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.

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.

  $\begin{array}{l}{\text{PRPP + glutamine + H}}_{\text{2}}\text{O}\to {\text{β-5-phosphoriboslyamine + glutamine + PP}}_{\text{i}}\\ \text{ By glutamine: PRPP amidophosphoribosyl transferase}\\ {\text{FGAR + ATP glutamine +H}}_2\text{O}\to {\text{FGAM +ADP + glutamine + P}}_i\\ \text{ By FGAM synthetase}\\ {\text{XMP + glutamine +ATP + H}}_2\text{O }\to {\text{ GMP + glutamine +AMP +PP}}_i\\ \text{ By GMP synthetase}\end{array}$

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

$\begin{array}{l}{\text{UTP + glutamine +ATP + H}}_2\text{O}\to {\text{CTP +glutamine + ADP + P}}_i\\ \text{ By CTP synthetase}\end{array}$

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:

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.

  $\begin{array}{l}{\text{PRPP + glutamine + H}}_{\text{2}}\text{O}\to {\text{β-5-phosphoriboslyamine + glutamine + PP}}_{\text{i}}\\ \text{ By glutamine: PRPP amidophosphoribosyl transferase}\\ {\text{FGAR + ATP glutamine +H}}_2\text{O}\to {\text{FGAM +ADP + glutamine + P}}_i\\ \text{ By FGAM synthetase}\\ {\text{XMP + glutamine +ATP + H}}_2\text{O }\to {\text{ GMP + glutamine +AMP +PP}}_i\\ \text{ By GMP synthetase}\end{array}$

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

$\begin{array}{l}{\text{UTP + glutamine +ATP + H}}_2\text{O}\to {\text{CTP +glutamine + ADP + P}}_i\\ \text{ By CTP synthetase}\end{array}$

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.

$\begin{array}{l}{\text{dUMP + N}}^{10}\text{-formyl-THF }\to \text{ dTMP +DHF}\\ \text{ By thymidylate synthase}\end{array}$

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.

$\begin{array}{l}{\text{GAR + N}}^{10}\text{-formyl-THF }\to \text{ FGAR + THF}\\ \text{ By GAR transformylase}\\ {\text{AICAR + N}}^{10}\text{-formyl-THF }\to \text{ FAICAR + THF}\\ \text{ By AICAR transformylase}\end{array}$

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

$\begin{array}{l}{\text{dUMP + N}}^{10}\text{-formyl-THF }\to \text{ dTMP +DHF}\\ \text{ By thymidylate synthase}\end{array}$

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.

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.

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.