Nucleotide Metabolism

Question 1

Nucleotides function as structural components of DNA and RNA. They are carriers of ______: ex. UDP-glucose in glycogen formation.

Answer 1

Nucleotides function as structural components of DNA and RNA. They are carriers of activated intermediates: ex. UDP-glucose in glycogen formation.

Question 2

Nucleotides function as structural components of several coenzymes:

Answer 2

Nucleotides function as structural components of several coenzymes: CoA, FAD, NAD+, and NADP+

Question 3

Nucleotides function as __________ in signal transduction (cAMP, cGMP).

Answer 3

Nucleotides function as secondary messengers in signal transduction (cAMP, cGMP).

Question 4

Nucleotides function as ____ “currency” of the cell (ATP).

Answer 4

Nucleotides function as energy “currency” of the cell (ATP).

Question 5

Nucleotides function as ____ of many pathways (i.e. ATP or AMP activating or inhibiting a pathway

Answer 5

Nucleotides function as regulators of many pathways (i.e. ATP or AMP activating or inhibiting a pathway

Question 6

What are the two main structures of nucleotides?

Answer 6

Structure of Nucleotides:

Features: Nitrogenous base and sugar

Question 7

What are the nitrogenous base in DNA and RNA?

Answer 7

Nitrogenous base:
Purines: Adenine and Guanine
Pyrimidines: Cytosine, Thymine (DNA), and Uracil (RNA)

Question 8

What sugar is found in RNA and what sugar is found in DNA?

Answer 8

Ribose in RNA

Deoxyribose in DNA

Question 9

What makes up a nucleoside?

Answer 9

Nucleoside = Nitrogenous base + Sugar

Question 10

What makes up a nucleotide?

Answer 10

Nucleotide = Nucleoside + 1,3 phosphate groups

Question 11

The anhydride bonds linking the ____ phosphate on a nucleoside triphosphate (i.e. ATP, GTP) are the high energy bonds driving many biochemical reactions.

Answer 11

2nd and 3rd

Question 12

Purine Nucleotide Synthesis:

The ribose 5-phosphate is from the ______ pathway.

Step 1: PRPP synthetase catalyzes the formation of the _________ (Phosphoribosyl-pyrophosphate).

Answer 12

HMP shunt

activated pentose

Question 13

Purine Nucleotide Synthesis:
PRPP synthetase regulation:

The activator is inorganic phosphate and the inhibitor is ______.

The ________ is attached at the 1’ carbon, which is where the nitrogenous base will be attached.

Answer 13

PRPP synthetase regulation:
The activator is inorganic phosphate and the inhibitor is purine ribonucleotides.

The pyrophosphate is attached at the 1’ carbon, which is where the nitrogenous base will be attached.

Question 14

Purine Nucleotide Synthesis:

Default: Production of ribonucleotides. If deoxyribonucleotides are needed, further steps will be taken. The rate limiting step is catalyzed by 1. _______(regulated, committed step).

In subsequent steps, the amino acids: 2. ____, _____, and ____ become part of the nitrogenous base structure.

Answer 14

1. PRPP Aminotransferase

2. glycine, aspartate, and glutamine

Question 15

Purine Nucleotide Synthesis:
Folate is also required for subsequent steps as a carbon donor. ________ is required to make THF (tetrahydrofolate), the form in which folate is used.

Answer 15

Dihydrofolate reductase

Question 16

Purine Nucleotide Synthesis:

What’s the form in which folate is used?

Answer 16

tetrahydrofolate

Question 17

Purine Nucleotide Synthesis:

PRPP Aminotransferase regulation is inhibited by 1._____ (end products) and activated by 2. _____.

Answer 17

1. purine nucleotides

2. PRPP (substrate)

Question 18

Purine Nucleotide Synthesis:
________ is a purine analog and as such it will inhibit PRPP Amidotransferase similar to the inhibition by high levels of the natural purines as shown in the pathway.

It may exert an additional effect if it is misincorporated into the synthesis of purines (so the structure will not be correct).

Answer 18

6-Mercaptopurine

Question 19

Purine Nucleotide Synthesis:
Methotrexate: folic acid analog; an anti-tumor drug that inhibits ______. Methotrexate works specifically in mammalian cells.

Answer 19

Dihydrofolate reductase.

Dihydrofolate reductase inhibits nucleotide biosynthesis and it inhibits rapidly dividing cells selectively (a common feature of many anti-tumor drugs).

Question 20

Purine Nucleotide Synthesis:
1._________ are structural analogs of Para-aminobenzoic acid (PABA). 2.________competitively inhibit bacterial production of folic acid. It inhibits bacterial purine synthesis. Humans do not rely on folic acid synthesis so they are unaffected. 3._____drugs function as antiobiotics -they are against bacteria.

Answer 20

1. and 2. Sulfonamides

3. Sulfa

Question 21

Pyrimidine Nucleotide Synthesis:

What is the rate-limiting, committed step in pyrimidine synthesis?

Answer 21

CPS II – carbamoyl phosphate synthetase II:

Question 22

Pyrimidine Nucleotide Synthesis:
CPS II – carbamoyl phosphate synthetase II is activated by 1. ______and inhibited by 2._____(end product). Note this is the second version of CPS, CPS I is the rate-limiting committed step in the urea cycle but CPS II is the rate-limiting step of pyrimidine synthesis!!!!

Answer 22

1. PRPP

2. UDP

Question 23

Pyrimidine Nucleotide Synthesis:
Two amino acids become part of the nitrogenous base structure of pyrimidines: ______ and ______. PRPP provides the _______for the pyrimidine.

Answer 23

Two amino acids become part of the nitrogenous base structure of pyrimidines: glutamine and aspartate. PRPP provides the pentose for the pyrimidine.

Question 24

Converting Ribonucleotides to Deoxyribonucleotides:

Ribonucleotides can be converted into deoxyribonucleotides by __________.

Answer 24

Ribonucleotides can be converted into deoxyribonucleotides by ribonucleotide reductase.

Question 25

Converting Ribonucleotides to Deoxyribonucleotides:

________ is an anti-tumor drug that inhibits ribonucleotide reductase. It is also used to treat sickle cell anemia, although the effect is not related to its use as an anti-tumor drug. It increases synthesis of fetal hemoglobin (by unknown mechanisms) that can alleviate the effects of sickle cell hemoglobin.

Answer 25

Hydroxyurea

Question 26

Converting Ribonucleotides to Deoxyribonucleotides:

Additional steps to convert dUMP into dTMP (remember uracil is used in ribonucleotides while thymidine is used in deoxyribonucleotides) use _____ (inhibited by the antitumor drug 5-fluorouracil or 5-FU). Hydroxyurea and 5-FU will affect the production of DNA, but not RNA, so are especially good at targeting rapidly dividing cells.

Answer 26

thymidylate synthase

Question 27

Converting Ribonucleotides to Deoxyribonucleotides:

As with purine synthesis, folate in the form of THF is required for ________.

Answer 27

thymidylate reductase

Question 28

Converting Ribonucleotides to Deoxyribonucleotides:

______ is inhibited by methotrexate (anti-tumor drug mentioned earlier). Trimethoprim is a class of antibiotic that is selective for the prokaryotic version of ______.

Humans require folate in the diet, while prokaryotes synthesize their own folate.

Answer 28

Dihydrofolate reductase

Question 29

Converting Ribonucleotides to Deoxyribonucleotides:

_________: an additional class of antibiotics, target enzymes in bacteria that make folic acid; since humans do not have these enzymes, the ____ are selectively toxic to prokaryotes, and their main mechanism of action is inhibiting nucleotide metabolism.

Answer 29

Sulfonamides

Question 30

Nucleotide Metabolism:

_____ are not salvaged to a significant degree. No high yield disease or enzymes are associated with their breakdown or salvage, so that pathway will not be discussed.

Answer 30

Pyrimidines

Question 31

Nucleotide Metabolism:
Important Facts About Purine Degradation and Purine Salvage Pathways:
______bases are more complex to synthesize than _____: dicyclic, many more steps involved, the salvage pathway for ______is much more critical.

Answer 31

Purine bases are more complex to synthesize than pyrimidines: dicyclic, many more steps involved, the salvage pathway for purine is much more critical.

Question 32

Nucleotide Metabolism:
Important Facts About Purine Degradation and Purine Salvage Pathways:

In the _______, the nitrogenous base is recovered after removing phosphate and sugar moieties which yield hypoxanthine or guanine, that be shuttled back into purine nucleotide synthesis.

Answer 32

salvage pathway

Question 33

Nucleotide Metabolism:
________ (autosomal recessive) is one of the causes of severe combined immunodeficiency disease (SCID) which is about 14% of cases.

Answer 33

Adenosine deaminase deficiency

Question 34

Nucleotide Metabolism:
The cells of the _______ system _________ are particularly affected by adenosine deaminase deficiency . This condition results in patients being susceptible to infection by almost any microorganism, requiring living in a sterile bubble.

Answer 34

The cells of the immune system (T-cells and B-cells) are particularly affected by this deficiency. This condition results in patients being susceptible to infection by almost any microorganism, requiring living in a sterile bubble.

Question 35

Nucleotide Metabolism:

Treatment for adenosine deaminase deficiency is ____ or _________. This particular disease was the target of the first reputedly successful gene therapy trial (this is a topic of debate, but an important landmark in gene therapy history).

Answer 35

bone marrow transplant or enzyme replacement.

Question 36

Nucleotide Metabolism:
In adenosine deaminase deficiency, at the point of the recovery of the nitrogenous base is the salvage/degradation pathway. At that point, the base can be shuttled (salvaged) back into purine synthesis or can be degraded to uric acid. The excretion pathway uses the intermediate ______ and the enzyme ______, which produces uric acid. Uric acid is excreted in the urine.

Answer 36

xanthine and xanthine oxidase

Question 37

Nucleotide Metabolism:
Gout is the result of ________ (elevated levels of uric acid in blood). It is the accumulation of uric acid crystals in the joints and leads to inflammation and gouty arthritis.

Answer 37

hyperuricemia

Question 38

What is the most common cause of gout?

Answer 38

Gout can be caused by the underexcretion of uric acid (most common) which can be caused by poor kidney function, acid-base imbalance, certain drugs, etc.

Question 39

Gout can also be caused by overproduction of uric acid. In “overproduction” the drug ________ inhibits xanthine oxidase which produces uric acid.

Hyperuricemia can be secondary to many conditions, for example the high cell turnover in cancer patients being treated with various anti-tumor drugs.

Answer 39

allopurinol

Question 40

1.___________ is a deficiency in the purine salvage pathway caused by a defect in hypoxanthine-guanine phosphoribosyltransferase (HGPRT). It is a deficit of 2._____. The blockage of the pathway forces the purine degradation products into the production of uric acid, resulting in extreme 3._________. Symptoms are: severe mental retardation, strange symptoms of self-destructive behavior and self-mutilation (i.e. chewing off lips and fingertips, scratching/gouging eyes, and severe gout symptoms.

Answer 40

1. Lesch-Nyhan syndrome (X-linked)
2. purines
3. hyperuricemia

Question 41

Gout can affect the eye:
Deposits of _____ in various locations:
Conjunctiva, cornea, iris, sclera, lens, other eye tissues, the formation of transparent vesicles, bleeding in the subconjunctival space and vascular changes.

Answer 41

tophi

Note: A tophus (Latin: “stone”, plural tophi) is a deposit of uric acid crystals, in the form of monosodium urate crystals, in people with longstanding hyperuricemia (high levels of uric acid in the blood). Tophi are pathognomonic for the disease gout.