Nucleotide Metabolism And Gout Flashcards Preview

Renal Course > Nucleotide Metabolism And Gout > Flashcards

Flashcards in Nucleotide Metabolism And Gout Deck (28)
Loading flashcards...

What two nitrogenous bases are purines

Adenine (A)

Guanine (G)


What three nitrogenous bases are pyrimidines?


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?







**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?



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**



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

- 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?

- 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)