Purine and Pyrimidine Metabolism Flashcards
What creates a nucleotide?
Base, sugar, phosphate groups
N-glycosidic bond
Phosphoric acid ester bond
and phosphoric acid anydride bonds
Define nucleoside, nucleotide and deoxynucleotide
a. sugar and the base
b. sugar, base and phosphate
c. deoxyribose sugar, base and phosphate (loss of O)
What breaks up the RNA polymers into short oligomers?
Ribonucleases
What breaks up the DNA polymers into short oligomers?
Deoxyribonucleases
Short DNA oligomer is unable to be broken down into a nucleotide monophosphates. What enzyme is defective?
Phosphodiesterase
What breaks down nucleotides into base and sugar?
First nucleotidase and then nucleosidase
What are “sulfa” drugs?
Antibacterial agents in the sulfonanilamide family act as a competitive inhibitor of the bacterial enzyme that incorporates PABA into folate. This inhibition disrupts DNA replication in bacteria. Wont effect humans bc they acquire folate as a vitamin
How can methotrrexate be helpful but also harmful in humans?
It targets dihydrofolate reductase that converts dietary folate to tetrahydrofolate in the liver. This inhibition disrupts DNA replication in rapidly dividing cancer cells. But the drug can also attack normal cells
What is the metabolic end point in the catabolism (oxygen added to a molecule to make it more polar) of purines and in most oxidized member of the common purines?
Uric acid: has an acidic hydrogen and limited aqueous solubility. The limited solubility of urate is a factor that plays a key role in gout
How does the inhibition of IMP dehydrogenase used for preventing graft rejection?
By inhibiting IMP dehydrogenase, it disrupts the DNA replication in B and T cells by depriving them of adequate supplies of GMP and hence dGTP
What is needed to convert a nucleotide diphosphate into a 2-deoxynucleotide diphosphate?
NADPH and ribonucleotide reductase
What important molecules can nucleotides contribute to?
Coenzyme A
NAD
FAD
What does ADA play a role in?
ADA (adenosine Deaminase) plays an important role in adensoine homeostasis and modulates signaling by extracellular adenosine.
What happens when there is an over production of ADA?
An erythrocyte form - causes hemolytic anemia (rare). increased degradation of adenosine depletes adenine nucleotide pool and triggers premature destruction of RBCs
What happens when there is an underproduction of ADA?
SCID: severe combined immunodeficiency
Results in high amounts of adenosine which is then converted into dATP, high levels bloc synthesis of all other dNDP’s and dNTPs. Impaired DNA synthesis and compromised immune system
What role does xanthine oxidase play?
Catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid
- has two FADs, 2 Mo atoms, and 8 Fe
- drug target for gout
What is a “bubble boy”?
SCID: Patients need to be protected from environment
Fatal genetic disorder in which B and T cells are defective
Most commonly X-linked; males
Mutations affect a protein needed by receptor for ILs involved in development and differentiation of both cells
Patient has intense pain and inflammation of the 1st metatarsal pharangeal joint. Diagnosis
Gout
What is the cause of gout symptoms?
overproduction of uric acid (primary hyperuricemia)
Under-excretion of uric acid (secondary)
Sodium urate crystals precipitate in synovial fluid of joints = pain
Phagocytic cells engulf crystals and release factors that initiate an acute inflammatory response
*deposits in kidney can cause kidney damage
What type of lifestyle causes gout?
Diet rich in purines (beans, lentils, spinach) together with meat, seafood, and alcohol
- beer has elevated purine
- alcohol metabolism increases uric acid production
What is the treatment of gout?
colchicine (decreases movement of granulocites to the affected area) and allopurinol that inhibits xanthine oxidase
- probenecid - increases excretion of uric acid
- urate oxidase - converts uric acid to soluble allantoin
What nucleotide can be catabolized to form Malonyl CoA?
Ketogenic uracil
What nucleotide can be catabolized to form succinyl CoA and Methylmalonyl CoA?
Thymine: glucogenic
What are the sources of ring atoms of purine bases?
CO2, Gln, Gly, Asp, formyl THF
What are the sources of ring atoms of pyrimidine bases?
HCO3-, Gln, Asp, N5, N10-methylene THF
What are the purine bases?
Adenine, Guanine, Xanthine, Hypoxanthine
What are the pyrimidine bases?
Cytosine, Thymine, Uracil, Orotate
What is the committed step in purine synthesis?
The formation of the pohsphoribosyl amine
What are two salvage enzymes of purine biosynthesis?
Hypoxanthine guanine phosphoribosyl transferase
Adenine phosphoribosyl transferase
What molecule begins the purine biosynthesis De Novo?
Alpha D-ribose 5-phosphate from the pentose pathway
What are the major products of the De Novo synthesis of purine nucleotides?
Fumerate
IMP
AMP
GMP
What is the pyrimidine ring synthesized from?
Carbamoyl phosphate and aspartate by aspartate-transcarbamoylase
*committed step
The pyrimidine ring reacts with PRPP which is catalyzed by what?
Orotate phosphoribosyl transferase
*disease Orotic aciduria
What is the immediate hydrogen donor for the reduction of robonucleoside diphosphate into deoxyribonucleotide?
Thioredoxin or glutaredoxin
The synthesis of purine nucleotides is controlled with what feedback inhibition?
IMP, AMP, GMP
What are two major control points of pyrimidine biosynthesis?
Carbamoyl phosphate synthetase is inhibited by UMP and purines and stimulated by PRPP
Aspartate transcarbamoylase is feedback inhibited by CTP
Concentration of what dNTP is the limiting factor of DNA synthesis?
dTTP
Describe the adenine salvage pathway
Adenine+ PRPP converted to AMP
- Enzyme APRT
- Disease: Renal lithiasis
Describe the guanine or hypoxanthine salvage pathway
guanine/hypoxanthine + PRPP = GMP or IMP
Enzyme: HGPRT
What causes Lesch-Nyhan syndrome?
Defect in HGPRT enzyme in purine salvage pathway. There is an overproduction of uric acid
What are the symptoms of Lesh-Nyhan syndrome?
Patients have primary hyperuricemia and hyperuricosuria (leading to gout)
Urate kidney stones, poor muscle control, mental retardation and tendency of self mutilation
What is the function of thymidine kinase?
phosphorylates the nucleoside dT to generate dTMP using ATP as a phosphoryl donor
What does acyclovir cause?
It resembles guanine rather than dT and undergoes phosphorylation by viral thymidine kinase at a rate that exceeds that of cellular thymidine kinase
Viral thymidine kinase converts acyclovir to acyclo GMP. Acyclo GMP is converted to acyclo GTP which is incorportated into DNA and terminates replication
