Flashcards in Purines and Pyrimidines Deck (34):
Describe the function of the antiporter ORNT1
Ornithine is transported in
Citrulline is transported out
What happens if you cannot run the urea cycle?
Cannot get nitrogen out, get a buildup of ammonia, which is toxic
Which organ is the main site of the urea cycle? How do you get nitrogen there?
- The liver
- get nitrogen to the liver via Glutamine (extra nitrogen relative to glutamate)
- Also can get delivery through alanine via a transamination reaction (recall that alanine can be produced from pyruvate!)
What are the control points for protein catabolism?
2. Carbamoyl phosphate synthetase I
3 & 4) Glu dehydrogenase
Refer to the figure for where these number occur
Creatine phosphate - high energy phosphate form, reservoir in the muscle, used during exercise
Branched Chain Amino Acids
Remove nitrogen through transamination. Get an alpha-ketoacid. You can then take this into Krebs for gluconeogenesis.
Which enzyme is broken in MSUD?
branched-chain alpha-keto acid dehydrogenase complex
What alpha-ketoacid do we see used in the TCA cycle regularly?
If we used PDHC, then you would go from pyruvate --> acetyl-CoA; this is similar to what we are doing with the other branched chain AAs now. Just trying to get into the TCA cycle
PURe As Gold; CUT the Py
Purines: Adenine and Guanosine
Pyrimidines: Cytosine, Uracil, Thymidine
Which pyrimidines are in RNA vs. DNA
What is the difference between nucleoside and nucleotide?
Nucleoside = Base + Sugar
Nucleotide = Base + Sugar + Phosphate
Can either build sugar and put a base on it or build a base and put a sugar on it
Where does the Urea Cycle occur?
The mitochondria and cytosol
Key differences in purine and pyrimidine nucleotide de novo synthesis:
- Purine base made on the ribose
- initial nucleotide product is IMP
- I is converted to G and A as a monophosphate
- Base ring is synthesized then attached to the ribose
- Initial nucleotide product is UMP
- U is converted to C as a triphosphate
De novo synthesis of purines:
1. Get ribose sugar from HMP Shunt (key enzyme: G6PD)
2. Ribose 5-phosphate --(PRPP Synthetase)--> 5-Phosphoribosyl-1-pyrophosphate (PRPP); key step because this requires ATP
3. PRPP --(Glutamine phosphorphoribosyl pyrophosphate aminotransferase)--> 5'-Phosphoribsoylamine; key step because this is at the front end and is allosterically regulated
4. End at IMP
What activates and inhibits PRPP synthase
1. Activation by Pi
2. Inhibition by purine ribonucleotides (end product inhibition)
First step is allosterically regulated
What activates and inhibits glutamine phosphoribosyl pyrophosphate aminotransferase?
Sources of atoms for purine synthesis
4. THF (methyl donor)
Converting IMP to AMP and GMP
Need to get extra nitrogens hooked on
AMP and GMP come from IMP, and there is feedback inhibition from end-products
Source of energy:
1. For AMP production: uses GTP
2. For GMP production: uses ATP
If you have a lot of AMP, then you will shift to making more GMP and vice versa
Generating Di and Tri-Phosphate forms
The following get us to the diphosphate form:
- Adenylate kinase
- Guanylate kinase
This gets us to the triphosphate form:
- Nucleoside diphosphate kinase
- ATP acts as energy donor to get the other ribonucleotides to the triphosphate form
Carbamoyl phosphate synthetases
1. 2ATP + CO2 + glutamine --(Carbamoyl phosphate synthetase II) --> Carbamoyl phosphate
- Carbamoyl phosphate synthetase I is in the mitochondria and is part of urea. Uses Ammonia as source of nitrogen and is activated by N-acetyl-glutamate.
- Carbamoyl phosphate synthetase II is in the cytosol and is part of pyrimidine biosynthesis. Uses gamma-amide group of glutamine and is inhibited by UTP (end product inhibition) and activated by ATP
Pyrimidine synthesis (Cytosol)
1. 2 ATP + CO2 + Glutamine -- (Carbamoyl phosphate synthetase II)--> Carbamoyl phosphate; key step because energy invested as 2 ADP
2. Get finished base (orotate) + add PRPP --> OMP --> UMP
3. Ends at UMP
Sources of atoms for pyrimidine synthesis
1. CO2 and glutamine
3. Ribose sugar is added last
Synthesizing CTP from UTP
UTP -- (CTP synthetase)--> CTP
1. Uses Glutamine -> Glutamate
2. Requires ATP
Conversion or ribonucleotides to deoxyribonucleotides
1. Ribonucleoside diphosphate --(Ribonucleotide reductase)--> deoxyribonucleoside diphosphate
On/Off sites and regulation of ribonucleotide reductase
1. Activity sites (on/off switch)
- ATP activates the enzyme
- dATP inhibits the enzyme
so based off of the ratio of dATP:ATP
2. Substrate specificity sites (determine which one is made)
- ATP, dATP, dTTP, or dGTP regulate the reduction of specific deoxyribonucleotides
Without U there's no T... what am I referring to?
You can't make dTMP or dTTP without first going through dUMP.
Things to remember about mono and di...
1. Ribonucleotide reductase uses dNDP or NDP (diphosphate)
2. UTP -> CTP
THF's role in U-->T
THF is a methyl donor
1. dUMP --(THF)--> dTMP
2. N5, N10 THF --> Dihydrofolate --> THF to recycle it.
Note: methotrexate inhibits THF recycling to N5,N10 THF, which is why it is used against cancer cells.
Degradation of purine and pyrimidines
Channel the base into uric acid
1. PRPP --> IMP --> inosine OR you can do step 2
2. AMP --> adenosine --(adenosine deaminase)--> inosine
3. Inosine -- (purine nucleoside phosphorylase) --> hypoxanthine
4. Hypoxanthine --(xanthine oxidase)--> xanthine
5. Xanthine -- (xanthine oxidase)--> uric acid
Deficiency of adenosine deaminase results in what?
Accumulation of dADP or dAMP and poisons ribonucleotide reductase.
Results in SCID!
Allopurinol is used to treat what disease process, and which enzyme specifically?
Tx for gout via xanthine oxidase
2 key enzymes in purine and pyrimidine degradation?
1. ADA (adenosine deaminase)
2. Xanthine oxidase
HGPRT deficiency results in what?
Inability to salvage hypoxanthine or guanine
Need to do a bunch of de novo synthesis, this results in excessive production of uric acid --> Lesch-Nyhan