Nucleotide Metabolism Flashcards
Nucleotides functions
- structural component of DNA and RNA
- carriers of activated intermediates (UDP-glucose formation)
- secondary messengers in signal transduction (cAMP, cGMP)
- energy currency of the cell (ATP)
- regulators of many pathways
Nucleotide structural components of coenzymes
- CoA
- NAD+
- FAD
- NADP+
Main structural features of nucleotides
- Nitrogenous base
- sugar (can have phosphate associated)
Types of nitrogenous bases
- purines
- pyrimidines
Purines
- nitrogenous base
- adenine and guanine
- dicyclic
Pyrimidines
- nitrogenous base
- cytosine, thiamine (DNA), uracil (RNA
- unicyclic
Sugar of a nucleotide
- ribose in RNA
- deoxyribose in DNA (missing O)
What links the 2nd and 3rd phosphate on a nucleoside triphosphate (ATP)?
Anhydride bonds, high energy bonds driving many biochemical reactions
-this is why we can use them as energy source
Nucleoside
Nitrogenous base + sugar (no phosphate)
Nucleotide
-nucleoside + 1-3 phosphate groups
Where is the ribose 5-phosphate from in purine synthesis
HMP shunt
Purine synthesis
- dicyclic so they are bigger and more complicated
- we are essentially building base on a sugar molecule
Step 1 of purine nucleotide synthesis
-PRPP synthetase catalyzes the formation of the activated pentose
PRPP synthetase
- in step 1 of purine synthesis
- catalyzes the formation of the activates pentose
PRPP activator
Inorganic phosphate
PRPP inhibitor
Purine ribonucleotides
Where is the pyrophosphate attached in purine synthesis?
1’ carbon, which is where the nitrogenous base will be attached
PUrine nucleotide synthesis default
Production of ribonucleotides
-if deoxyribonucleotides are needed, further steps will be taken
Is the rate limiting step the first step of purine synthesis?
No
Rate limiting step of purine synthesis
- catalyze by PRPP amidotransferase
- committed step
After PRPP amidotransferase catalyzes purine synthesis…
The following steps are basically just modifying your base to get your purine
-amino acids become part of the nitrogenous bases
Folate
Required for purine synthsis, required for subsequent steps as a carbon donor
What form does folate need to be in to be activated?
THF
Dihydrofolate reductase
Required to make THF, the form in which folate is used
- have to have this enzyme to continue pathway.
- obtained from diet
- bacteria synthesize there own
PRPP amidotransferase inhibited by
Purine nucleotides (end products)
PRP amidotransferase reductase activated by
PRPP (substrate)
IMP can be utilized as…
AMP and GMP
What is the rate limiting and committed step in purine synthesis catalyzes by?
PRPP amidotransferase
6-Mercaptopurine
- purine analog
- acts like IMP, GMP, and AMP
- inhibits the PRPP amidotransferase
- cancer treatment
- can be misincorporated into the synthesis of purines and script the structure
What drug inhibits PRPP amidotransferase?
6-Mercaptopurine
Methotrexate
- folic acid analog
- anti-tumor
- inhibits dihydrofolate reductase
How does methotrexate affect dihydrofolate reductase?
- inhibits nucleotide biosynthesis
- inhibiting rapidly dividing cells selectively
- specific to mammalian cells
What is a drug that inhibits dihydrofolate reductase?
Methotrexate
Sulfonamides is the analog to…
PABA
What does sulfonamides do
Competitive inhibit of bacterial production of folic acid
-bacterial purine synthesis inhibited
What do sulfa drugs act as?
Antibiotics
What do sulfa drugs do in bacteria?
-binds to enzyme that produces folate, inhibits THF, can’t produce purines
CPS II (Carbamoyl phosphate synthetase II)
-rate limiting, committed step in pyrimidine synthesis
What is the rate limiting, committed step in pyrimidine synthesis?
CPS II
What is CPS II activated by?
PRPP
What is CPS II inhibited by?
UTP (End product)
What two amino acids become part of the nitrogenous base structure of pyrimidines?
- glutamine
- aspartate
What provides the pentose for the pyrimidine?
PRPP
Once the pyrimidine bases are produced, what happens?
They are attached to PRPP
How do ribonucleotides get converted into deoxyribonucleotides?
Ribonucleotide reductase
Hydroxyurea
-anti tumor drug that inhibits ribonucleotide reductase
What drug inhibits ribonucleotide reductase?
Hydroxyurea
Hydroxyurea in sickle cell anemia treatment
-increases the synthesis of fetal hemoglobin
Thymidilate synthase
Plays a role in additional steps to convert dUMP into dTMP
What is thmidylate synthase inhibited by?
5-FU
What will affect the production of DNA, but not RNA?
Hydroxyurea and 5-FU
-are especially good at targeting rapidly dividing cells
What is required for thymidylate synthesis?
Folate, which then requires dihydrofolate reductase
What is dihydrofolate reductase inhibited by?
Methotrexate
Trimethoprim
Class of antibiotics that is selective for the prokaryotic version of dihydrofolate reductase
Class of antibiotics that is selective for the prokaryotic version of dihydrofolate reductase
Trimethoprim
Sulfonamides
- antibiotics
- target enzymes in bacteria that make folic acid
What are sulfonamides selectively;y toxic for?
Prokaryotes
What is the main mechanism of action of sulfonamides?
Inhibiting nucleotide metabolism in prokaryotes
Pyrimidine salvaging
- not salvaged to a significant degree
- no high yield diseases or enzymes are associated with their breakdown or salvage
Which bases are more complex?
Purine
Why are purines more complex than pyrimidines
- dicyclic
- many more steps involved
- salvage pathway is more critical
Salvage pathway for purines
- nitrogenous base is recovered after removing phosphate and sugar moieties
- yield hypoanthine or guanine which can be shuttled back into purine nucleotide synthesis
What does the salvage pathway for purines yield
-hypoxanthine or guanine
What happens to the hypoxanthine and guanine that is yielded from purine salvaging?
Shuttled back into purine nucleotide synthesis
Adenosine delaminase deficiency
Causes severe combined immunodeficiency disease (SCID)
SCID results from what deficiency?
-adenosine deaminase
What happens in SCID
- cells of the immune system are particularly affected by this deficiency
- condition results in patients being susceptible to infection by almost any microorganism, requiring living in a sterile bubble
What is the treatment for SCID?
Bone marrow transplant
What happens to the nitrogenous base in the salvage/degradation pathway?
The base can be shuttled back into purine synthesis or can be degraded to Uric acid
What enzyme does the excretion pathway of purine synthesis use?
Xanthine oxidase
Xanthine oxidase
- excretion
- intermediate is xanthine
- product is uric acid excreted in urine
Gout is the result of what?
- Hyperuricemia (elevated levels of uric blood
- accumulation of uric acid crystals in the joints
- leading to inflammation and gouty arthritis
What can cause Gout?
- underexcretion of uric acid (most common)
- which can be caused by: poor kidney function, acid-base balance imbalance, certain drugs
- overporduction of uric acid
Overproduction of uric acid treatment
Allopurinol
What does allopurinol do?
Treats gout in “overproducers” by inhibiting xanthine oxidase which produces uric acid
Hyperuricemia as a secondary condition
Can be secondary to many conditions such as high cell turnover in cancer patients being treated with various anti tumor drugs
Lesch-Nyah’s syndrome
- deficiency in the purine salvage pathway
- defect in HGPRT
- deficit of purines
- extreme hyperuricemia
Symptom of Lesch-Nyhan
- severe mental retardation
- self destructive behavior
- self mutilation
Chewing off lips and fingertips
Scratching/gouging eyes
Severe gout symptoms
How can gout affect the eye?
Deposits tophi in
- the conjunctiva
- cornea
- iris
- sclera
- lens
- other eye tissue
- the formation of transparent vesicles
- bleeding in the subconjunctival space and vascular changes
