Biochemistry
Biochemistry
6th Edition
ISBN: 9781305577206
Author: Reginald H. Garrett, Charles M. Grisham
Publisher: Cengage Learning
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Chapter 26, Problem 4P

Inhibition of Purine and Pyrimidine Metabolism by Pharmacological Agents Indicate which reactions of purine or pyrimidine metabolism are affected by the inhibitors (a) azaserine, (b) methotrexate, (c) sulfonamides, (d) allopurinol, and (e) 5-fluorouracil.

Expert Solution
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Interpretation Introduction

(a)

Interpretation:

A reaction of purine or pyrimidine metabolism is affected by the azaserine.

Concept Introduction:

Azaserine and DON are equivalents of glutamine and bind to glutamine-binding proteins. They can react with nucleophiles, leading to covalent modification and inactivation.

Answer to Problem 4P

Azaserine and DON are equivalents of glutamine and bind to glutamine-binding proteins. They can react with nucleophiles, leading to covalent modification and inactivation. The following reactions in purine synthesis are sensitive to these inhibitors.

  PRPP + glutamine + H2Oβ-5-phosphoriboslyamine + glutamine + PPi    By glutamine: PRPP amidophosphoribosyl transferaseFGAR + ATP glutamine +H2OFGAM +ADP + glutamine + Pi     By FGAM synthetaseXMP + glutamine +ATP + H2 GMP + glutamine +AMP +PPi                By GMP synthetase

There is another reaction that's sensitive to those inhibitors for the synthesis of pyrimidines.

UTP + glutamine +ATP + H2OCTP +glutamine + ADP + Pi                By CTP synthetase

Explanation of Solution

There are 3 structures that are analogs to amino acid, and that they are azaserine (O-diazoacetvl-Lserine) and a connected compound DON, and 6-diaxo-5-oxo-L-norleucine. Their structures are shown below:

Biochemistry, Chapter 26, Problem 4P , additional homework tip  1

Biochemistry, Chapter 26, Problem 4P , additional homework tip  2

Azaserine and DON are equivalents of glutamine and bind to glutamine-binding proteins. They can react with nucleophiles, leading to covalent modification and inactivation. The following reactions in purine synthesis are sensitive to these inhibitors.

  PRPP + glutamine + H2Oβ-5-phosphoriboslyamine + glutamine + PPi    By glutamine: PRPP amidophosphoribosyl transferaseFGAR + ATP glutamine +H2OFGAM +ADP + glutamine + Pi     By FGAM synthetaseXMP + glutamine +ATP + H2 GMP + glutamine +AMP +PPi                By GMP synthetase

There is another reaction that's sensitive to those inhibitors for the synthesis of pyrimidines.

UTP + glutamine +ATP + H2OCTP +glutamine + ADP + Pi                By CTP synthetase

Expert Solution
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Interpretation Introduction

(b)

Interpretation:

A reaction of purine or pyrimidine metabolism is affected by the methotrexate.

Concept Introduction:

Methotrexate is analogous to dihydrofolate in this it competes with folic acid with high affinity for binding sites on enzymes. Some reactions in purine synthesis are affected.

Answer to Problem 4P

The formation of tTMP in pyrimidine synthesis will be blocked by methotrexate sodium. The reaction is seen below.

dUMP + N10-formyl-THF  dTMP +DHF           By thymidylate synthase

Explanation of Solution

Methotrexate is analogous to dihydrofolate in this it competes with folic acid with high affinity for binding sites on enzymes. Some reactions in purine synthesis are affected.

GAR + N10-formyl-THF  FGAR + THF           By GAR transformylaseAICAR + N10-formyl-THF  FAICAR + THF    By AICAR transformylase

The formation of tTMP in pyrimidine synthesis will be blocked by methotrexate sodium. The reaction is seen below.

dUMP + N10-formyl-THF  dTMP +DHF           By thymidylate synthase

Expert Solution
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Interpretation Introduction

(c)

Interpretation:

A reaction of purine or pyrimidine metabolism is affected by the sulfonamides.

Concept Introduction:

Sulfonamides are structurally the same as para-aminobenzoic acid. They inhibit the assembly of folacin in bacterium.

Answer to Problem 4P

Ester synthesis in animals won't be littered with sulfonamides since folacin is an element of a dietary demand for animals.

Explanation of Solution

Sulfonamides are structurally the same as para-aminobenzoic acid. They inhibit the assembly of folacin in bacterium. This inhibition can happen as a result of they cannot produce folacin because of lack of substrate. Ester synthesis in animals won't be littered with sulfonamides since folacin is an element of a dietary demand for animals.

Expert Solution
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Interpretation Introduction

(d)

Interpretation:

A reaction of purine or pyrimidine metabolism is affected by the allupurinol.

Concept Introduction:

Xanthine enzyme can hydroxylate Zyloprim, a suicide substance of organic compound enzyme, to create alloxantine that binds to the catalyst and inactivates it.

Answer to Problem 4P

Organic compound is regenerate to uric acid via the catalyst organic compound enzyme, and excrement acids will not form as a result of its blocked because of each nucleoside and nucleoside that are metabolized to organic compound.

Explanation of Solution

Xanthine enzyme can hydroxylate Zyloprim, a suicide substance of organic compound enzyme, to create alloxantine that binds to the catalyst and inactivates it. Organic compound is regenerate to uric acid via the catalyst organic compound enzyme, and excrement acids will not form as a result of its blocked because of each nucleoside and nucleoside that are metabolized to organic compound.

Expert Solution
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Interpretation Introduction

(e)

Interpretation:

A reaction of purine or pyrimidine metabolism is affected by the 5-fluorouracil.

Concept Introduction:

5-fluorouracil is converted to 5-fluorodeoxyuridylate (FdUMP), which is a powerful inhibitor of thymidylate synthase.

Answer to Problem 4P

Even though 5-fluorouracil is not a significant inhibitor of nucleotide metabolism, it is converted to 5-fluorodeoxyuridylate (FdUMP), which is a powerful inhibitor of thymidylate synthase.

Explanation of Solution

Even though 5-fluorouracil is not a significant inhibitor of nucleotide metabolism, it is converted to 5-fluorodeoxyuridylate (FdUMP), which is a powerful inhibitor of thymidylate synthase.

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