Nucleotide Metabolism And Gout

Question 1

What two nitrogenous bases are purines

Answer 1

Adenine (A)

Guanine (G)

Question 2

What three nitrogenous bases are pyrimidines?

Answer 2

Cytosine

Uracil (only in RNA)

Thymine (only in DNA)

Question 3

Difference between nuclotides and nucleosides

Answer 3

Nucleotides: has all 3 components

• nitrogenous base
• 5 carbon sugar
• phosphate groups**

Nucleosides: has the following 2 components

• nitrogenous base
• 5 carbon sugar

Question 4

What are the “one-carbon units” in the body used for purine synthesis?

Answer 4

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

Question 5

What amino acid is combined with tetrahydrofolate (FH4) to make (N10-formyl-FH4) which is required for de novo purine synthesis?

Answer 5

Tryptophan

Question 6

What amino acid is combined with tetrahydrofolate (FH4) to make (N5,N10-formyl-FH4) which is required for de novo pyrimidine synthesis?

Answer 6

Glycine and serine

Question 7

What are PABA analogs (sulfonamides/sulfa drugs)

Answer 7

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)

Question 8

What is the Warburg effect

Answer 8

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

Question 9

Methotrexate

Answer 9

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

Question 10

Mycophenolic acid

Answer 10

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

Question 11

Lesch-Nyhan syndrome

Answer 11

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**

Question 12

Severe combined immunodeficiency syndromes (SCID)

Answer 12

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

Question 13

Purine nucleotide phosphorylase (PNP) deficiency

Answer 13

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

Question 14

Orotic aciduria

Answer 14

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

Question 15

What are the two pathways that gout is caused?

Answer 15

1) decreased urate excretion
- MOST common (90%)

2) increased urate synthesis
- less common (10%)

Question 16

What does Allopurinol target?

Answer 16

Targets xanthine oxidase enzymes and inhibts them to produce uric acid

Question 17

What is the enzyme used to produce deoxyribonucleotides from ribonucleotides?

Answer 17

Ribonucleotide reductase

Question 18

How does the drug Hydroxyurea work?

Answer 18

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

Question 19

How does 5-fluorouracil work?

Answer 19

Inhibits thymidylate synthase

- 5-FU gets converted into 5-FdUMP which permanently binds to thmidylate synthase (suicide inhibitor)

Question 20

Information about digestion of nucleic acids

Answer 20

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

Question 21

What are the products of pyrimidine rings?

Answer 21

CMP/UMP -> B-alanine

TMP -> B-aminoisobutyrate, ammonia, CO2

Question 22

Is pryrimidine or purine degradation more clinically significant?

Answer 22

Purines
- due to less solubility which leads to gout

Pyrimidine salvage is the basis for using uridine in the tx of hereditary orotic aciduria

Question 23

Degradation of purine nucleotides

Answer 23

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

Question 24

How does Von gierke disease cause hyperuricemia

Answer 24

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

Question 25

Tumor lysis syndrome

Answer 25

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

Question 26

How does hereditary fructose intolerance causes hyperuricemia?

Answer 26

Increases build up lactic acid which lowers clearance rates of uric acid (directly)

Question 27

How does vitamin B 12 deficiency cause hyperuricemia

Answer 27

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

Question 28

What is the purpose of recombinant urate oxidase enzymes?

Answer 28

To help gout and hyperuricemia by allowing uric acid to be converted to -> allantoin (which is very water soluble and easy to excrete)