Nucleotide Metabolism I Flashcards
What are nucleotides made up of?
Nitrogenous base - purine or pyrimidine
Ribose or 2-deoxyribose
Phosphate
Why do we need to worry about nucelotides?
Components of nucleic acids
Energy metabolism
Components of coenzymes
Activated intermediates
Physiological modulators
Allosteric modulators
What are the purine bases?
Adenine and Guanine
Intermediates are hypoxanithine and xanthine
What are the pyrimidine bases?
Uracil
Cytosine
Thymine
What is the nomenclature for a base + ribose?
Nucleoside
What is the nomenclature for a base + ribose + phosphate?
Nucleotide
Name the bases and their corresponding nucleosides
Adenine - Adenosine
Guanine - Guanosine
Cytosine - Cytidine
Thymine - Thymidine
Uracil - Uridine
What are the characteristics of the de novo synthesis of purines?
Extremely energy intensive process
Salvage of pre-formed elements preferred
Purine ring assembled stepwise upon a base of 5-phosphoribosyl-1-pyrophosphate (PRPP) and generated by PRPP synthetase
What is the importance of PRPP?
Participates in both purine and pyrimidine biosynthesis
What is the committed step of de novo purine biosynthesis?
Formation of 5-phosphoribosylamine (PRA)
Catalyzed by amidophosphoribosyltransferase
What is the first purine synthesized in the de novo synthesis of purines?
Inosine 5’-monophosphate (IMP)
Converted from 5-phosphoribosylamine (PRA)
What are important characteristics of the formation of IMP from PRA?
Nine reactions convert PRA to IMP
Four reactions require ATP hydrolysis
Carbon and nitrogen atoms donated by amino acids
HCO3- contributes carbon and oxygen
N10-formyl THF donates one carbon groups
What is IMP the precursor for?
AMP and GMP
How is IMP converted to AMP?
AMP converted to adenylosuccinate by adenylosuccinate synthetase by adding aspartate
Adenylosuccinate converted to AMP by adenylosuccinase and fumarate is released
What inhibits adenylosuccinate synthetase?
AMP
How is IMP converted to GMP?
IMP converted to xanthosine 5’-monophosphate by IMP dehydrogenase and NADH and H released
Xanthosine 5’-monophosphate converted to GMP by GMP synthase and glutamate is released
What inhibits IMP dehydrogenase?
GMP
What is requires to convert AMP and GMP to ATP and GTP?
Kinase active
Nuceloside 5’-monophosphate kinases
Nucleoside 5’-disphosphate kinases
What are the substrate specificities and examples of Nuceloside 5’-monophosphate kinases?
Differing substrate specificities
Adenylate kinase and guanylate kinase
What are the substrate specificities and examples of Nucleoside 5’-disphosphate kinases?
Broad substrate specificity
Transfer phosphate from one nucleotide to another
What does PRPP synthetase do and how is it regulated?
Converte ribose 5-phosphate to PRPP
Inhibited by purine nucleotides - ADP and GDP
Excess purine nucleotides reduces number of precursor molecule - self-limiting
PRPP required for purine and pyrimidine synthesis so both classes of nucleotides impacted
What does amidophosphoribosyltransferase do and how is it regulated?
Converts PRPP to PRA
Committed step
Inhibited by AMP and GMP
Activated by PRPP - both substrate and allosteric activator
Increased PRPP stimulates purine synthesis
What does adenylosuccinate synthetase do and how is it regulated?
Converts adenylosuccinate to AMP
Inhibited by AMP
What does IMP dehydrogenase do and what regulates it?
Converts Xanthosine 5’-monophosphate to GMP
Inhibited by GMP
Where does purine degradation occur largely?
Liver
How does degradation of GMP occur?
Phosphate removed from GMP and generates guanosine by 5’-nucleotidase
Ribose removed from guanosine and generate free guanine by purine nucleoside phosphorylase
How does degradation of AMP occur?
Utilizes two different aminases to convert AMP to inosine ->
AMP deaminase converts AMP to IMP and 5’ nucleotidase converts IMP and inosine
OR
5’nucleotidase converts AMP to Adenosine. Adenosine deaminase converts adenosine to inosine.
Inosine metabolized to hypoxanthine by purine nucleoside phosphorylase
Where is AMP deaminase expressed and where is it abundant?
Widely expressed in skeletal muscle, brain, liver, and red blood cells
Abundant in muscle and loss of function can cause exercise intolerance. Sometimes called myoadenylate deaminase
How is adenosine deaminase expressed and where is it abundant?
Widely expressed
Abundant in lymphocytes and loss of function impacts immune system
How is uric acid generated?
Guanine and hypoxanthine converted to xanthine by guanine deaminase and xanthine oxidase, respectively.
Xanthine is then converted to uric acid
What is the end product of purine degradation?
Uric Acid
Eliminated in urine
What is uric acid and its characteristics?
Metabolic endpoint in humans and great apes
Weak acid
What does it mean that uric acid and urate salts are both of limited solubility?
Urate levels in serum typically close to saturation even in normal, healthy individuals
