the purine ring.
  3. The whole aspartate molecule (at least the carbons and nitrogen) becomes part of the pyrimidine ring.
  4. Maintenance of the adenine nucleotide pool involves salvaging hypoxanthine and then converting IMP to AMP using aspartate.
  5. Most, probably all, proteins include aspartate.
    • Various antineoplastic and antibiotic drugs function by interfering with nucleotide synthesis: (A VeryhIgh yield MCQ Topic)
      • Leflunomideinhibits dihydroorotate dehydrogenase (MCQ)
      • Mycophenolate and ribavirin inhibit IMP dehydrogenase (MCQ)
      • Hydroxyureainhibits ribonucleotidereductase (MCQ)
      • 6-mercaptopurine (6-MP) and its prodrug azathioprine inhibit de novo purine synthesis (MCQ)
      • 5-fluorouracil (5-FU) inhibits thymidylate synthase (deoxythymidine monophosphate [dTMP]) (MCQ)
      • Methotrexate (MTX), trimethoprim (TMP), and pyrimethamineinhibit dihydrofolatereductase (dTMP) in humans, bacteria, and protozoa, respectively (MCQ)

 

  • Exam MCQ

 

Methotrexate is an inhibitor of dihydrofolatereductase. Administration of methotrexate would inhibit:

  1. de novo synthesis of UMP.
  2. conversion of dUMP to dTMP.
  3. conversion of IMP to GMP.
  4. de novo synthesis of IMP.
  5. 1, 2 and 3
  6. 1 and 3
  7. 2 and 4
  8. 4 only
  9. All four

The correct answer is (C).

Comments:

  1. de novo synthesis of UMP.: Pyrimidine synthesis doesn’t involve the one-carbon pool.
  2. conversion of dUMP to dTMP: The methyl group that appears in dTMP is synthesized during the transfer of the methylene group from the one-carbon pool.
  3. conversion of IMP to GMP : This conversion involves an oxidation and an amination but no additional carbons.
  4. de novo synthesis of IMP : Purine synthesis requires two components of the one-carbon pool. In the absence of this enzyme, dietary folate could not be reduced to the tetrahydro form necessary for carbon carriage.

 

Exam MCQ

Allopurinol is an inhibitor of xanthine oxidase. Administration of allopurinol to a patient with gout and normal HG-PRT levels would be expected to lead to all of the following EXCEPT:

 

  1. decreased de novo synthesis of IMP.
  2. decreasedurate in the urine.
  3. an increase of hypoxanthine in the blood./a>
  4. increased levels of PRPP .
  5. increased xanthine in the blood.

The correct answer is (D).

Comments:

  1. As long as HG-PRT is available, the increased xanthine and hypoxanthine will be salvaged to GMP and IMP, both of which inhibit the rate limiting step of the synthesis..
  2. Allopurinol directly inhibits the production of urate.
  3. Hypoxanthine is a substrate for the inhibited enzyme and, therefore, increases.
  4. As long as HG-PRT is available, the increasing xanthine and hypoxanthine will consume PRPP. Contrast this to the situation with the Lesch-Nyhan syndrome.
  5. Xanthine is a substrate for the inhibited enzyme.

 

 

Purine salvage deficiencies

 

  • Adenosine deaminase deficiency

 

      • Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotidereductaseprevents DNA synthesis and thus decreases  lymphocyte count.
      • One of the major causes of autosomal recessive SCID.

 

  • Lesch-Nyhan syndrome

 

      • Defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP

 

  • Results in excess uric acid production and de novo purine synthesis.

 

    • X-linked recessive.
    • Findings: intellectual disability, self-mutilation, aggression, hyperuricemia, gout, dystonia.
    • Treatment: allopurinol or febuxostat (2nd line).

 

Exam MCQ

A 7-year-old boy suffers from mental retardation and self mutilation and has an increased levels of serum uric acid. These symptoms are characteristic of LeschNyhan syndrome, which is due to defective-

  1. a) Salvage pathway for pyrimidine biosynthesis
  2. b) Denovo synthesis of pyrimidines
  3. c) Xanthine oxidase
  4. d) HGPRT (Hypoxanthine Guanine PhosphoRibosylTransferase)
  5. e) Formyltransferase

Ans D

Exam MCQ

A 58-year-old man is awoken by a throbbing ach in his great toe. He had a similar attack earlier also, after indulging in a rich meal. On examination, he is noted to have an angry inflammed great toe and several nodules on the antihelix of his ear. Inhibition of which of the following enzymes might prevent the occurrence of such symptoms ?

  1. a) Amidotransferase
    b) PRPP synthetase
    c) Xanthine oxidase
    d) Orotatephosphoribosyltransferase
  2. e) Carbamoyl phosphate synthetase-II

Ans C

Exam MCQ

A child is noted to have recurrent respiratory infections that necessitate hospitalization. His lab tests demonstrate a decrease in T cells, B cells , natural killer cells and decreased antibodies. He is found to have severe combined immunodeficiency . The enzyme that is defective in this disorder is important in which of the following processes ?

  1. a) Conversion of ribonucleotides to deoxyribonucleotides
  2. b) Formation of AMP
  3. c) Synthesis of UMP
    d) Conversion of dUMP to dTMP
    e) Conversion of adenosine to inosine

Ans E

Exam MCQ

A physician evaluates a 32-year-old patient for fatigue. The patient is found to have an elevated white blood cell count and an enlarged spleen. A referral to an oncologist results in a diagnosis of chronic myelogenous leukemia. Treatment with hydroxyurea, a ribonucleotidereductase inhibitor is begun. The normal functioning of this enzyme is to do which of the followings ?

  1. a) Converts xanthine to uric acid
  2. b) Converts ribonucleotides to deoxyribonucleotides
  3. c) Degrades guanine to xanthine
    d) Degrades AMP to IMP
    e) Converts PRPP to phosphoribosylamine

Ans B

 

Exam MCQ

A 56-year -old diabetic with end stage renal disease receives a kidney transplant from his son. His nephrologist is concerned for the possibility of transplant rejection and puts the patient on mycophenolic acid, that inhibits which of the following enzyme in the synthesis of nucleotides ?

  1. a) PRPP synthetase
  2. b) IMP dehydrogenase
  3. c) Adenylo succinate synthetase
  4. d) Ribonucleotidereductase
    e) Adenylosuccinase

Ans B

Exam MCQ

The conversion of Inosine mono phosphate-

  1. a) To Adenosine mono phosphate (AMP) is inhibited by Guanosine mono phosphate(GMP)
  2. b) To AMP requires uridine mono phosphate (UMP)
    c) To GMP requires GMP kinase
    d) To GMP requires Glutamine
  3. e) To Guanosine di phosphate (GDP) requires ribonucleotidereductase

Ans D

Exam MCQ

Which is the rate limiting step of pyrimidine synthesis that exhibits allosteric inhibition by cytidine triphosphate-

  1. a) Aspartate transcarbamoylase
    b) Hypoxanthine Guanine phosphoribosylTransferase
  2. c) Thymidylate synthase
    d) Xanthine oxidase
    e) PRPP synthetase

Ans A

Exam MCQ

Which of the following is an analogue of hypoxanthine ?

  1. a) Ara C
  2. b) Allopurinol
  3. c) Ribose phosphate d) PRPP

e)5-FU

Ans B

Exam MCQ

Which of the following is a required substrate for purine biosynthesis ?

  1. a) 5- methyl thymidine
  2. b) Ara -C
    c) Ribose phosphate
  3. d) PRPP
  4. e) 5-Fluoro uracil

Ans D

Exam MCQ

A 4- year old presents to a pediatric clinic with megaloblastic anemia and failure to thrive. Blood biochemistry reveals “Oroticaciduria”. Enzyme measurement of the white blood cells reveals a deficiency of pyrimidine biosynthesis enzyme OrotatePhospho ribose

transferase and abnormally high activity of the enzyme Aspartate transcarbamoylase. Which of the following treatment will reverse all symptoms ?

  1. a) Plasmaphresis
  2. b) Dietary supplementation of PRPP
  3. c) Oral thymidine monophosphate
    d) Oral Uridine monophosphate

Ans d

Administration of cytidine monophosphate and uridine monophosphate reduces urinary orotic acid and the anemia.

Administration of uridine, which is converted to UMP, will bypass the metabolic block and provide the body with a source of pyrimidine.

Exam MCQ

In patients with LeschNyhan Syndrome, purine nucleotides are overproduced and over excreted. The hypoxanthine analogue Allopurinol, which effectively treats gout , has no effect on the severe neurological symptoms of Lesch- Nyhan patients because it does not-

  1. a) Decrease de novo purine synthesis
  2. b) Decrease denovo pyrimidine bio synthesis
  3. c) Decrease urate synthesis
  4. d) Increase PRPP levels(Phosphoribosyl pyrophosphate)
  5. e) Inhibit xanthine oxidase

Ans A

Exam MCQ

Which out of the following conditions is associated with hypouricemia ?

  1. a) LeschNyhan syndrome
    b) Adenosine deaminase deficiency
  2. c) Over activity of PRPP synthetase
  3. d) Over activity of amidotransferase
  4. e) Von Gierke’s disease

Ans B

Exam MCQ

Which of the following contributes nitrogen atoms to both purine and pyrimidine rings ?

  1. a) Aspartate
    b) Carbamoyl phosphate
  2. c) Carbon dioxide
    d) Glutamate
    e) Tetrahydrofolate

Ans A

 

Exam MCQ

Purine nucleotide biosynthesis can be inhibited by which of the followings ?

  1. a) Guanosine triphosphate
  2. b) Uridine mono phosphate
  3. c) Adenosine mono phosphate

d)Adenosine tri phosphate
e) Inosinediphosphate

Ans C

Exam MCQ

Which base derivative can serve as a precursor for the synthesis of two of the other pyrimidine base derivatives ?

  1. a) Cytidine triphosphate
    b) Uridine mono phosphate
    c) Adenosine mono phosphate
    d) deoxy thymidine mono phosphate
  2. e) deoxy Adenosine mono phosphate

Ans B

Exam MCQ

 

Which statement best describes Xanthine ?

  1. a) It is a direct precursor of Guanine
    b) It covalently binds to Allopurinol
    c) It is oxidized to form Uric acid
    d) It is oxidized to form Hypoxanthine
    e) It is a substrate rather than a product of the enzyme Xanthine oxidas