Flashcards in Purine & Pyrimidine Deck (54):
Base + Pentose + p
Which type of base has 2 rings?
Which are the Purines?
Which are Pyrimidines?
Where is the OH attached on Ribose?
What can be salvaged?
Both Purines and Pyrimidines
Denovo synthesis takes place mainly where?
Brain and Liver
How do we build purines?
Start with R5P and build on the purine base
How do we build pyrimidines?
Synthesize with the pyrimidine ring then attach the R5P
Purine ring energy cost
6 ATP per nucleotide
How many N's in Purine ring?
Where does N1 come from on purine?
Where does N3 come from on Purine?
Where does N9 come from on Purine?
Where does N7 come from on Purine?
Where to the Purine Carbons come from?
C2 and C8 from THF
C6 from Bicarb
C4 and C5 from Glycine
Purine Synthesis requires what substrate?
What are the constituents of PRPP
R5P, ATP, Pyrophosphate
Committed step of Purine Synthesis?
Phosphoribosyl Amidotransferase (PRAT)
Purine Synthesis major intermediate
IMP synthesis Pathway?
(Glutamine+PRPP), Glycine, Formyl THF, Glutamine, CO2, Aspartate, Formyl THF
4 Regulated Reactions of Purine Synthesis (and what regulates them)
1. PRPP Synthase (-ADP/GDP)
2. PRAT (A & G Mono, Di, Triphosphates)
3. IMP DH (-GMP)
4. Adenylosuccinate Synthetase (-AMP)
Lesch Nyhan Syndrome Cause, Sx, Tx?
HGPRTase deficiency = No salvage pathway
Everything shunted to URIC ACID (via increased de novo synthesis)
Sx = Severe Neuro and Nephrolithiasis
Tx = Allopurinol (helps Nephro Sx but not CNS)
Purine Nucleoside Phosphorylase (PNP) ... What does it do, and what happens when you don't have it?
Normally takes inosine-> Hypoxanthine, Adenosine -> Adenine, and Guanosine -> Guanine. Basically converts nucleosides to free bases + Ribose-1P.
Nucleosides accumulate = Elevated dGTP = NO T-CELL function.
SCID cause, Effects,
Adenosine Deaminase deficiency.
Buildup of dATP. This is toxic to T cells, B cells, and NK cells.
Also inhibits SAM hydroxylase = reduced methylation rxns and accumulation of S-Adenosylhomocysteine (SAH)
Describe regulation in the Purine Salvage Pathway (3 ways is regulated or regulates stuff)
IMP/GMP inhibits HGPRTase
AMP inhibits APRTase
These also feed back to the de novo synthesis path enzymes (IMPDH and Adenylosucc. Synthetase)
PRPP is used in salvage, so it isn't available as a substrate for de novo.
Causes of Hyperuricemia and Gout
High PRPP Synthetase activity (R5P --> PRPP)
How the hell does VonGierke's result in hyperuricemia and gout anyway?
No Glucose 6 Phosphatase = Buildup of G6P, which gets shunted into the Pentose Phosphate Pathway. This results in increased R5P, which is a precursor to PRPP, resulting in increased denovo synthesis of purines and synthesis of uric acid.
Overall salvage pathway
AMP --> IMP --> HX ---> Xanthine Uric Acid ---> Urate
Link Between Fructose and gout?
Fructose metabolism = increased Fructose-6P
This drains the (P) pool, which lowers ATP available.
This results in increased Uric Acid.
Pyrimidine synthesis starts with
N base, then you add sugar and phosphate
Where do N's come from on Pyrimidine? C's?
Asp gives C4+5 and N1
Bicarb gives C2
Glutamine gives N3
Overall Pyrimidine Synthesis Reaction
Carbamoyl Phosphate --> N-CP --> Dihidroorotate --> Orotate --> OMP --> UMP
High orotate is indicative of what?
OTC defect in urea cycle
Orotate is a small base and can leak out cell
UMP synthase function? What happens when you are deficiency?
Dual function enzyme...
(takes Orotate --> OMP and OMP--> UMP)
Deficiency = HEREDITARY OROTIC ACIDURIA
Difference between NDP and NTP synthesis...
NDPs are made base-specific
NTPs are made with broad specificity
NDP synthesis (enzyme and reaction)
Adenylate Kinase and Guanylate Kinase
(=Nucleoside Monophosphate Kinases)
AMP + ATP --> 2ADP
NTP synthesis (enzyme and reaction)
Nucleoside Diphosphate Kinase
GDP + ATP ---> GTP + ADP
Deoxynucleotide Synthesis first 2 steps (including RLS)
make the ribonucleotide first, then deoxify!
RLS / 1st step = Ribonucleotide reductase (ex. ADP-->dADP)
2nd Step = Nucleoside-5-diphosphate kinase (ex. dADP --> dATP)
Weird stuff with dNT synthesis
dCDP --> dCTP
dCMP --> dUMP via DEOXYCYTIDYLATE DEAMINASE
dUDP --> dUMP
dUMP (from either of the above)-->dTMP via THYMIDYLATE SYNTHASE
Effect of deoxyribonucleotides? When are they elevated?
Toxic! Normally only elevated in S-Phase
Ribonucleotide Reductase properties (4)
RLS for dNT synthesis
2 sites: Activation and Specificity
ATP activates, dATP feedback inhibits
dTMP synthesis enzyme
Thymidylate synthase, needs N5N10 THF
N5N10THF is converted to ___ during dTMP synthesis?
(1) Dihydrofolate Reductase (-->THF)
(2) Hydroxymethyltransferase (N5N10)
Inhibitors of dihydrofolate reductase
Aminopterin and Methotrexate
The Thymidylate Synthase inhibitor that also inhibits dTMP synthesis is...
Fluorouracil function, use, and mechanism
Inhibits thymidylate synthase
Treatment for SOLID tumors
f-UTP is incorporated into RNA which inhibits Ribosome maturation
What is fdUMP? and what does it do?
Inhibitor of thymidylate synthase (via fluorouracil), keeps dUMP to incorporate into DNA, resulting in strand breakage.
Cytosine Arabinoside Mechanism and use
5' Triphosphate that incorporates into DNA and inhibits synthesis
Used for leukemia
What does methotrexate inhibit? why doesn't this work on all cells?
It inhibits Dihydrofolate Reductase (DHF-->THF)
Normal cells are rescued by N5-Formyl-THF (LEUCOROVIN, an analog that can be used similarly)
Hydroxyurea function and mechanism
Inhibits DNA synthesis (not RNA or protein)
Acts on Ribonucleotide reductase
Acyclovir and Gancyclovir properties, mechanism, uses
Purine analog that inhibits viral Thymidine Kinase (mammals can't use it)
In virus it is activated to monophosphate
Acyclovir for HSV, Gan for CMV retinitis
AZT properties and mechanism
Blocks HIV by inhibiting DNA