Nucleic Acid Metabolism - Biochem Flashcards
In the IMP biosynthesis pathway, where does PRPP come from and what is the final product?
Ribose-5-P and ATP
IMP
What are the major key regulatory steps in the IMP biosynthesis pathway?
Inhibitors: NTP, NDP, NMP
activators: PRPP
What is Inosinate (IMP) a derivative of?
Adenylate (AMP), Guanylate (GMP)
What is added to IMP to create adenylosuccinate?
aspartate, GTP, adenylosuccinate synthetase
What is added to adenylosuccinate to create adenylate (AMP), and what is removed?
adenylosuccinate lyase
fumarate is removed
What is added to IMP to make XMP?
H20, NAD+
What is added to XMP to create GMP? WHat is removed?
Gln, and ATP
Glu, AMP + PPi
In the IMP biosynthesis pathway, glutamine is turned to glutamate with what enzyme?
glutamine-PRPP amidotransferase
What are building blocks of IMP?
○ Co2 ○ Glycine ○ Formyl-THF ○ Glutamine ○ Aspartate
What are 2 major Enzymes in the IMP biosynthesis pathway?
glutamine-PRPP amidotransferase
adenylosuccinate lyase
What does adenylosuccinate lyase do?
Creates AMP and fumarate in the IMP biosynthesis pathway. In addition it incorporates an aspartate
What does glutamine-PRPP amidotransferase do?
conversts glutamine to glutamate in the IMP biosynthesis pathway
How do the products of the IMP pathway (GMP and AMP) balance each other out?
GMP conversts to GTP which drives the other reaction. AMP turns into ATP which drives the other reaction. Buildup of either reaction inhibits itself and drives the other
Each product of IMP (GMP or AMP) utilizes how many Energy equivalents?
one (either GTP or ATP)
Does GMP utilize ATP or GTP?
ATP
Does AMP utilize ATP or GTP?
GTP
In the creation of IMP and the regulation of GMP and AMP Synthesis what inhibits PRPP from turning into 5 phosphoribosylamine via glutamine PRPP amido transferase.
AMP, GMP, IMP
In the creation of IMP and the regulation of GMP and AMP Synthesis what inhibits IMP dehydrogenase ( turning IMP to XMP)
GMP
In the creation of IMP and the regulation of GMP and AMP Synthesis what inhibits adenylosuccinate synthetase ( turning IMP to AMP)
AMP
In pyrimidine biosynthesis, what contributes to the ring structure?
glutamine, CO2 (via carbamoyl phosphate), Ribose 5-phosphate and aspartate.
What are the 2 main components of the UMP synthesis pathway?
carbamoyl phosphate and Aspartate
The purine ring is synthesized on ribose, while the pyrimidine is synthesized when?
before the ribose is added
The carbamoyl phosphate for pyrimidine synthesis is made where?
in the cytoplasm
In UMP synthesis, apartate transcarbamoylase (ATCase) is inhibited by what?
CTP
The UMP synthesis pathway begins with what three things?
carbamoyl phosphate, aspartate, and orotic acid
In the UMP synthesis pathway, what enzyme utilizes aspartate to convert Carbamoyl phosphate?
Aspartate transcarbamoylase (ATCase)
When does PRPP come into the UMP synthesis pathway?
after orotate
ATP + AMP -> 2ADP
What is this?
an adenylate kinase
ATP + NMP ->ADP + NDP
What is this?
nucleoside monophosphate kinases
ATP + NDP ->ADP + NTP
What is this?
Nucleoside diphosphate kinases
UTP->CTP
What is this?
cytidylate synthetase
ATP + AMP -> 2ADP
ATP + NMP ->ADP + NDP
ATP + NDP ->ADP + NTP
UTP->CTP
These are all ways to form what?
NTPs
There is a large sequence of (blank) reactions that occur in the process of removing the oxygen to make dNDP for DNA.
oxidation reduction
The heterocyclic ring systems of purines and pyrimidines are assembled form (blank), whereas the ribose portion of the nucleotides comes from (blank).
Simple precursors.
PRPP
(blank) is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides.
ribonucleotide reductase
the ribonucleotide reductase consists of a large RNR1 and small RNR2 subunits which associate to form an active heterodimeric tetramer What are they and what do they do?
RNR1= have regulatory sites and allosteric sites, binds ATP, dGTP,dATP,dTTP,dATP RNR2= active site
The creation of deoxyribonucleoside diphosphates are highly what?
regulated
In thymidylate synthesis, what inhibits thymidylate synthase resulting in decreased amount of dTMP?
5-fluorouracil
In the thymidylate synthesis, how is dTMP formed?
DHF is recycled via dihyrdofolate reductase which makes methylene THF which reacts with dUMP and thymidylate synthase to create dTMP
THF requires what?
folic acid
To salvage RNA and DNA molecules what 3 things do you need?
G/HX-PRT, A-PRT, Pyrimidines need orotic acid transferase
What are the steps in cytosine and uracil degradation?
cytosine->uracil->dihydrouracil->carbamoyl beta-alanine-> acetyl-SCoA
What is important about thymine degradation?
It makes methylmalonyl semialdehyde which is converted to succinyl sCOA which needs B12 so if you have a B12 deficiency you will have issues
What is the common product between GMP and AMP degredation?
Xanthine
Why is the GMP and AMP degredation clinically relevant?
because it results in uric acid and a build up of this can lead to gout. People treat gout by inhibiting Xanthine pathway
What are three treatments to gout?
Colchicine: anti-inflammatory
Probenecid: Increases uric acid excretion
Allopurinol: Xanthine oxidase inhibitor
WHat is gout?
the build up of uric acid at low ph which forms crystals that can irritate joints
B12 is required by what?
methylmalonyl CoA mutase and methionine synthetase
If B12 is lacking what clinically will occur?
pernicious anemia autoimmune disease that destroys parietal cells, megaloblastic anemia, neurological dysfunction, deficiency of folate.
B12 is utilized in what three types of reactions?
methionine synthesis, thymine degredation, valine isoleucine threonine degredation
What does B12 do in the methionine synthesis pathways?
converts homcysteine and metyhl-THF into THF and methionine
What does B12 do in the Thymine degredation?
methylmalonylsemialdehyde to succinyl-SCoa
What does B12 do in the valine, isoleucine, threonine degradation pathway?
turns methylmalonyl-coa into succinyl coa
Folate deficiency decreases (blank) and dTMP synthesis, arresting cell cycle in the S-phase and resulting in megaloblastic anemia.
purine
Folic acid is important in what?
THF
What does THF do?
It is a one carbon carrier involved in amino acid metabolism and nucleotide synthesis
Where do we get folic acid?
yeast, liver, fruits, green vegetables
What are the clinical consequences of not having enough folic acid?
Impaired dTMP synthesis, megaloblastic anemia (arrests RBC’s in S phase). Hyperhomocysteinemia with increased risk for cardiovascular disease. Deficiency in pregnancy can lead to neural tube defects (spina bifida) in baby.
Explain how folic acid deficiency influences purine synthesis
Folic acid is needed to create THF, since THF is a necessary reactant in the Purine synthesis pathway, this will decrease purine synthesis and arrest cell cycle in the S phase resulting in megablastic anemia.
What is the ATP requirement for purine biosynthesis?
5
What are the key regulated steps in purine synthesis?
Rate limiting step is the very first step of having glutamine to glutamate which is regulated by NTP, NDP, NMP. If a lot of these it will inhibit the pathway. If PRPP is elevated it will be upregulated.
Folic acid deficiency will inhibit creation of THF
The (blank) base is synthesized prior to addition of the ribose moiety. Whereas Purine synthesis begins with the ribose moiety.
pyrimidine
(blank) inhibits dihydrofolate reductase competitively, thereby depleting the cell of tetrahydrofolate.
Methotrexate
(blank) is inhibited by the antineoplastic agent 5-fluorouracil (5-FU). 5-FU is converted by (blank) to 5-FdMP, which remains bound to the enzymes, as a suicide inhibitor. 5-FU is an important agent in the treatment cancers such as breast and colon cancer.
Thymidylate synthase
Thymidylate synthase
Allopurinol is used as a treatment for gout. Describe the mechanism in the context of GMP and AMP degradation.
GMP and AMP degredation results in uric acid and a build up of this can lead to gout. People treat gout by inhibiting Xanthine pathway allopurinol is a Xanthine oxidase inhibitor.
