Nucleotide Metabolism Flashcards
What drug inhibits synthesis of guanine nucleotides by competitively inhibiting the IMP dehydrogenase?
Mycophenolate & Ribavarin
What causes gout?
Overproduction or under-excretion of uric acid due to enzyme deficiency
How does gout differ from Lesch-Nyhan Syndrome?
Gout has many causes, one of which is a partial mutation in the Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) of purine salvage. Lesch-Nyhan syndrome is caused by a deficiency of HGPRT causing overproduction of purines de novo and increased uric acid. Symptoms include hyperuricemia, megaloblastic anemia, cognitive deficits, behavioral problems, and self-mutilation
The UMP synthase is a bifunctional protein with 2 catalytic domains. What molecule does the synthase synthesize and how?
Synthesizes UMP by combining Orotic Acid & PRPP
What molecule is the parent of purines?
IMP
What enzyme is responsible for GDP/GTP synthesis from IMP?
IMP dehydrogenase
What is the mechanism of action of Sulfonamides?
Inhibit folate synthesis to prevent synthesis of purines and thymidine
What is the committed step of purine synthesis?
Amidophosphoribosyl transferase
What step in pyrimidine synthesis is rate limiting? How is the step regulated?
Synthesis of carbamoyl phosphate by the Carbamoyl Phosphate Synthetase II. The enzyme is activated by ATP & PRPP and inhibited by UDP/UTP.
What is Fluorouracil? What is its function?
Pyrimidine analog that inhibits the thymidylate synthase to block dTMP synthesis
What molecule donates a methyl group to dUMP to synthesize dTMP?
N5, N10-Tetrahydrofolate
What drug inhibits the ribonucleotide reductase to decrease synthesis of deoxyribonucleotides?
Hydroxyurea
How is kidney stone formation associated with purine metabolism?
Deficiency of the Adenine Phosphoribosyl Transferase (APRT) in purine base salvage causes kidney stone development
What are the four enzymes involved in purine synthesis?
PRPP Synthetase, Amidophosphoribosyl transferase, Adenylosuccinate synthetase, IMP dehydrogenase
Briefly summarize purine catabolism.
GMP/AMP are broken down into guanine/adenosine by the guanosine/adenosine deaminase, respectively, to form xanthine. The xanthine oxidase then converts xanthine to uric acid for excretion in the urine.
What are the products of pyrimidine degradation?
B-alaine & B-aminoisobutyrate - Carbon skeletons can enter TCA
What vitamins play a role in 1-Carbon Metabolism?
Vitamins B6, B12, & Folate
What molecule is a common intermediate in the de novo synthesis of both purines and pyrimidines?
PRPP
How is the rate of purine synthesis controlled?
Purine synthesis is controlled by the concentration of PRPP. High PRPP increases the rate of synthesis
What enzyme in pyrimidine synthesis is allosterically regulated by CTP (inhibited) and ATP (activated)?
Aspartate Transcarbamoylase to form Carbamoyl Aspartic Acid (CAA)
What molecule is the parent of pyrimidines?
OPP
What drug inhibits the DHF reductase to limit THF availability and inhibit dTMP synthesis?
Methotrexate - treats rheumatoid arthritis, psoriasis, cancer
What is the function of Allopurinol?
Inhibits the xanthine oxidase to prevent uric acid synthesis for gout treatment
How is acute gout treated?
With anti-inflammatory agents, such as Colchicine
What is Orotic Aciduria? How is the disease caused?
Defect of the UMP synthase causing orotic aciduria, megaloblastic anemia, growth failure, developmental delays, and immune defect. NH4+ levels remain unchanged.
What is the process of pyrimidine base salvage?
Free bases are converted to nucleosides by a non-specific nucleoside phosphorylase. A nucleoside-specific kinase converts the nucleoside to a nueclotide.
How is CTP synthesized?
CTP is synthesized from UTP by the CTP Synthase
How is dTMP synthesized?
UDP is converted to dUDP by the ribonucleotide reductase. Though 1-Carbon metabolism & the Thymidylate synthase, dUMP is converted to dTMP.
What is the function of Leflunomide?
Reversibly inhibits UMP synthesis to treat arthritis
The PRPP Synthetase synthesizes PRPP from Ribose-5-Phosphate. How is this enzyme regulated?
Activated by phosphate and inhibited by purine nucleotides (GDP, ADP)
What is the function of 6-Mercaptopurine?
Purine analog that competes for binding to HGPRT and inhibits reactions involving IMP to prevent purine synthesis
What group of nitrogenous bases are these?
Purines - Adenine & Guanine
De novo purine and pyrimidine synthesis both utilize CO2, Aspartate, & Glutamine. What additional molecules are needed for pyrimidine synthesis?
Glycine & Formate
What enzyme is responsible for ADP/ATP synthesis from IMP?
Adenylosuccinate synthetase
What is Severe Combined Immunodeficiency (SCID)?
SCID is caused by deficiencies in the adenosine deaminase. ATP building up in cells leads to apoptosis of B, T, & NK cells.
What is Von Gierke’s Disease?
Deficiency in the glucose-6-phosphatase of the PPP that results in gout
What group of nitrogenous bases are these?
Pyrimidines - Thiamine & Cytosine
What is the function of the ribonucleotide reductase?
Reduces the ribose sugar to deoxyribose
What enzymes are responsible for purine base salvage?
Adenine Phosphoribosyl Transferase (APRT)
Adenine –> AMP
Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT)
Hypoxanthine –> IMP
Guanine –> GMP
How does a nucleoside differ from a nucleotide?
A nucleoside is only the nitrogenous base attached to a sugar. Nucleotide refers to the nitrogenous base, sugar, and phosphate group
