Purine/Pyrimidine Metabolism Flashcards
PRPP Synthesis
- Reactant
- Enzyme
- Other substrates
Ribose-5-phosphate —> PRPP
- PRPP Synthase/ Ribose Phosphate
Pyrophosphokinase - ATP —> AMP
What is the role of PRPP Glutamine Amidotranferase? How is it controlled?
- Takes amino group from Glutamine and converts PRPP to Phosphoribosylamine
Allosterically regulated:
Positive: PRPP
Negative: IMP, AMP, GMP
What is the action of Mercaptopurine?
Inhibits PRPP amidotranferase
What pathway is Phosphoribosylamine committed to?
De Novo Purine synthesis
What enzyme is used to build purines from Phosphoribosylamine? What other reactants are used?
GAR Synthase
- Gly
- ATP
After GAR Synthase, what reaction occurs in De novo purine synthesis of IMP?
A charged THF is used to transfer a formal group
What high energy molecules are needed for production of AMP/GMP?
AMP: requires GTP
GMP: requires ATP
Describe how IMP is used to produce AMP
IMP —> Adenylosuccinate —> AMP
- Adenylosuccinate Synthetase
- Uses Asp + GTP
- 2nd step releases Fumarate
Describe how IMP is used to produce GMP.
IMP —> XMP —> GMP
Step 1: IMP DH
- Uses H2O, NAD+ -> NADH
Step 2: XMP-GLNG Amidotranferase
- Gln -> Glu
- ATP —> AMP + PPi
What are the various origins of the different parts of a purine molecule?
- N3/9 —> Glutamine
- C2/8 —> Formyl Group
- C6 —> BiCarb Keto
- N1 —> Aspartate
- C4/5, N7 —> Glycine
What is the importance of folate in nucleic acid synthesis?
- Folate needed to produce THF
- THF important for 1 carbon units transfers —> Amino acids and nucleic acid synthesis
*N10 Formyl THF in NA synthesis
What is used to detoxify methanol poisoning?
Folate
What two drugs interact with THF production?
Sulfonamides: inhibits folate production
Trimethoprim: Inhibits DHFR Which Conversion DHF to THF
What enzymes are used for Purine Salvage?
HGPRT (Guanine breakdown)
APRT (Adenine Breakdown)
What enzyme can also break down a nucleic acid to IMP?
HGPRT
What is the significance of the salvage pathways?
RBCs —> No nuclei —-> Rely on salivate pathways
What does NDPK catalyze?
Conversion of all nucleoside diphosphates to triphosphates
What are the three components of Folate?
- PABA
- Pteridine ring
- Glutamate
What does 5-Fluorouracil block?
Thymidylate Synthase
Conversion of dUMP —> dTMP
Conversion of N5N10 Methylene THF
What does Methotrexate block?
Recycling of Folate; DHF reductase
Conversion of DHF —> THF
What amino acid is need to convert THF to N5N10THF?
Serine —> Glycine
Describe pathology of megaloblastic anemia.
- Folate or Vit B12 Deficiency
- Decreased DNA/RNA Synthesis
Which organ synthesizes nucleic acids (De novo synthesis)?
Liver
What enzyme can transfer hypoxanthine to PRPP?
HGPRT
What is the final product of Purine degradation?
Uric Acid
What is Lesch-Nyah’s Syndrome?
HGPRT r other purine salvage enzyme Deficiency (X-linked recessive)
- Spastic cerebral palsy
- Self mutilation
- Hyperuricemia/gout
What results fro Adenosine deaminase deficiency?
- Cannot convert adenosine —> Inosine
- Severe combined immunodeficiencies —> Both T and B Cell function
- dATP and dGTP not catabolized
- Indirect inhibition of ribonucleotide reductase —> Inhibition of DNA synthesis
- Autosomal recessive
What are the important enzymes in purine degradation?
- Purine Nucleoside phosphorylase (Inosine —> Hypoxanthine)
- Adenosine deaminase (Adenosine —> Inosine)
- Xanthine Oxidase (Xanthine —> Uric Acid)
What is the action of Allopurinol?
Blocks Xanthine Oxidase
Describe pathology of Gout.
- Hyperuricemia —> Sharp Na+-Urate Crystals in Joints/Kidneys
- Podagra and Gouty attacks
- Exacerbating factors: Increased Purine consumption/production, Decreased clearance (Dehydration), Obesity, and diabetes
- Kidney stenosis and urate nephropathy
What are the reactant molecules which form the pyrimidine ring? What is initially formed from them? The enzyme?
Gln+HCO3+H2O+ATP —> Carbamoyl Phosphate
- CPS II
What is formed from carbamoyl phosphate in pyrimidine synthesis? Enzyme? Other reactants?
Carb-Pho + Aspartate —> Carbamoyl Aspartic Acid
- Aspartate Transcarboxylase
What type of enzyme is Aspartate transcarboxylase?
ATCase
What is converted from Carbamoyl Aspartate acid in pyrimidine synthesis? Enzyme?
CAA —> Orotate
- Dihydroorotase
What is made from orotate in pyrimidine synthesis? Enzyme? Other reactants?
Orotate + PRPP —> OMP
- OPRT
What is the final precursor in Pyrimidine synthesis? Enzyme?
OMP —> UMP
- UMP Synthase
Describe pathology of Orotic aciduria.
- Autosomal recessive
- Megaloblastic Anemia
- Atypical —> Not a Vit B or Folate deficiency
- Inhibition of UMP Synthase —> Decreased Pyrimidine synthesis + Build up of Orotic acid in blood
What is the action of Hydroxyurea?
Blocks DNA synthesis by inhibiting ribonucleotide reductase
What else is needed for Robinucleotide reductase to function?
Reducing agents:
- Thioredoxin
- Glutathione
Which subunits of ribonucleotide reductase is the catalytic sites?
R1 subunits
- One os On/Off
- One is specificity
What is special about the R2 subunit of Ribonucleotide Reductase?
R2 have a Tyr radical
What inhibits ribonucleotide reductase?
dATP
Describe the production of CTP from UTP
UTP + Gln + ATP —> CTP
-CTP Synthase
What are the Regulators of CPS II?
PRPP + ATP —> Allosteric activators
CTP —> Inhbiitor
What is AZT?
- Blocks DNA Polymerization
- Very similar to thymidine
- No 3’-OH; NH3 group instead
What are Pyrimidines broken down to?
Uridine —> Ribose-1P —> Uracil —> Beta-Alanine
