Lecture 50 Flashcards
What are 6 key roles of nucleotides in cellular processes?
1) Activated precursors of RNA & DNA
2) Adenine nucleotides are components of the major co-enzymes: NAD, NADP, FMN, FAD, & CoA
3) Nucleotide derivatives are activated intermediates in biosynthetic processes (UDP-glucose, SAM)
4) Serve as metabolic regulators (e.g. cAMP and the activation of cell signaling)
5) Serve as major currency of energy in all cells (ATP & GTP)
6) Several metabolic diseases have their etiology in nucleotide metabolism
What are the purine DNA nucleotide bases?
1) Adenine
2) Guanine
What are the pyrimidine DNA nucleotide bases?
1) Thymine
2) Cytosine
What are the purine RNA nucleotide bases?
1) Adenine
2) Guanine
What are the pyrimidine RNA nucleotide bases?
1) Uracil
2) Cytosine
What is the difference between adenine, adenosine, & adenosine monophosphate (AMP)?
1) Adenine is a base
2) Adenosine contains the adenine base in addition to a ribose sugar (or deoxyribose)
3) Adenosine monophosphate (AMP) contains the adenine base, a ribose (or deoxyribose sugar), & a phosphate group
How can you form a diphosphate?
Using nucleoside monophosphate kinase & a tri-phosphate, you can phosphorylate a monophosphate to form a diphosphate
How can you form a triphosphate?
Using nucleoside diphosphate kinase & a tri-phosphate, you can phosphorylate a diphosphate to form a triphosphate
What are two common purine bases aside from adenine and guanine?
1) Hypoxanthine (6 oxy purine)
2) Xanthine (2,6 dioxy purine)
3) Adenine (6 amino purine)
4) Guanine (2 amino, 6-oxy purine)
What are two biosynthetic pathways for obtaining purine and pyrimidine bases?
1) De novo pathway (building the bases from non-purine molecules)
2) Salvage pathway (the reutilization of bases from dietary or catabolic sources)
How can you form uracil from cytosine?
Oxidative deamination
Which of the following types of cells has the highest activity of ribonucleotide reductase and why? (Epithelial, nerve, or muscle)
When there is a need for DNA synthesis in a cell, such as in a rapidly dividing cell, RNA will be converted to DNA by Ribonucleotide reductase. This occurs most often in an epithelial cell, which needs to rapidly divide
When a pharmaceutical company produces a purine or pyrimidine based drug, it is best administered as a base, nucleoside, or nucleotide?
Nucleoside because it is unphosphorylated and can easily cross the cell membrane
What is a byproduct of the pentose phosphate pathway that is used in the biosynthesis of purines?
Ribose 5-phosphate
What is the first step of purine biosynthesis in the de novo pathway?
1) Ribose 5-phosphate + ATP → PRPP + AMP (uses ribose phosphate pyrophospho-kinase (PRPP) synthetase)
2) Can be inhibited by products IMP, AMP & GMP through feedback inhibition
Once PRPP is formed, what is the first unique step to purine biosynthesis in the de novo pathway?
1) Phosphate pyrophospho-kinase (PRPP) + Glutamine → 5-phosphoribosylamine + Glutamate + PPi
2) Can be inhibited by products IMP, AMP, & GMP through feedback inhibition
Describe the de novo pathway of purine biosynthesis
1) It is a nonregulatory pathway (once it begins, it goes to completion)
2) The end product is Inosine Mono-Phosphate (IMP)
3) The Nitrogens that make up IMP are taken from aspartate, glycine, & glutamine
4) The carbons that make up IMP are taken from 10-formyl THF, 5,10-methenyl THF, CO2, & Glycine
What is Inosine Monophosphate (IMP) used for?
It is a precursor for both AMP & GMP
How is AMP formed from IMP?
1) IMP + Aspartic Acid + GTP → Adenylosuccinate + GDP (uses Adenylosuccinate synthetase)
2) Adenylosuccinate → Fumarate + AMP (uses Adenylosuccinase)
3) The presence of GTP positively regulates this pathway
How is GMP formed from IMP?
1) IMP + H2O + NAD+ → Xanthosine monophosphate + NADH + H+ (uses IMP dehydrogenase)
2) Xanthosine monophosphate + Glutamine + ATP → GMP + Glutamate + AMP + PPi (uses GMP synthetase)
3) The presence of ATP positively regulates this pathway
How is Adenine formed from Hypoxanthine-IMP?
Hypoxanthine-IMP + Aspartate → Adenine (Aspartate donates N)
How is Guanine formed from Xanthine-XMP?
Xanthine-XMP + Glutamine → Guanine (Glutamine donates N)
What is unique about the salvage pathways of purine synthesis?
Instead of synthesizing new purines (like the de novo pathway), it re-utilizes existing purines
What are two main enzymes with different specificities associated wit the salvage pathways?
1) Adenine phosphoribosyl transferase (APRT)
2) Hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
Describe the reaction catalyzed by APRT
PRPP + Adenine → AMP
Describe the reaction catalyzed by HGPRT
PRPP + Hypoxanthine/Guanine → IMP/GMP
What enzyme catalyzes the degradation of a nucleotide into a nucleoside?
Nucleotidase
What enzyme catalyzes the degradation of a nucleoside into a base?
Phosphorylase
What are two diseases correlated with a deficiency in HGPRT?
Gaut & Lesch–Nyhan syndrome
How can adenosine be degraded to uric acid?
1) Adenosine + H2O → Inosine + NH4+ (uses Adenosine deaminase (ADA))
2) Isosine + Pi → Hypoxanthine + Ribose-1-phosphate (uses purine nucleoside phosphorylase)
3) Hypoxanthine → Xanthine (uses xanthine oxidase)
4) Xanthine → Uric Acid (uses xanthine oxidase)
How can guanosine be degraded to uric acid?
1) Guanosine + Pi → Guanine + ribose-1-phosphate (uses purine nucleoside phosphorylase)
2) Guanine + H2O → Xanthine + NH4+ (uses guanine deaminase)
3) Xanthine → Uric Acid (uses xanthine oxidase)
What causes Gout?
Gout results from hyperuricemia. This can be caused by:
1) Decreased Uric Acid excretion: 80% of gout – idiopathic, renal disease, diabetes insipidus, hypertension, Downs syndrome, & many others
2) Increased Uric Acid production: 20% of gout
a) PRPP synthetase overactivity, hemolytic diseases, lymphoproliferative disease, & many others
b) HGPRT deficiency (Lesch-Nyhan syndrome)
What exacerbates gout?
1) Alcohol
2) Purine rich diet
3) Obesity
How exactly does PRPP synthetase overactivity lead to gout?
Lost regulation of PRPP synthetase allows it to continuously convert Ribose 5-phosphate to phosphoribosyl amine, which is then converted to purines. When there is an excess of purines, they must be degraded into uric acid
How exactly does HGPRT deficiency lead to gout?
Without HGPRT, PRPP + Guanine cannot be converted to GMP. There is therefore a buildup of guanine, resulting in elevated uric acid levels
How can gout be treated?
Administration of allopurinol inhibits xanthine oxidase, causing:
1) Decrease urate
2) Increase xanthine & hypoxanthine
3) Decrease PRPP
What is Lesch-Nyhan syndrome?
1) X-linked recessive
2) Severe HGPRT deficiency, which causes decreased IMP & GMP, & Increased PRPP & de novo purine pathway
3) Hyperuremia: gouty arthritis, kidney stones, tophi
4) Neurologic disability: spasticity & hyperreflexia
5) Behavioral problems: cognitive dysfunction, aggression, & self-injury
What is SCIDS (Severe Combined Immunodeficiency Syndrome)?
1) Autosomal recessive disorder
2) Mutations in Adenosine Deaminase (ADA) causes a deficiency of ADA
3) Infants subject to bacterial, candidiasis, viral, & protozoal infections
4) A buildup of of dATP is toxic and causes reduction of both T band C cells
