Purines And Pyrimidines Flashcards
What are the 3 c9mponents 9f nucleotides?
- Nitrogenous base
- Add a cyclic pentose monosaccharide ribose(5 Carbon sugar)
- Add one or more phosphate groups
Nomenclature changes with the addition of components
What are the nitrogenous bases?
Purines (2 rings)
-A and G in both DNA and RNA
Pyrimidines( 1 ring)
- T and C bases in DNA
- C and U bases in RNA
How are bases modified?
- Found mainly in transfer RNA (tRNA) ADH viral viral DNA
- about 5% of tRNA
-modifications to the bases may occur: Methylation Glycosylation Acetylation Reduction
What are the possible pathways of purines and pyrimidines?
- De novo
2. Salvage pathways
Describe ribose and deoxyribose
Ribose is an aldopentose sugar or monosaccharide containing five carbons (C)
-base is linked to sugar by B-N-glycosidic linkage
- ribose has -OH attached to C2’
- base + ribose = Ribonucleoside
-Deoxyribose has -H attached to C2’
Base + deoxyribose = deoxyribonucleoside
What happens when one or more phosphates to a nucleoside?
It becomes a nucleotide
-base+ribose+ phosphate =ribonucleotide
Building blocks of RNA; Adenosine triphosphate (ATP)
- Base+ deoxyribose+ phosphate= deoxyribonucleotide
- building blocks of DNA; deoxyadenosine triphosphate(dATP)
Ribose sugar and phosphate are donated by PRPP in purine and pyrimidine nucleotide biosynthesis
Give a general description of de novo-purine synthesis pathway
- constructing the purine ring by a series of reactions that add the carbon and nitrogen toa performed ribose 5-phosphate
- carbon and nitrogen of the purine ring from amino ac8ds shown, CO2 and THF
- ribose-5-phosphate synthesis by pentose phosphate pathway
- in humans, all of the enzymes necessary for the de novo purine synthesis ware found in the cytoplasm of the cell
What must occur before de novo purine synthesis?
Activation of sugar must first occur
-formation of 5-phosphoribosyl-1-pyrophosphate (PRPP) is the first step in purine biosynthesis catalyzed by ribose phosphate pyrophosphokinase (PRPP synthetase)
PRPP synthetase is one of the regulated enzyme of purine nucleotide synthesis
-PRPP is involved in de novo synthesis of purines and pyrimidines, salvage of purines and pyrimidines, in the synthesis of NAD+, histidine biosynthesis and conversion of guanine to GMP
What is the committed p/rate-limiting step of de-novo of purines?
PRPP —> 5-phosphoribosylamine reaction catalyzed by:
-glutamine: phosphoribosylpyrophosphate amidotransferase (GPAT).
Uses glutamine and water and releases glutamate and PPi
Rate of reaction is controlled by concentration of Substrates:
-intracellular concentrations of glutamine and PRPP(activators)
Reaction is inhibited by the purine nucleotides
-AMP, GMP & IMP
How is inosine monophosphate
Occurs in de novo purine synthesis
Series of 9 reactions in which C and N atoms are donated sequentially to form inosine monophosphate (IMP also known as Hypoxanthine-ribose-phosphate )
Explain : Conversion of IMP to AMP or GMP—> separate pathways
Occurs in purine de novo synthesis
- the formation of AMP from IMP requires GTP (adenylosuccinate synthetase)
- reaction is inhibited by end product AMP
- The formation of GMP from IMP requires ATP(GMP synthetase)
- reaction is inhibited by end product GMP
- this ensures that the cellular [ATP]= [GTP]
- AMP and GMP are converted to ADP and GDP and later to ATP and GTP by nucleoside monophosphate kinases (base specific) which add phosphate groups
Summarize regulation of purine biosynthesis
- Regulatory enzymes are PRPP synthetase and Glutamine Phosphoribosyl pyrophosphate andi transferase (phosphoribosylamidotrabsferase)
- Purine nucleotides (ATP and GTP) inhibit PRPP synthetase and the phosphoribosylamidotrabsferase (feedback inhibition/ product inhibition)
- PRPP is a feedforward activator of phosphoamidotransferase. High levels of PRPP activate this enzyme to increase purine nucleotide synthesis
What are the inhibitors of bacterial metabolism?
PABA analogs (sulfonamides; sulfadrugs ) inhibit bacterial folate synthesis
- trimethoprim inhibits bacterial dihydrofolate reductase
- sulfanoamide-trimethoprim combination is used as an antibacterial agent
What are the inhibitors of eukaryotic folate metabolism?
-methotrexate (folate analog) is used as an anti cancer agent
Methotrexate inhibits human dihydrofolate reductase and reduces the amount of tetrahydrofolate available for purine synthesis and slows down DNA replicatio/cell division in mammalian cells
What are the folic analogues?
Methotrexate(MTX) is a structural analogue of folic acid and inhibitor of dihydrofolate reductase
-trimethoprim is also an analog inhibits THF synthesis in prokaryotes
How does methotrexate used to treat cancer?
Folate analogs are used to treat leukemia’s and other cancers
Methotrexate is the most commonly used analog
Inhibit the reduction of dihydrofoloate to tetrahydrofolate by dihydrofoloate reductase thus limits purine synthesis and DNA replication
Cancer cells can become resistant to. MTX by upregulating the expression of dihydrofolate
What is the most common vitamin deficiency?
Folic acid
Bacteria synthesis their own folate: required vitamin in mammalian diet
Folate deficiency in humans:
Cause birth defects (spina bifida and anencephaly )
Megaloblastic anemia (hemoglobin levels are low and bone marrow shows many large, abnormal, immature erythrocytes)
Sulfonamides are…
PABA (p-aminobenzoate) analogues that competitively inhibit the synthesis of folate in bacteria.
Purine synthesis requires tetrahydrofolate as coenzyme thus slow this pathway in bacteria
How much purine bases are recycled?
80%
What 2 enzymes are involved in salvage pathway?
- hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
- adenine phosphoribosyltransferase (APRT)
How are free bases derived for salvage?
Hydrolysis of cellular dna and rna
What does lack of HGPRT lead to? Give details
Lesch Nyhansyndrome (x-linked)
Blood Uris acid levels are elevated
Purine bases are not reused, causing increased degradation of the purines to form Uris acid
Characterized by:
- orange crystals in baby’s diapers first sign
- development problems
- behavioral disturbances(self mutilation, biting of lips and fingers)
- Gout(hyperurecemia, unrated crystals in the joints)
- urticaria acid stones in kidney
Contrast CPS 1 and CPS 2
CPS 1-mitochondria
Cps2 - cytosol
CPS 1- urea cycle
CPS 2- pyrimidine synthesis
CPS 1- source of nitrogen is ammonia
CPS 2- source of nitrogen is y-amide group of glutamine
CPS 1- REGulated by: N-acetylglutamate
CPS 2- Activater: PRPP
Inhibitir- UTP