Lect 9 Nucleotide Metabolism Flashcards
Nucleoside
Base + Sugar
Nucleotide
Base + Sugar + Phosphate
Purines
Pure As Gold (Ring)
Double Ring
Adenine & Guanine
Xanthine & Hypothanxine
Pyrimidine
CUt The Pye
Single Ring
Cytosine & Thymine
Uracil
What are 3 Roles of Nucleosides and Nucleotides
Components of Cofactors
Regulatory Roles
Important biomolecules
What is the overall Purine Nucelotide Synthesis process?
Sugar Molecule Synthesis —> Ring Formation
What occurs in Purine synthesis Phase I?
What enzyme is used?
Ribose 5P Activation
Ribose 5P –> PRPP/Phosphoribosyl pyrophosphate
(PRPP Synthetase)
Purine Phase II
What is the enzyme?
Why is this step special?
Convert PRPP to PRA (Phosphoribosylamine)
Glutamine Phosphoribosyl Pyrophosphate Amidotransferase (GPPA)
Rate Limiting Step
Purine Phase III
Why is methotrexate an inhibitor?
Why is it an anticancer drug?
Construct IMP Ring (PRA –> IMP in 9 Steps)
Methotrexate inhibits (competitive) oxidation of NADPH by DHFR/Dihyrofolate Reductase
Methotrexate: Competitive Inhibitor of enzymes utilizing folate (disrupts DNA replication in rapidly dividing cell)
Purine Phase IV
Convert IMP to AMP and GMP
What are Sulfa Drugs and what are their importance?
Competitive inhibitors of bacterial enzyme incorporating PABA into folate
Dirsupts DNA replication selectivley in bacteria
Feeback Inhibition
Purine inhibition example
Accumulation of end product inhibit own synthesis
PRPP: inhibitted by IMP, AMP, GMP
Cross Regulation
Synthesis is stimulated by production of other substrate
AMP synthesis stimulated by GTP
GMP stimulated by ATP
Pyrimidine Nucleotide Synthesis Overall View
Pyrimidine Ring Formation –> Sugar Attachment
Sources: HCO3-, Gln, Asp, N, N-methylene THF
Cytosol and Mitochondria
What does Pyrimidine Synthesis Phase I consist of?
What is the rate limiting step?
Formation of the orotate ring –> Committed Step
Carbamoyl phosphate + Asp –> carbamoyl aspartate via aspartate transcarbamoylase
What does Pyrimidine Synthesis Phase II consist of?
What is orotic aciduria? and how is it treated?
Attach PRPP to Orotate Ring form UMP
Orotic Aciduria: Deficiency of UMP synthase
Tx: Oral Uridine
What occurs in Pyrimidine Synthesis Phase III?
What is 5-fluorouracil and what does it do?
Convert UMP –> uridine, ctyosine, and thymidine (deoxy)nucelotides
(anticancer agent) inhibits thymidylate synthase (dUMP–>dTMP) and stops DNA production
What does Thymidine Kinase do?
What is the mechanism of Acyclovir (Antiviral)
What is it used for?
- Phosphorylates dT –> dTMP –> DNA
- Acyclovir (resembles guanine) is phosphorylated by viral thymidine kinase
- Convert to acyclo GMP –> aGTP –> DNA –> terminate DNA synthesis in infected cell
- Chicken Pox and Herpes
Ribonucleases/Deoxyribonucleases Function
Convert RNA/DNA to short oligomers
Phosphodiesterases Function
Convert short oligomers to nucleotides or deoxynucleotides
Nucleotidases Function
Convert to nucleosides/deoxynucleosides
Nucleosidases Funcations
Removes ribose group to form Pyrimidines / Purines Rings
Purine Nucelotide Catabolism: GMP
Oxidative Process
GMP –> Guanosine –> Guanine –> Xanthine –> Uric Acid (via xanthine oxidase)
Purine Nucelotide Catabolism: AMP
Oxidative Process
Allopurinol inhibits what enzyme? What steps does this affect?
AMP –> IMP –> Inosine
AMP –> Adenosine –> Inosine (Adenosine Deaminase (ADA)) –> Hypoxanthine –> Xanthine (Xanthine Oxidase) –> Uric Acid (Xanthine Oxidase)
Xanthine Oxidase inhibited by Allopurinol
Adenosine Deaminase (ADA) is involved with what?
What do overproductions and deficiencies cause?
- Involved with Adenosine homeostasis
- Overproduction ADA: Hemolytic anema (increased adenosine degradation –> premature RBC destruction)
- Underproduction ADA: second most common form of severe combined immunodeficiency (SCID).
What is GOUT
Where is it mostly affected?
Intense pain and inflammation in joints
Big toe most affected (metatarsal pharangeal joint)
When do MSU (Monosodium Urate) crystals precipitate in joints?
Why does GOUT occur in extremities more often
When there is high concentration and at low temperatures
Lower temperature away from core
Pyrimidine Nucelotide Catabolism
Cytosine/Uracil
What is the fate of the final product?
UTP/CTP –> Uridine –> Uracil –> B-alanine –> Maonyl CoA (water soluble)
FA Synthesis
Pyrimidine Nucleotide Catabolism
Thymine
What does B-aminoisobutyrate indicate?
What is the fate of the final products?
Thymine –> B-aminoisobutryate (estimates DNA turnover) –> Methmalonyl CoA & Succinyl CoA (water soluble)
TCA Cycle
Purine Nucelotide Salvage Pathway
Adenine –> AMP
Adenine + PRPP –> AMP via adenine phosphoribosyl transferase (APRT)
Renal Lithiasis (kidney stone) occurs with APRT defect
Purine Nucleotide Salvage Pathway
Guanine/Hypoxanthine –> GMP/IMP
What is caused by this defective enzyme?
Guanine/Hpoxanthine + PRPP –> GMP / IMP (Hyoxanthine guanine phosphoribosyl transferase (HGPRT)
Lesch-Nyhan Syndrome & Kelly Seegmiller Syndrome occur with HGPRT defect
Lesch Nyhan Syndrome
What does this cause?
Defect in HGPRT enzyme in purine salvage pathway
Overproduce uric acid –> Primary hyperuricemia and hyperuricosuria (leading to gout)
Urate kidney stones
Pyrimidine Nucelotide Salvage Pathway
Uracil + Ribose –> Uridine –> UMP –> UDP –> UTP
Thymin + deoxyribose –> Deoxythymidine –> dTMP (thymidine kinase - acyclovir)–> dTDP –> dTTP
