Skildlum- Nucelotide Metabolism Flashcards
Which bases are purines?
GA
Which bases are pyrimidines?
CT U
What are hypoxanthine and inosine?
Intermediates when nucleotides are being converted to fuel sources
What are nucleotide functions?
- To make DNA and RNA
- Handles“Handles” for enzyme cofactors:
CoASH
NAD+
FAD
Adenosylcobalamin - Energizing substrates–prepares them for reactions
UDP-glucose
CDP-choline - Second messengers
cAMP - Allosteric activators
AMP, ADP, ATP
What is PRPP?
- An activated ribose sugar
2. Created by the transfer of pyrophospahte to ribose 5 phosphate by PRPP synthetase
What inhibits PRPP synthetase?
GDP and ADP
What is the first step in purine synthesis?
The transfer of an amine from glutamine by the glutamine phosphoribosyl amidotransferase.
What is the second step in purine synthesis?
Addition of glycine to make glycinamide ribosyl 5-Phosphate.
How do you make IMP (inosine monophosphate)?
- Add C and N from tetrahydrofolate
- Add CO2
- Add glutamine
- Add aspartate
What happens in the conversion of IMP to AMP?
- Aspartate bonds to IMP to make adenylosuccinate (hydrolysis of GTP)
- Fumarate is cleaved off to make AMP
How do you form GMP?
- IMP is oxidized to xanthine monophosphate
2. Amine group is transferred from glutamine (using ATP hydrolysis to power reaction)
What happen to AMP and GMP?
- Phosphorylated to diphosphates
THEN - ADP and GDP can be phosphorylated again and: hydrolyzed for energy/incorporated into RNA
OR - Ribose sugar of ADP and GDP can be reduced to make dADP and GDP
What is thioredoxin?
A protein redox cofactor, like glutathione, that can exist in reduced or oxidized states depending on cysteine side chain sulfur atom.
What happens in purine salvage?
Cells expend a lot of energy to make nucleotides. To conserve this energy, there are different pathways to recycle nucleosides and bases in the cell
What can adenosine kinase do that is special? What must the other purine nucleosides do?
- It directly phosphorylates Adenosine to AMP
2. Have their ribose sugars removed, then added back from PRPP, to make monophosphate nucleosides.
What causes Lesch Nyhan Syndrome?
An inherited deficiency in hypoxanthine-guanine phophoribosyltransferase
What causes SCID (Severe combined immunodeficiency)?
An inherited deficiency in adenosine deaminase
What cause CID (Combined immunodeficiency)?
An inherited deficiency in purine nucleoside phosphorylase (PNP)
What does PNP deficiency cause and what are the symptoms?
- Combined immunodeficiency
2. Low but not absent T cells, chronic infection, FTT, neurological symptoms
What is the second most common cause of autosomal recessive SCID?
ADA deficiency
What does ADA deficiency lead to? What are the symptoms? What is the treatment?
- Accumulation of 2 deoxyadenosine in the blood. This is toxic to lymphocytes.
- Symptoms: Lymphocytes < 500 / mm3 (normal 3,000 – 9,000/mm3 for children), Costrochondral junction dysplasia (skeletal abnormalities)
- Treatment: Bone marrow transplant, +/- chemotherapy
What is Lesh Nhyan Disease? What are the symptoms?
HGPRT–He’s got purine recylcing trouble
- A rare X linked syndrome due to inherited deficiency in hypoxanthine-guanine phosphoribosyltransferase.
- Symptoms: Self injury (biting of the fingers and lips), Elevated uric acid in urine, mental retardation, dystonia, recurrent vomiting
What do patients with LND often die from?
Renal failure in their 30s. Can be prevented with drugs (allipurinol) that reduce uric acid.
What is the cause of self mutilation in LND?
Disturbance in dopamine signaling
In purine metabolism, GMP and AMP are degraded to xanthine, which is oxidized to uric acid by what enzyme?
xanthine oxidase
What is gout?
The precipitation of uric acid in distal joints, caused by purine degradation.
**If you eat a lot of organ meat, you get a lot of nucleotides coming in that get degraded to uric acid. Xanthine oxidase makes uric acid, which is the normal rout of excretion for excess nucleotides.
Treatment is a COMPETITOR of xanthine oxidase.
How do purines and pyrimidines differ in synthesis/assembly?
- Purines: assembled on ribose sugar
2. Pyrimidines: assembled than transferred to ribose sugar
What does CPS II do?
Uses glutamine as an amine donor to form carbamoyl phosphate.
2. Allosterically inhibited by: UTP, activated by PRPP
How do you make UMP?
- Carbamoyl phosphate bonds to aspartate to make carbamoyl aspartate.
- This is cyclized to ORotATE
- Orotate combines with PRPP to make a nucleotide, which is then decarboxylated to form UMP
**Carbamoyl phosphate is used in urea cycle, but it is also a substrate for pyrimidine synthesis
What is characteristic of urea cycle disorders downstream of CPS I?
Elevated urinary orotic acid
What happens in pyrimidine degradation?
Cytosine > uracil > CO2, NH4+, and b-alanine
Thymine > CO2, NH4+, and b-aminoisobutyrate
**Accumulation of pyrmidine metabolites is not associated with pathology
