Week 3 - Nucleotide Metabolism - Skildum Flashcards
How is PRPP created?
- The pentose phosphate pathway converts glucose-6-phosphate to ribose-5-phosphate.
- Ribose-5-phosphate converts to PRPP via PRPP sythetase
How is PRPP synthetase regulated?
PRPP synthetase is allosterically inhibited by downstream GDP and ADP
Describe the steps from PRPP to inosine monophosphate in purine synthesis:
1- transfer an amine from glutamine to PRPP
2- Addition of glycine
3- Carbons and nitrogens are added from THF, CO2, glutamine, and aspartate to make inosine monophosphate.
How is inosine monophosphate(IMP) converted to AMP in purine synthesis?
Aspartate binds to IMP to make adenylsuccinate and then fumarate is cleaved off to form AMP!
(very similar to the point in the urea cycle when aspartate is added to cutrulline to form arginosuccinate and then fumarate is cleaved off)
How is inosine monophosphate(IMP) converted to GMP in purine synthesis?
IMP is oxidized and then an amine group is transferred from glutamine to male GMP!
What do you do once you have AMP and GMP?
You can phosphorylate it to diphosphates and triphosphates to use it for energy and enzyme regulation
Use for RNA
You can also reduced ADP and GDP to dADP and dGDP, later use to make DNA
What purine salvage reaction is unique to Adenosine?
The adenosine kinase reaction that phophorylates adenosine directly to AMP
Other purine bases must robose sugars removed then added back form PRPP
What problems occur as a result of Purine Nucleoside Phosphorylase (PNP) deficiency?
Combined Immunodeficiency
- low but not absent T-cells
- chronic infections
- failure to thrive
- neuro problems
What problems occur in the case of Adenosine Deaminase (ADA) deficiency?
SEVERE combined immunodeficiency!
ADA deficiency leads to accumulation of 2-deoxyadenosine in the blood. TOXIC to lymphocytes
Symptoms: low lymphocytes, Costrochondral junction dysplasia
(skeletal abnormalities) (like in scurvy, bone and cartilage junction in ribs, messed up)
Treated with Chemo or Bone marrow transplant
What is Lesch Nyhan Syndrome? What causes it?
Rare X linked syndrome due to inherited deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
(He’s Got Purine Recycling Trouble)
Symptoms: Self-injury by biting fingers and lips
elevataed uric acid in urine, mental retardation, vomiting, renal failure often cuases death by 30’s
Allopurinol can reduce renal problems by decreasing uric acid
How are GMP and AMP degraded enough to enter urine? What problems can occur?
After AMP and GMP turn to xanthin, Xanthin Oxidase is responsible for converting them into uric acid, which is excreted in urine.
If there is TOO much uric acid it can precipitate because it’s not very soluble. It will actually precipate in the distal joints (becuz its colder there)
The condition is called GOUT!
Gout can be treated by allopurinol, which inhibits xanthin oxidase!
What is a big overarching difference between purine and pyrimidine sythesis
Purine bases are assembled on a ribose sugar
Pyrimidine bases are first assembled then transferred to a ribose sugar afterward.
Explain pyrmidine synthesis from carbamoyl phosphate to UMP (uridine monophosphate)
- carbamoyl phosphate synthase (CPS) 2 takes an amine from glutamine to form carbamoyl phosphate ( CPS-2 allosteically activated by PRPP)
- Orotic acid is made a couple reactions down
- Orotic acid combines with PRPP to form UMP
Elevated Orotic Acid would indicate?
Urea cycle disorders, downstream of CPS-2
What pathologies are assocaited with pyridimine degradation?
NONE
