Nucleotide Metabolism And Gout Flashcards
What two nitrogenous bases are purines
Adenine (A)
Guanine (G)
What three nitrogenous bases are pyrimidines?
Cytosine
Uracil (only in RNA)
Thymine (only in DNA)
Difference between nuclotides and nucleosides
Nucleotides: has all 3 components
- nitrogenous base
- 5 carbon sugar
- phosphate groups**
Nucleosides: has the following 2 components
- nitrogenous base
- 5 carbon sugar
What are the “one-carbon units” in the body used for purine synthesis?
Serine
Glycine
Histidine
Formaldehyde
Tryptophan
Formate
all bind to tetrahydrofolate-4 to produce serine and purines after going through the 1 carbon pool of methylene and methyl
What amino acid is combined with tetrahydrofolate (FH4) to make (N10-formyl-FH4) which is required for de novo purine synthesis?
Tryptophan
What amino acid is combined with tetrahydrofolate (FH4) to make (N5,N10-formyl-FH4) which is required for de novo pyrimidine synthesis?
Glycine and serine
What are PABA analogs (sulfonamides/sulfa drugs)
Are structural analogs of para-amino benzoacid
Competitively inhibit bacterial synthesis of folic acid since bacterial cells need tetrahydrofolate unbound to anything as a coenzyme, it kills them
doesnt affect humans since humans cant synthesize folic acid de novo and need to get it externally (vit. B9)
What is the Warburg effect
In cancer cells, glucose consumption and oxidation are dysregulated in order to allow for rapid growth and proliferation of cells by generating an abundance of one-carbon units
cells require one-carbon units for nucleotide synthesis and generation of cofactors
Methotrexate
Folic acid analog which inhibits dihydrofolate -> tetrahydrofolate reduction by dihydrofolate reductase
Limit the amount of tetrahydrofolate available for purine synthesis and slows down replication of DNA in mammalian cells
- useful in cancer but has toxic effects widespread
Mycophenolic acid
Reversible inhibitor of Inosine mono-phosphate dehydrogenase
- slows T and B cell synthesis due to preventing ATP and GTP build up and that T and B cells cant use purine salvage pathway.
Is an immunosuppressant drug often used in prevention graft host rejection
Lesch-Nyhan syndrome
Rare x-linked recessive disorder which results in a complete deficency of HGPRT enzymes
Results in:
- increases PRPP and decreased IMP/GMP
- increased de novo synthesis of purines
- increased degradation and turnover
- accumulation of large levels of uric acid stones
Symptoms:
- early onset gout and kidney stones (hyperuricemia)
- motor dysfunctions
- cognitive defects including self-mutilation**
Severe combined immunodeficiency syndromes (SCID)
Very rare autosomal recessive disorder that results in adenosine detainees (ADA) deficiency
Causes severe deficiency- NO T/B cells, lymphocytes and NK cells being produced
Children typical before 2 yrs due to overwhelming sepsis
Treatment = BMT/ERT and gene therapy
- *most severe = SCID
- 2nd most severe = ADA deficiency
- least severe = purine nucleotide phosphylase deficency
Purine nucleotide phosphorylase (PNP) deficiency
Autosomal recessive deficiency where purine nucleoside phosphorylase is deficiency
Affects T cell production only
Results in recurrent infections and severe neuro developments delays
**still severe, however less severe than SCID
Orotic aciduria
Deficiency in either or both of:
- orotate phosphoribosyltransferase
- OMP decarboxylase
Results in poor growth, megaloblastic anemia, large amounts of orotate in the urine
Treatment = uridine tablets
What are the two pathways that gout is caused?
1) decreased urate excretion
- MOST common (90%)
2) increased urate synthesis
- less common (10%)
What does Allopurinol target?
Targets xanthine oxidase enzymes and inhibts them to produce uric acid
What is the enzyme used to produce deoxyribonucleotides from ribonucleotides?
Ribonucleotide reductase
How does the drug Hydroxyurea work?
Inhibits ribonucleotide reductase enzymes thereby inhibiting the generation of substrates for DNA synthesis
is used for cancer treatment and sickle cell hemoglobin treatment
in sickle cell disease, it indirectly increases HbF level by increasing gene expression
How does 5-fluorouracil work?
Inhibits thymidylate synthase
- 5-FU gets converted into 5-FdUMP which permanently binds to thmidylate synthase (suicide inhibitor)
Information about digestion of nucleic acids
The following enzymes play a role:
- ribonucleases
- deoxyribonucleases
- phosphodiesterase
Nucleosides are taken into enterocytes by sodium-dependent transporters and degraded to free bases
Dietary purine bases are NOT used for synthesis
- only degraded directly to uric acid and excreted in urine
What are the products of pyrimidine rings?
CMP/UMP -> B-alanine
TMP -> B-aminoisobutyrate, ammonia, CO2
Is pryrimidine or purine degradation more clinically significant?
Purines
- due to less solubility which leads to gout
Pyrimidine salvage is the basis for using uridine in the tx of hereditary orotic aciduria
Degradation of purine nucleotides
Final product is always uric acid
- ***this is because humans do not express the enzyme uricase (urate oxidase) which is used to cleave purine rings/uric acid and generate allantoin (water soluble product).
- because of this uric acid cyclic compounds can build up and aggregate in hyperuricemia conditions
Hyperuricemia by itself doesn’t always produce gout, but gout is ALWAYS caused by hyperuricemia
How does Von gierke disease cause hyperuricemia
Impaired gluconeogenesis casues pyruvate to build up
Build up in pyruvate blocks lactate -> pyruvate conversions and causes a build up in lactate
Build up in lactate causes lowered clearance of uric acid
Tumor lysis syndrome
Caused when many tumor cells are lyse at once by a treatment
- releases large amounts of tumor cell contents and hyperuricemia from purine nucleotide breakdown
How does hereditary fructose intolerance causes hyperuricemia?
Increases build up lactic acid which lowers clearance rates of uric acid (directly)
How does vitamin B 12 deficiency cause hyperuricemia
Vitamin B-12 adequate levels limit the amount of Homocysteine
High levels of homocysteine impairs renal function especially as it pertains to excretion of uric acid. There for a build up of homocysteine limits the ability of the kidney to excrete uric acid, leading to increased risk of gout
What is the purpose of recombinant urate oxidase enzymes?
To help gout and hyperuricemia by allowing uric acid to be converted to -> allantoin (which is very water soluble and easy to excrete)
