Nucleotide Metabolism Flashcards
What is the function of deoxyribonucleoside triphosphates?
synthesis of DNA
What is the function of ribonucleoside triphosphates?
- synthesis of RNA
- energy metabolism
What are the deoxyribonucleoside triphosphates?
dATP, dGTP, dCTP, dTTP
What are the ribonucleoside triphosphates?
ATP, GTP, CTP, UTP
What is the purpose of ATP
Main energy currency of the cell
What is the purpose of GTP?
provides energy for protein synthesis
What is the purpose of UPT?
Provides energy for synthesis of glycogen and glycoproteins
What is the purpose of cTP?
Provides energy for phospholipid synthesis
Ribonucleotides are __________ of many enzymes
allosteric regulators
What are some ribonucleotide derivatives?
- Cell regulators (cAMP, cGMP, poly ADP-ribose)
- Components of many coenzymes (NAD, FAD, coenzyme A)
Do non-proliferating cells require more ribonucleoside triphosphates or deoxyribonucleoside triphosphates?
Lots of ribonucleoside triphosphates
- RNA synthesis and metabolic roles
Very little deoxyribonucleoside triphosphates for DNA repair
Do proliferating cells require more ribonucleoside triphosphates or deoxyribonucleoside triphosphates?
Lots of deoxyribonucleoside triphosphates for synthesis of new DNA
What is the difference between nucleotides and nucleosides?
Nucleotides have a nitrogenous base, sugar and phosphate
Nucleosides have nitrogenous base and sugar
Nucleosides can pass in and out of cells but nucleotides cannot. Why?
Because it is phosphorylated
What are the purine ribo/deoxyribonucleosides?
(deoxy) adenosine = adenine + (deoxy)ribose
(deoxy) guanosine = guanine + (deoxy)ribose
What are the pyrimidine ribo/deoxyribonucleosides?
(deoxy)cytidine = cytosine + (deoxy)ribose
uridine = uracil + ribose
thymidine = thymine + deoxyribose
*D in pyrimidine, D in their names
What happens to dietary nucleotides taken up by intestinal cells? They are metabolized to ____
waste products eg uric acid
How do we get most of the purines and pyrimidines we need?
de novo synthesis - synthesized from scratch in our bodies
Where are purines and pyrimidines synthesized?
many tissues, especially the liver
After synthesis, how are purines and pyrimidines transported?
in the blood to other tissues in the form of nucleosides and free bases (has to be nucleosides b/c it isnt phosphorylated)
What happens to tissues that have low levels of de novo synthesis?
How do they get their purines/pyrimidines?
They import it from the liver = salvage pathways
What are some problems associated with deficiency of salvage pathwats?
immunodeficiency
neurological abnormalities
Where do the atoms that make up newly synthesized purine and pyrimidine come from?
amino acids
Describe de novo synthesis of purines
- Purine assembly
- one atom at a time
- takes place on a ribose phosphate scaffold, donated from PRPP
- the completed ring structure first appears as a nucleotide, IMP - IMP is converted to AMP and GMP
- Add more phosphates and convert ribonucleotides to deoxyribonucleotides
How id PRPP made?
from ribose-5-phosphate, a product of the PPP
The pyrophosphate in PRPP is donated from ATP
What is the purpose of PRPP?
Which pathways can it be found?
- it is a high energy ribose-phosphate donor
- de novo purine synthesis
- de novo pyrimidine synthesis
How is ribose 5-phosphate produced via the oxidative pathway?
In the fed state, the oxidative pathway produces NADPH and ribose 5-phosphate (2:1 ratio) from G-6-P
How is ribose 5-phosphate produced via the non-oxidative pathway?
In the fasted state, the non-oxidative pathway produces ribose 5-phosphate only from glycolysis/GNG intermediates
- it bypasses the oxidative reactions
Ribose-5-P and nucleotide synthesis is (independent/dependent) of dietary status?
independent
What are the AA that contribute to the purine ring?
glutamine
glycine
aspartate
What is the first step in the assembly of the purine ring structure?
- transfer of an AA group from glutamine to PRPP forming phosphoribosyl amine
- Pyrophosphate is released in this step, so it has a large negative delta G
What is the first committed step in the synthesis of purines?
transfer of an AA group from glutamine to PRPP forming phosphoribosyl amine
After the ring is formed in purine synthesis, were are additional atoms added
to the phosphoribosyl amine
After the ring is formed in purine synthesis, what is the second step?
Glycine is added, forming an amide bond with the nitrogen of phosphoribosyl amine. ATP hydrolysis provides energy to drive the reaction
Two of the carbon atoms in the purine ring are donated by ________
tetrahydrofolate (FH4)
The donor atoms carried by tetrahydrofolate comes from?
amino acids
What is the precursor of FH4?
folic acid
Generally, what happens when there is a folic acid deficiency?
inadequate DNA synthesis in proliferating cells
What happens when there is a folic acid deficiency in adults?
megaloblastic anemia - RBC precursors fail to divide properly
What happens when there is a folic acid deficiency in developing fetus?
neural tube defects
_______ deficiency mimics folate deficiency. Why?
vitamin b12
w/o b12, our FH4 gets trapped in the form of methyl-FH4 = a form of functional FH4 deficiency
What are the two essential functions of B12?
Methyl acceptor
Methyl Donor
What is the function of B12 as methyl acceptor?
to recycle tetrahydrofolate - maintain adequate folate levels
deficiency mimics folate deficiency
megaloblastic anemia - easily detected
What is the function of B12 as methyl donor?
to provide methyl groups to SAM (S-adenosyl methionine) for a variety of methylation reactions
deficiency causes neurological problems - often overlooked
What is the first purine ring structure produced by the de novo pathway?
Inosine monophosphate (IMP)
Which enzyme converts monophosphates to diphosphates and diphosphates to triphosphates using ATP as a phosphate donor?
nucleotide kinases
What is the enzyme specific for nucleoside diphosphates?
ribonucleotide reductase
Is ribonucleotide reductase base specific?
no
What type of inhibition is the purine de novo biosynthesis regulated by?
feedback inhibition
Which is the committed step in purine biosynthesis?
phosphoribosyl amine synthesis
What inhibits PRPP synthesis in purine biosynthesis?
ADP and GDP (acting at different allosteric sites)
What inhibits phosphoribosyl amine synthesis in purine biosynthesis?
AMP and GMP
Which nucleosides inhibit their own formation in purine biosynthesis?
AMP and GMP (from IMP)
Describe purine salvage
Nucleosides are converted to free bases by purine nucleoside phosphorylase
Free bases can be converted back to nucleotides by phosphoribosyl transferases using PRPP
What is the dual role of purine salvage?
- recycles purine ring - spares AA and reduces uric acid production
- Main source of purine nucleotides for some cells
What is the key enzyme of purine salvage?
What does it do?
phosphoribosyl transferase
Converts free purine bases to nucleotides using PRPP as a ribose phosphate donor
What does APRT do?
adenosine phosphoribosyl transferase
-converts adenine to AMP
What does HGPRT do?
hypoxanthine-guanine phosphoribosyl transferase
converts guanine to GMP
and hypoxanthine to IMP
Can our bodies break down purine ring structure?
no
How do we get rid of purines?
In the liver, purines are converted into uric acid
Uric acid is transported by the blood to he kidney and excreted by urine
During the degradation of purines, what is GMP, AMP and IMP converted to?
GMP - guanine
AMP and IMP - hypoxanthine
What is guanine and hypoxanthine degraded?
converted to xanthine which is converted to uric acid
Why cant uric acid be broken down in humans?
we don’t have uricase enzyme to break it down
What is a problem associated with uric acid?
- uric acid is not very water soluble
- decrease in rate of uric acid excretion from kidney/increase in rate of uric acid formation = accumulation of uric acid
- monosodium urate crystals form in the synovial fluid of joints = gout
Treatment of acute gout
NSAIDs
Treatment of chronic gout
allopurinol - suicide inhibitor of xanthine oxidase
