Nucleotide Synthesis and Metabolism Quiz

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Questions and Answers

What are the two primary methods by which purine and pyrimidine bases can be synthesized?

Oxidation or reduction

Through fermentation or degradation

De novo synthesis or salvage pathways (correct)

Photosynthesis or respiration

Which of the following best describes 'salvage pathways' in nucleotide synthesis?

Creating nucleotides from free nucleotides and phosphate

Recycling existing bases to form nucleotides (correct)

Synthesizing nucleotides from amino acids

Recruiting nucleotides from cellular degradation processes

Which statement is true regarding the synthesis of nucleotide bases?

Pyrimidine bases cannot be formed through salvage pathways.

Both purine and pyrimidine bases can only be synthesized de novo.

Only purine bases are synthesized through salvage mechanisms.

Purine and pyrimidine bases can be synthesized both de novo and via salvage pathways. (correct)

What is the significance of de novo synthesis in nucleotide metabolism?

It provides a means to synthesize nucleotides from simple precursors. Signup and view all the answers

Which of the following compounds would be primarily involved in salvage pathways?

Nucleosides and free bases Signup and view all the answers

What is produced when a pentose sugar is added to a base?

A nucleoside Signup and view all the answers

Which of the following combinations correctly pairs a base with its corresponding nucleoside?

Adenine – deoxyadenosine Signup and view all the answers

What is the relationship between nucleosides and nucleotides?

Nucleotides contain one or more phosphate groups added to nucleosides. Signup and view all the answers

Which sugar is associated with the formation of deoxyribonucleosides?

2-Deoxyribose Signup and view all the answers

Which of the following statements is true regarding pyrimidine bases?

Uracil is a pyrimidine that pairs with adenine in RNA. Signup and view all the answers

What type of linkage is formed between a ribose and a base to create a nucleoside?

N-glycosidic linkage Signup and view all the answers

Where does the degradation of dietary nucleic acids primarily occur?

Small intestine Signup and view all the answers

What enzyme is responsible for degrading RNA to oligonucleotides?

Ribonuclease Signup and view all the answers

Which compound is produced when mononucleotides are hydrolyzed?

Nucleosides Signup and view all the answers

What do nucleosidases release from nucleosides during degradation?

Free purine and pyrimidine bases Signup and view all the answers

Which enzyme hydrolyzes oligonucleotides to mononucleotides?

Phosphodiesterase Signup and view all the answers

What component is released alongside free bases from the degradation of nucleosides?

Ribose-1-phosphate Signup and view all the answers

What is the first step in the degradation of dietary nucleic acids in the intestine?

Degradation to oligonucleotides Signup and view all the answers

Which enzyme is not involved in the degradation of dietary nucleic acids?

Pancreatic lipase Signup and view all the answers

What is the role of ribonucleotide reductase in cellular processes?

It maintains the supply of deoxyribonucleotides for DNA synthesis. Signup and view all the answers

How does dATP affect ribonucleotide reductase activity?

It inhibits the enzyme by binding to an allosteric site. Signup and view all the answers

What is the significance of the allosteric sites on ribonucleotide reductase?

They regulate both enzymatic activity and substrate specificity. Signup and view all the answers

During the purine salvage pathway, what is the ultimate goal?

To recycle nucleosides and free bases for RNA and DNA synthesis. Signup and view all the answers

What molecules act as immediate donors of hydrogen atoms in the enzymatic reaction described?

Two thiol (SH) groups on the enzyme Signup and view all the answers

Which tissue types are mentioned as deficient in the de novo synthesis of purines?

Brain cells, red blood cells, and white blood cells Signup and view all the answers

What is the effect of ATP binding at the allosteric site of ribonucleotide reductase?

It activates the enzymatic activity. Signup and view all the answers

NADPH plays a crucial role in which aspect of enzyme function?

In the regeneration of reduced thioredoxin. Signup and view all the answers

The activity of ribonucleotide reductase is necessary for which critical cellular process?

DNA replication Signup and view all the answers

Study Notes

Nucleotide Metabolism

Nucleotides are building blocks of nucleic acids (DNA & RNA)
They are non-essential nutrients, because they can be synthesized in the body.
Nucleotides are the main source of energy in the cell (e.g. ATP)
Nucleotides are components of many coenzymes (e.g. NAD, NADP, and FAD).
Nucleotides are components of secondary messengers of hormones (e.g. cAMP and cGMP).
Nucleotides are important regulatory compounds for many pathways of intermediary metabolism, inhibiting or activating key enzymes.
Purine and pyrimidine bases found in nucleotides can be synthesized de novo or obtained through salvage pathways.

Nucleotide Synthesis Outline

Nucleotide synthesis:
- A- Purine synthesis:
  - Purine salvage pathway
  - Purines degradation
- B- Pyrimidine synthesis:
  - Salvage of Pyrimidine
  - Pyrimidines degradation
  - Synthesis of deoxyribonucleotides (necessary for DNA synthesis)
  - Thymine nucleotide synthesis

Nucleotide Structure

Nucleic acids are linear polymers specialized for storage and transmission of genetic information for cellular growth and reproduction.
Purine base contains adenine and guanine.
Pyrimidine base contains cytosine, uracil and thymine.
T and U differ in that only T has a methyl group.
Structures of purine and pyrimidine bases are provided in the notes.

Unusual bases

Some species have unusual (modified) bases in their DNA and RNA
tRNA for example
Base modifications include methylation, acetylation, reduction, glycosylation

Nucleosides

Addition of a pentose sugar (ribose/deoxyribose) to a base (purine/pyrimidine) produces a nucleoside through an N-glycosidic linkage.
Ribose → ribonucleoside
2-Deoxyribose → deoxyribonucleoside
List of nucleosides for DNA and RNA are provided.

Nucleotides

Addition of one or more phosphate groups to a nucleoside produces a nucleotide.
Nucleotide consists of a base (purine-pyrimidine), pentose (ribose-deoxyribose), and phosphates.
Phosphate bind C5 atoms of the pentose sugar through ester linkage to the 5'-OH of the pentose.

Two Important Points about Nucleotides

The phosphate groups are responsible for the net negative charge associated with DNA and RNA.
One phosphate group is attached to pentose → nucleoside monophosphate (e.g., adenosine monophosphate (AMP), adenylate).
Second or third phosphate is added to pentose → a nucleoside diphosphate (e.g., adenosine diphosphate (ADP)) or triphosphate (e.g., adenosine triphosphate (ATP)).

Naming Nucleotides

Listing of RNA and DNA bases, nucleosides, and nucleotides.

Nucleoside Biosynthesis

Three pathways:
- De novo synthesis
- Salvage pathways
- Conversion of ribonucleotide to deoxyribonucleotide
- details about each steps with the related enzymes are presented.

Purine Biosynthesis

Purine ring atoms are contributed by a number of compounds.
The purine ring is synthesized by series of reactions adding donated carbons and nitrogens to a preformed ribose 5-phosphate.
In humans, all necessary enzymes are found in the cytoplasm of the cell.
Most de novo synthesis occurs in the liver.

Step 1: 5-phosphoribosyl-1-pyrophosphate (PRPP) synthesis

This step involves the production of 5-phosphoribosyl-1-pyrophosphate (PRPP) from ribose-5-phosphate with ATP by the enzyme phosphoribosyl phosphate synthetase (PRPP synthetase).
PRPP synthetase is regulated but not the committed step in purine synthesis.

Step 2: Synthesis of 5'-phosphoribosylamine

A highly regulated enzyme (rate limiting step) in purine nucleotide biosynthesis.

Step 3: Synthesis of glycinamide ribosyl 5-phosphate or glycinamide ribotide

Glycine provides C4,C5,and N7 of the purine ring.
This step requires ATP.

Step 4, 5, 6, 7, 8, 9, 10, 11

Steps in the synthesis of Inosine monophosphate (IMP).
Requires 6 ATP steps

Adenosine and guanosine monophosphates synthesis

Details about the reaction and enzymes involved.
Cross regulation between AMP and GMP (Guanosine monophosphate)

Mycophenolic acid

The drug inhibits inosine monophosphate dehydrogenase.
The drug deprives rapidly proliferating T and B cells of key components of nucleic acids.
The drug is used to prevent graft rejection.

Conversion of nucleoside monophosphates to diphosphates and triphosphates

NDPs are synthesized from NMPs by base-specific nucleoside monophosphate kinases.
These kinases do not discriminate between ribose and deoxyribose in the substrate.
ATP is the source of the transferred phosphate.
Adenylate kinase is active in liver and muscle.
It maintains equilibrium among AMP, ADP, and ATP.
NDP and NTP are interconverted by nucleoside diphosphate kinase.

Synthetic Inhibitors of Purine Synthesis

Sulfonamides inhibit the growth of microorganisms.
Analogs of para-aminobenzoic acid (PABA) inhibit bacterial synthesis of folic acid (TH4).
Methotrexate, a structural analog of folic acid, controls cancer spread by interfering with nucleotide synthesis.

Methotrexate and Cancer

Methotrexate affects rapidly growing cells by inhibiting the enzyme that converts folic acid to tetrahydrofolate (dihydrofolate reductase).
Methotrexate is toxic to all dividing cells.

Purine Salvage Pathway

Two enzymes (HGPRT and APRT) are involved in the purine salvage pathway.
Both enzymes use PRPP as a source of ribose-5-phosphate.
This pathway is irreversible due to pyrophosphate release by pyrophosphatase.
Absence of HGPRT causes Lesch-Nyhan syndrome.

Lesch-Nyhan Syndrome

A rare inherited disorder caused by a deficiency of the enzyme HGPRT.
Leads to the inability to salvage hypoxanthine or guanine.
Accumulation of uric acid in the body.
Lack of salvage pathway leads to increased PRPP levels and decreased IMP and GMP levels.
Increases the de novo pathway.
Decrease purine reutilization and increase purine degradation > increase uric acid..
Characterized by behavioral disturbances including self-mutilation (biting of lips and fingers).

Synthesis of deoxyribonucleotides

Nucleotide required for DNA synthesis (deoxyribonucleotides) are produced from ribonucleoside diphosphates by ribonucleotide reductase.
The enzyme is specific for reduction of purine/pyrimidine nucleoside diphosphates (NDP).
The immediate donors of hydrogen atoms are two SH groups on the enzyme itself.
Reduced enzyme regenerates thioredoxin as coenzyme and NADPH + H+.

Regulation of deoxyribonucleotide synthesis

Ribonucleotide reductase is responsible for maintaining a supply of deoxyribonucleotides required for DNA synthesis.
Regulation is complex; besides the catalytic site, R1 contains two allosteric sites.
Activity sites: dATP inhibits enzyme activity while ATP activates it.
Substrate specificity sites: binding of different NTPs (ATP, dATP, dTTP or dGTP) regulates substrate specificity resulting in increasing the conversion of ribonucleotides to deoxyribonucleotides.

Degradation of purine nucleotides

Occurs in the small intestine.
RNA and DNA from food are degraded to oligonucleotides by pancreatic ribonucleases and deoxyribonucleases.
Oligonucleotides are hydrolyzed by pancreatic phosphodiesterase to mononucleotides.
Mononucleotides are hydrolyzed to nucleosides by nucleotidases.
Nucleosides are degraded to free purine and pyrimidine bases+(deoxy)ribose 1- phosphate.
Purine bases are oxidized to uric acid and pyrimidines bases are oxidized to CO2 and ammonia, which are excreted in the urine.

Formation of uric acid

An amino group is removed from AMP to produce IMP, or from adenosine to produce inosine by AMP deaminase or adenosine deaminase.
IMP and GMP are converted to their nucleoside forms inosine and guanosine (action of 5' nucleotidase).
Inosine and guanosine convert to their purine bases (action of purine nucleoside phosphorylase): Guanosine is deaminated to form xanthine by guanase.
Hypoxanthine is oxidized to xanthine by xanthine oxidase and Xanthine oxidized to uric acid by xanthine oxidase uric acid is the final product.

Diseases associated with purine degradation

Gout: Disorder initiated by high levels of uric acid in blood (hyperuricemia).
Hyperuricemia leads to deposition of monosodium urate (MSU) crystals.
Crystals can deposit in joints causing gouty arthritis.

Diagnosis of Gout

Definitive diagnosis possible by aspirating and inspecting fluid from infected joints.
Polarized microscopy confirms presence of needle-shaped MSU crystals.

Treatment of Gout

Acute attack: anti-inflammatory drugs.
Decrease uric acid synthesis (e.g., allopurinol inhibits XO enzyme).

Adenosine deaminase (ADA) deficiency

ADA enzyme is present in all cells.
Human lymphocytes have the highest activity.
Deficiency leads to accumulation of adenosine.
ATP and dATP accumulation inhibits ribonucleotide reductase.
DNA production stops, and cells cannot divide.
Causes severe combined immunodeficiency (SCID).
Treatment: Bone marrow transplantation, enzyme replacement therapy, and gene therapy.

Pyrimidine Synthesis Outline

Synthesis of pyrimidine (De novo, Salvage)
Degradation of pyrimidine

Pyrimidine Synthesis : Sources of Atoms

Amide nitrogen of glutamine
Aspartate
CO2
Unlike purine synthesis, the base is synthesized first then attached to the ribose-5-phosphate sugar.

First step in the De Novo pyrimidine synthesis pathway

Carbamoyl phosphate synthesis.
Analogous to reaction in the urea cycle.

Pyrimidine Nucleotide Synthesis

Cytidine triphosphate (CTP) synthesis.
CTP is produced from UTP by amination via CTP synthetase.
This is the third step

Deoxythymidine monophosphate (dTMP) synthesis

dUMP is converted to dTMP via thymidylate synthase enzyme
Inhibition by 5-fluorouracil and methotrexate (inhibitor of dihydrofolate reductase)
THF needed for the conversion

Salvage of pyrimidine bases

Pyrimidine bases are salvaged via two steps.
Non-specific pyrimidine nucleoside phosphorylase converts pyrimidine base to their respective nucleosides.
More specific nucleotide kinases then react with the nucleoside to form nucleotide.

Degradation of pyrimidine

Pyrimidine nucleotide is dephosphorylated.
Pyrimidine nucleoside is cleaved to free pyrimidine+ribose-1-phosphate.
Cytosine is deaminated to uracil
Uracil, thymine, and the resulting products of pyrimidine degradation, such as beta-alanine and beta-aminoisobutyrate, are excreted in the urine.

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Description

Test your knowledge on nucleotide synthesis, including the primary methods for purine and pyrimidine base synthesis. This quiz also explores the significance of salvage pathways and the metabolism of nucleotides, providing an in-depth look at nucleosides and their relationships with nucleotides. Perfect for students in biochemistry and molecular biology.