Nucleotide Metabolism Flashcards
What is the difference between nucleotides and nucleosides?
Nucleotides = base + sugar + phosphate
Nucleosides = base + sugar
Describe the structure of Adenosine Triphosphate (ATP)
Base = adenine
Sugar = ribose
Phosphate groups = alpha, beta, gamma
What type of bond connects the base to the sugar in a nucleotide?
N-glycosidic bond
What enzyme is required to go from a nucleotide diphosphate to a 2’ deoxynucleotide diphosphate?
Ribonucleotide reductase (also requires NADPH)
[note that this is positively regulated by ATP and negatively regulated by dATP]
What is the nucleoside form of adenine?
Adenosine
What is the nucleoside form of guanine?
Guanosine
What is the nucleoside form of xanthine?
Xanthosine
What is the nucleoside form of hypoxanthine?
Inosine
What is the nucleoside form of cytosine?
Cytidine
What is the nucleoside form of uracil?
Uridine
What is the nucleoside form of thymine?
Thymidine
NADH differs from NADPH in that NADPH has an additional phosphate group.
NADH is produced in _________ reactions and is later used in the ______.
NADPH is primarily produced in the oxidative part of the ______ and is used in _________ syntheses, hepatic detoxification (as an antioxidant), and in drug metabolism via CYP450
Catabolic; ETC
PPP; anabolic
How does NADPH function in drug metabolism in the liver?
Adds an OH group to make the drug a more polar metabolite so that it is more readily absorbed across cell membranes for further breakdown
The production of NADPH and its conversion to NADP+ is coupled to what enzymatic process for protection against oxidative stress?
Glutathione reductase activity
What are the 2 primary products of the PPP?
NADPH and ribose 5 phosphate
Purine bases are a structural component of which of the following?
A. Coenzyme A B. NAD+ C. FAD D. All of the above E. B and C only
D. All of the above
Purine catabolism is an __________ process
Oxidative
What is the mechanism of action of methotrexate?
Methotrexate inhibits the synthesis of nucleic acids by inhibiting the formation of THF, which is a major carbon-donor for purine and pyrimidine synthesis
What is the initial building block in de novo purine synthesis?
Sugar (alpha-D-ribose-5P)
What is the rate limiting step of de novo purine synthesis?
PRPP to PRA
Enzyme = glutamine:phosphoribosyl pyrophosphate amidotransferase
In de novo purine synthesis, how does alpha-D-ribose-5P become PRPP?
PRPP synthetase (utilizes ATP)
What purine is converted into either GMP or AMP in de novo purine synthesis?
IMP (inosine monophosphate)
What are the 2 salvage pathway enzymes for purine biosynthesis?
HGPRT
APRT
What byproduct of de novo purine synthesis can directly enter the TCA cycle?
Fumarate
What are the positive and negative regulators on glutamine:phosphoribosyl pyrophosphate amidotransferase (the rate limiting enzyme of de novo purine synthesis)
(+) PRPP
-) purine nucleotides (GMP, AMP, IMP
What enzyme is directly targeted by methotrexate via competitive inhibition?
Dihydrofolate reductase (DHFR), which is responsible for reducing dihydrofolic acid to tetrahydrofolic acid (THF) using NADPH as an electron donor
Cross regulation of purine nucleotide biosynthesis means that AMP synthesis is stimulated by ______, while GMP synthesis is stimulated by _______
GTP; ATP
What is the initial building block in pyrimidine nucleotide synthesis?
The base (as opposed to the sugar in de novo purine synthesis)
Methotrexate is a commonly utilized anticancer agent that inhibits THF formation in purine biosynthesis. What common anticancer agent is utilized in a similar way in pyrimidine biosythesis?
5-fluorouracil (inhibits thymidylate synthase)
Pyrimidines include C, U, and T. What is the first pyrimidine to be formed in de novo pyrimidine synthesis that can then be further converted into the other two?
UMP
What enzyme is responsible for converting cabamoyl phosphate to carbamoyl aspartate in de novo synthesis of pyrimidines? Is this the rate limiting step?
Aspartate transcarbamoylase - Yes this is the rate limiting step
What enzyme is responsible for synthesizing carbamoyl phosphate in order to begin the process of pyrimidine biosynthesis? What are its positive and negative regulators?
Carbamoyl phosphate synthetase II
(+) PRPP
(-) UTP
In general, what are the 3 phases of de novo pyrimidine synthesis?
Phase I: Fabrication of orotate ring
Phase II: attach PRPP to form UMP
Phase III: convert UMP to uridine, cytosine, and thymidine
What hereditary disorder is associated with the process of de novo pyrimidine synthesis and is typically treated using oral uridine?
Orotic aciduria
Deoxyribonucleotides are formed from ribonucleotides. The hydrogen donor = reduced ___________
Thioredoxin (ribonucleotide reductase)
What clinical condition is characterized by a mutation in HGPRT leading to allosteric activation of glutamine:phosphoribosyl pyrophosphate amidotransferase by PRPP, making PRPP available for more purine synthesis?
Lesch-Nyhan Syndrome
[clinical presentation includes urate kidney stones, gout, poor muscle control, mental retardation, self-mutilation]
What drug is used to heal chickenpox and herpes lesions by inhibiting viral enzymes for DNA synthesis?
Acyclovir
What type of drugs act as competitive inhibitors of the bacterial enzyme that incorporates p-aminobenzoic acid (PABA) into folate, thus disrupting DNA replication selectively in bacteria?
Sulfa drugs
What enzyme is required to convert a long DNA chain into short oligomers?
Deoxyribonuclease (would be ribonuclease for RNA)
What enzyme is required to convert short DNA oligomers into NMPs or dNMPs?
Phosphodiesterase
What enzyme is required to convert NMPs or dNMPs into nucleosides and deoxynucleosides?
Nucleotidases
What enzyme is required to remove ribose group and convert into pyrimidine and purine base?
Nucleosidase
Allopurinol is a preventative treatment for gout, which may result from a dysfunction in the purine nucleotide catabolism pathway. What specific enzyme does allopurinol inhibit?
Xanthine oxidase
Adenosine deaminase is required to convert adenosine to inosine in purine nucleotide catabolism. ____________ may result from excess adenosine deaminase, while ________ may result from a deficiency of this enzyme.
Hemolytic anemia
SCID
What are the 3 possible end products of pyrimidine nucleotide catabolism? Are they glucogenic or ketogenic?
Malonyl CoA = ketogenic (from UMP and CDP)
Methylmalonyl CoA and Succinyl CoA = glucogenic (from dTDP)
Compare the subcellular location of purine synthesis vs. pyrimidine synthesis
Purine synthesis takes place in the cytosol
Pyrimidine synthesis takes place in the cytosol and mitochondria
Which nucleotide is more expensive to make, purines or pyrimidines?
Purines, because they require 4 ATP to generate IMP while only 3 ATP are required to generate UMP
SCID involves defective ______ and _____ cells. It is an ___-linked disorder, so most patients are male.
Patients end up with a buildup of __________, and thus impaired DNA synthesis and a compromised immune system
B; T; X
Adenosine
In terms of purine salvage, defects in _________ lead to renal lithiasis, while defects in _______ lead to excess uric acid production
APRT
HGPRT
