Purine and Pyrimidine Nucleotide Metabolism Flashcards
What are the three components of a nucleotide?
Base- purine or pyrimidine
Pentose- ribose or deoxyribose
Phosphoryl group/s- one or more
Differentiate the structure of the two purine bases
Adenine: amino group (NH2)
Guanine: NH2 and =O
Differentiate the structure of the three pyrimidine bases
Cytosine: NH2 and =O
Uracil: two =O
Thymine: two =O and a methyl group
Which bases are found in DNA vs RNA?
AGCT= DNA AGCU= RNA
Differentiate base, nucleoside and nucelotide
Base: ring bases only (AGCTU)
Nucleosides: base + sugar
Nucleotide: Base, sugar and phosphate
Differentiate ribose from deoxyribose
Deoxyribose: one less -OH group
What are the three sources of atoms in the purine ring structure?
Amino acids- glycine, aspartate and glutamine
CO2
Tetrahydrofolate (FH4) derivative
In the synthesis of purines, is the purine ring synthesized first and then attached to ribose, or is the purine ring synthesized on top of ribose?
The purine ring is built up atom by atom on top of the ribose
What is the precursor molecule for purines?
Ribose-5-phosphate
What are the first two enzymatic steps in purine biosynthesis starting with ribose-5-phosphate?
Step 1: activation of ribose-5-phosphate to give PRPP (Pi from ATP)
Step 2: formation of 5-phosphoribosylamine (NH2 from glutamine)
What is the source of ribose-5-phosphate?
Pentose-phosphate pathway
What enzyme catalyzes the committed and major regulated step of purine synthesis?
The second step, the formation of 5-phosphoribosylamine, is the committed step and major regulated step
Catalyzed by Glutamine PRPP amidotransferase
Which nucleotide stands at the branch point leading to the synthesis of AMP and GMP?
IMP
IMP becomes the precursor for both AMP and GMP
What are the major allosteric regulators (negative feedback) in purine synthesis?
High levels of IMP, AMP and GMP negatively inhibit purine biosynthesis
Why might an inhibitor of purine biosynthesis be useful in slowing tumor growth?
Tumors are very dependent on the purine biosynthetic pathway to produce purine nucleotides for DNA and RNA synthesis.
In contrast, most normal tissues are less dependent on de novo synthesis and instead recycle existing purine bases (salvage pathway)
What tumor pathway is inhibited by the anti-tumor agent, 6-mercaptopurine
6-mercaptopurine inhibits enzymes in the purine biosynthetic pathway.
It is used to treat acute lymphocytic leukemia (ALL)
What three molecules contribute atoms to the pyrimidine ring?
aspartate, glutamine and CO2
What is the regulated step in pyrimidine biosynthesis?
Step 1: glutamine + CO2 + 2ATP
Catalyzed by carbamoyl phosphate synthetase II
Indicate whether the pyrimidine ring is synthesized first and then attached to the ribose, or whether the pyrimidine ring is synthesized on top of ribose.
The pyrimidine ring structure is formed first and then attached to a ribose-5-phosphate (activated form)
Name the pyrimidine nucleotide that is biosynthesized first and becomes a precursor for the synthesis of the other pyrimidine nucleotides
UMP is the precursor for synthesis of the other pyrimidine nucleotides
Indicate which metabolic pathway is blocked by the rheumatoid arthritis drug, leflunomide
Leflunomide, an immunosuppressive drug used to treat rheumatoid arthritis, blocks pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase
Briefly describe the synthesis of dTMP from dUMP
dTMP is synthesized from dUMP and N5,N10-methylene tetrahydrofolate by thymidylate synthase.
Describe how 5-fluorouracil acts as an antitumor agent.
5-fluorouracil is converted to f-dUMP which then acts as a pseudosubstrate and covalently binds to, and inhibits, thymidylate synthase
TLDR: Inhibition of thimidylate synthase
Describe how methotrexate acts as an antitumor agent
Methotrexate is a potent competitive inhibitor of dihydrofolate reductase and increases dihydrofolate and causes an intracellular tetrahydrofolate deficiency.
TLDR: Tetrahydrofolate deficiency
