Nucleotide Metabolism Flashcards
Which amino acid is an important precursor for de novo synthesis of nucleotides?
glutamine
What is the first step in purine de novo synthesis?
alpha-D-Ribose 5-phosphate to Phosphoribosyl pyrophosphate (PRPP)
What enzyme synthesizes the first step in purine de novo synthesis?
PRPP Synthetase
What cofactor does PRPP Synthetase need?
ATP
What is the second step of purine de novo synthesis?
A glutamine and water is added to PRPP, resulting in 5-Phospho-beta-d-ribosylamine
What enzyme catalyzes the addition of glutamine and water to PRPP?
PRPP Glutamyl Amidotransferase
Which enzyme adds a formyl group in purine de novo synthesis?
Formyltransferase
What is the donor to formyltransferase and what is left over?
Donor is 10-formyltetrahydrofolate and what’s left is tetrahydrofolate
Adenylosuccinate synthetase is the second to last step in de novo synthesis of adenosine monophosphate (purine). What does it require?
GTP, Mg2+
Transamidinase is the last step in de novo synthesis of guanosine monophosphate (purine). What does it require?
ATP, Glutamine
What do ADP and GDP inhibit in purine de novo synthesis?
PRPP synthetase
What do GMP, IMP, and AMP collectively inhibit in purine de novo synthesis?
PRPP glutamyl amidotransferase
Which enzyme converts ribonucleoside diphosphate to 2’-deoxyribonucleoside diphosphates?
Ribonucleotide reductase
What reaction “recharges” the ribonucleoside to deoxyribonucleoside conversion?
Thioredoxin reductase, NADPH and H+
Which enzyme salvages AMP from adenine?
Adenine phosphoribosyl transferase
Which enzyme converts hypoxanthine to IMP and guanine to GMP? (Purine salvage)
Hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
What do both purine salvage pathways need as an input?
PRPP
Multi-reaction enzyme complex at the start of pyrimidine de novo synthesis?
“CAD”
1) Carbamoyl phosphate synthetase II
2) Aspartate transcarbamoylase
3) Dihydroorotase
What downregulates “CAD” in pyrimidine de novo synthesis?
UTP and UDP (negative feedback)
What upregulates “CAD” in pyrimidine de novo synthesis?
PRPP
Where does PRPP appear in pyrimidine de novo synthesis?
As an input in the reaction catalyzed by orotate phosphoribosyltransferase
Folate’s role in pyrimidine de novo synthesis?
Last step forming TMP; thymidilate synthase uses 10-methyltetrahydrofolate and outputs TMP and dihydrofolate.
CTP synthetase, the last step before forming CTP, requires what reactants?
UTP, ATP, and glutamine
Is it the products of purine or pyrimidine metabolism which are insoluble?
Purine
How does PRPP synthetase factor into coordinated regulation of purine and pyrimidine metabolism?
It is inhibited by nucleotide products of both pathways
How is pyrimidine biosynthesis regulated by purine biosynthesis (crossregulation)?
ATP is necessary for pyrimidine biosynthesis (remember it’s a purine)
Which antineoplastic agents are analogs of glutamine, meant to inhibit the pathways and prevent cell division?
Azaserine and Acivicin
What does 5-fluorouracil do directly in the body?
Nothing. It’s a prodrug and must be metabolized into FdUMP first.
What is 5-fluorouracil’s (metabolized into FdUMP) mechanism of action
Competitive inhibitor of Thymidylate Synthase (normally uses 5,10-Methylenetetrahydrofolate)
What does allopurinol do to help in the treatment of gout?
Inhibits xanthine oxidase
How do methotrexate and aminopterin treat cancer and rheumatoid arthritis?
They inhibit dihydrofolate reductase (dihydrofolate conversion to tetrahydrofolate)
What PABA analog and competitive inhibitor did we learn about?
Sulfonamides
What is significant about PABA?
Bacteria are able to generate dihydrofolate from it. Competitive inhibition by sulfonamides interferes with folate metabolism.
What does trimethoprim, an antibiotic, do?
Inhibits dihydrofolate reductase
What does 6-mercaptopurine do in the purine salvage pathway?
Acts as a competitive inhibitor of Hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
What is formed instead of IMP/GMP when 6-mercaptopurine competes with hypoxanthine and guanine as a substrate for HGPRT?
TIMP
What does HGPRT stand for?
Hypoxanthine-guanine phosphoribosyl transferase
What is a drug treatment for a regular case of gout (hyperuricemia)?
Allopurinol
A rare inherited disorder caused by a deficiency of the enzyme HGPRT and causing extreme hyperuricemia
Lesch-Nyhan Syndrome (LNS)
What can be said about the inheritance pattern of Lesch-Nyhan Syndrome
X-linked
Glucose-6-phosphatase deficiency characterized by glycogen build up and hyperuricemia
von Gierke disease
Why does von Gierke disease cause hyperuricemia
lt causes chronic lactic acidosis. lactic acid and uric acid compete for the same renal tubular transport mechanism
What inherited disorder related to purine metabolism damages the immune system and causes severe combined immunodeficiency (SCID)?
Adenosine Deaminase Deficiency
Which purine metabolism disorder results in severe deficiency of T cells and immune dysfunction?
Purine Nucleoside Phosphorylase Deficiency
Autosomal recessive metabolic disorder characterized by neurological problems
Dihydropyrimidine dehydrogenase deficiency
Orotic Aciduria
Disorder involving disorder of orotate phosphoribosyltransferase (Type 1) and Orotidylic acid decarboxylase (Type 1, 2). Characterized by orotic acid build up due to inability to convert to UMP
Which two molecules coregulate purine/pyrimidine production?
ATP and PRPP
Drugs that prevent the production of both purine/pyrimidine synthesis pathways?
Azaserine (glutamine analog) and methotrexate (inhibit dihydrofolate reductase)
