14. Nucleotide Metabolism

The pyrmidines are ________

Cytosine, Uracil, Thymine

True or False: A folic acid deficiency will result in a decrease in both purine and pyridine biosynthesis.

True

During step one of purine synthesis the enzyme Ribose Phosphate Pyrophosphate is present. What does the name of the enzyme suggest if ATP is also present?

Two phosphates from ATP will be attached to the Ribose molecule resulting in PRPP and AMP.

In glycogen metabolism, ________ is utilized as a ________ to aid in the biosynthetic pathway to ensure that glucose is incorporated into the growing polymer.

UDP , Activated Intermediate

What compounds inhibit salvage pathways?

antiparasite drug

Where does Carbomoyl Phosphate Synthase II (CPS II) function? A. In the urea cycle B. In pyrimidine synthesis C. In both pyrimidine and purine synthesis D. In purine synthesis

b

In the biosynthesis of pyrimidines, the exocyclic amine comes from _______ A. Gly B. Asp C. Gln D. Glu

c

What is considered a feedback inhibitor in the pyrimidine synthesis? (select all that apply) A. UDP B. PPRP C. ATP D. UTP

c

Which two enzymes are used in the Salvage Pathway? A. PPRP and APRT B. HGPRT and PPRP C. HGPRT and APRT

c

In the body, Folic acid is converted to Dihydrofolate (DHF) and then to Tetrahydrofolate (THF) by which enzyme?

dihydrofolate reductase

The committed step of De novo synthesis is subject to what?

feedback inhibition

Activating the Ribose Sugar using PRPP is which step of De novo purine synthesis

first step

Thymidylate synthase-requires N5, N10 Methylene-THF which is derived from?

folic acid

What acid gets degraded down to free base & ribose sugar but can be reassembled later?

nucleic acid

Includes a Base + Sugar

nucleosides

Includes a base + sugar + P

nucleotide

This condition leads to an increase of organic acids which ultimately decreases kidney function and uric acid production

prolonged hypoglycemia

What is a nucleoside containing two rings called? Adenine, Guanine, Hypoxanthine

purines

What is a nucleoside containing one ring called? Cytosine, Uracil, Thymine

pyrimidines

Which pathway includes bases from our diet or nucleic acid turnover?

salvage

Transferring the amine from glutamine to ribose sugar takes place in which step of De novo synthesis?

second step

Ribonucleotide Reductase removes 2'-OH replacing it with 2'-H. This requires the use of which Enzyme to catalyze the rxn?

stable radical

What compound is made from Folic Acid or Vitamin B9?

tetrahydrofolate

What is the final product Produced via Xanthine Oxidase?

uric acid

A cancer patient walks into the pharmacy to pick up a prescription for an anticancer medication and explains to the pharmacist that they have been experiencing intense pain in their hands and feet, especially the big toe. The patient is at a slightly overweight and eats a lot of meat and seafood. 1. What pathway is most likely causing the pain?

Primary Purine Degradation Scheme

A patient is concerned about their caloric intake and diet as they are trying to lose weight. After conducting some research on the internet, they understand that they are consuming carbohydrates, amino acids, nitrogenous bases, and fatty acids in their daily diet. To prevent weight gain, which of these molecules will need to be monitored and why? Which of these molecules will not need to be monitored and why?

Carbohydrates, amino acids, and fatty acids will all need to be monitored in their diet. This is because these molecules, when broken down, release energy as ATP. If too much ATP is produced from the breakdown of these molecules, it will be stored as fat. This does apply to nitrogenous bases as their breakdown does not produce any ATP, therefore there is no potential for excess energy to be stored as fat.

Many parasites lack de novo pathways as a method of purine biosynthesis. With this in mind, what may be a promising option for anti-parasite therapy?

Compounds that inhibit salvage pathways, as this is the parasites only pathway to biosynthesize purines.

How does an increased level of PRPP potentially explain the mental impairments and behavioral issues associated with Lesch-Nyhan Syndrome?

Increased PRPP levels allow excess PRPP to remain which is typically used up in purine salvage. This results in an increase in de novo purine synthesis. This overproduction in purines results in increased purine breakdown, which results in uric acid production. This extra uric acid production causes gout-like damage to tissues as well as CNS damage, thus explaining the mental impairments and behavioral issues associated with Lesch-Nyhan Syndrome.

A complete lack of HGPRT causes what SEVERE Clinical Disorder?

Lesch Nyhan Syndrome

A complete lack of HGPRT causes severe _______

Lesch-Nyhan Syndrome

In a patient with impaired Adenine metabolism, which cofactors would be affected and how would they be affected.

NAD, FAD, and Co-A levels would all be decreased.

Nucleotidases convert nucleotides into _______

Nucleosides

Nucleases convert nucleic acids into _______

Nucleotides

1) Why. must folic acid be ingested? 2) Furthermore, why is it very important for pregnant women to ingest plenty of folic acid?

1) The pteridine ring cannot be synthesized by the human body. 2) Folic acid is necessary to purine and pyridine biosynthesis which is necessary for the synthesis of DNA in the growing embryo.

1) A patient has a disease state in which amino acid synthesis is getting progressively worse! As of today, this patient is now suddenly experiencing a decrease in purine synthesis. With their disease state in mind, why may this of happened? 2) After performing some labs on the patient it has been determined that the decrease in purine synthesis is not due to an amino acid deficiency, but rather a vitamin deficiency. What vitamin may this be?

1) There has been a sharp decrease in the patient's ability to synthesize Aspartate, Glutamine, and Glycine. 2) Folic Acid

1) A patient is experiencing uric acidosis. What enzyme is likely to be targeted with drug therapy and what drug is commonly used to do this? 2) Unfortunately, the drug therapy was not enough to control the patient's uric acid levels and the patient is now experiencing gout. What areas of the patient's body are likely to be affected by gout and why? 3) What foods do you suspect this patient has been eating regularly?

1) Xanthine Oxidase and Allopurinol 2) Gout is likely to be localized to the joints because these extremities are cooler than in the core, which decreases the solubility of uric acid, causing crystallized uric acid deposits. 3) Seafood and liver.

BRIEFLY describe the two methods in which nucleosides are biosynthesized.

1. De novo synthesis- Nucleosides are synthesized from scratch. 2. Salvage: Nucleosides are synthesized from scavenged bases from diet or from nucleic acid turnover.

Ribonucleotide reductase replaces a _______ with 2'-H

2'-OH

At which site can AMP, ADP & ATP bind an inhibit?

A site

IMP can be converted to _______

AMP and GMP

_______ and _______ are enzymes needed for purine salvage pathway

APRT, HGPRT

The purines are ________

Adenine, Guanine, Hypoxanthine

Explain the rationale for drugs that inhibit the de novo pathway being a promising treatment for autoimmune diseases.

Auto-immune diseases are characterized by patients having overactive white blood cells. White blood cells are rapidly diving cells, therefore limiting their access to nucleotides though inhibition of the de novo synthesis pathway will decrease the rate at which they divide. This will suppress the immune system and slow the progression of the auto-immune disease.

Gln:PRPP Amidotransferase is the enzyme present during the committed step of purine synthesis. Due to this it is regulated by feedback regulation. What is necessary to banish all activity?

Binding at both sites- AMP, ADP, or ATP bound to the A sight and GMP, GDP, and GTP bound to the G sight. *Note: Inhibition at just one sight will not stop all activity!

Purine synthesis is a ______ pathway and pyridine synthesis is a ______ pathway.

Branched, Unbranched.

Which Biosynthesis of nucleotides is considered new or started from scratch?

De Novo Synthesis

In the body, Folic acid is converted to Dihydrofolate (DHF) and then to Tetrahydrofolate (THF) by the enzyme _______

Dihydrofolate Reductase

In patients with rapidly dividing cells, such as in cancer patients, what process is often targeting by drug therapy. Explain why this may be.

Drugs that target and inhibit de novo synthesis. This is because cancer cells often need more nucleotides than provided by the salvage pathway alone due to their rapid division. Therefore, limiting the amount of nucleotides made from scratch will limit the nucleotides available to the cancer cells, thus slowing their division.

In pyridine synthesis, the committed step is the action of the enzyme _________ which is inhibited by _____ and _____, and is activated by ______ and ________.

Enzyme: Carbamoyl Phosphate Synthase (CPS) Activated by: UDP, UTP Inhibited by: PRPP, ATP

In a patient with a high ratio of nucleosides to nucleotides, enzymes responsible for what process are likely to be impaired.

Enzymes responsible for the phosphorylation of nucleotides.

In purine salvage, nucleic acid is broken down into _______ and _______ but can be ___________ later.

Free base, Ribose sugar, Reassembled

At which site can GMP, GDP & GTP bind and inhibit?

G site

The committed step in De Novo Synthesis uses this enzyme _______

Glutamine-PRPP Amidotransferase

The conversion of UTP to CTP may be inhibited by a lack of what amino acid. Why?

Glutamine. It is necessary for CTP Synthase to add an exocyclic-amine to UTP.

What enzyme is utilized in the synthesis of DNA that is not utilized in the synthesis of RNA.

Ribonucleotide reductase is only used in the synthesis of DNA as it catalyzes the conversion of Ribose to Deoxyribose.

How does the first step of pyridine synthesis differ from that of purine synthesis in regards to the base and ribose sugar.

The free base is formed first then attached to the ribose sugar in pyrimidine synthesis. Whereas in purine synthesis, the base is formed while attached to the ribose sugar.

A cancer patient walks into the pharmacy to pick up a prescription for an anticancer medication and explains to the pharmacist that they have been experiencing intense pain in their hands and feet, especially the big toe. The patient is at a slightly overweight and eats a lot of meat and seafood. 6. What can the patient do to prevent future problems?

The patient can prevent gout flair-ups by limiting their intake of purine rich foods and beverages, consuming more low-fat dairy products as a protein source and drink plenty of water. The patient can also talk to their doctor to get diagnosed for gout so they can be prescribed allopurinol. Allopurinol inhibits the enzyme xanthine oxidase decreasing uric acid production.

A cancer patient walks into the pharmacy to pick up a prescription for an anticancer medication and explains to the pharmacist that they have been experiencing intense pain in their hands and feet, especially the big toe. The patient is at a slightly overweight and eats a lot of meat and seafood. 5. How does their cancer diagnosis and treatments make them more susceptible to this condition?

The patient who has cancer and receives chemotherapy treatments is more susceptible to experiencing joint pain because cancer chemotherapy increases purine degradation due to the increased death/turnover of cells

A cancer patient walks into the pharmacy to pick up a prescription for an anticancer medication and explains to the pharmacist that they have been experiencing intense pain in their hands and feet, especially the big toe. The patient is at a slightly overweight and eats a lot of meat and seafood. 4. What could have caused the patient to experience joint pain?

The patient's diet contains high amounts of purine which is converted to uric acid. Uric acid is dissolved in the blood but when too much uric acid is present not all of it is able to dissolve. This excess uric acid will crystallize in joints and kidneys causing intense pain

A cancer patient walks into the pharmacy to pick up a prescription for an anticancer medication and explains to the pharmacist that they have been experiencing intense pain in their hands and feet, especially the big toe. The patient is at a slightly overweight and eats a lot of meat and seafood. 3. Why is the patient experiencing pain in these specific locations?

This condition predominately occurs in the joints (hands and feet) first because extremities are cooler in temperature causing solubility to decrease. Thus the uric acid is less soluble and falls out of solution (precipitates/crystallizes); whereas, the core is warmer in temperature and allows larger amounts of uric acid to dissolve. If the amount uric acid continues to increase, it can cause precipitate in the kidneys, causing damage and worsening the condition due to decreased clearance by the kidney

A patient has respiratory alkalosis. How may this affect their nucleotide levels?

This may decrease their purine and pyrimidine levels due to decreased levels of carbon dioxide present in their body.

In cancer patients undergoing chemotherapy, an increase in purine degradation may result in buildup of what? Why is this?

Uric acid. This is due to the death / turnover of cells during to chemotherapy resulting in many purines being broken down into uric acid.

1) In the process of converting IMP to GMP, why is water necessary?

Water is necessary to add add a carbonyl through the action of IMP dehydrogenase. This carbonyl group is then converted to the extra-cyclic amine in GMP through the action of XMP-glutamineamidotransferase.

A cancer patient walks into the pharmacy to pick up a prescription for an anticancer medication and explains to the pharmacist that they have been experiencing intense pain in their hands and feet, especially the big toe. The patient is at a slightly overweight and eats a lot of meat and seafood. 2. What enzyme is involved and what does it do?

Xanthine Oxidase converts the purines that are being degraded to uric acid for excretion. It first converts the purine to the intermediate xanthine and then xanthine to uric acid

IMP can be converted to _____ (select all that apply) A. AMP B. GMP C. CMP D. UMP

a, b