64 - Nucleotide Metabolism Pt 2

Ribonucleotide Reductase

Converts Ribonucleotides to Deoxyribonucleotides

-SH on Ribonucleotide Reductase

The immediate donors of -H for dNTP conversion

Thioredoxin

Coenzyme of Ribonucleotide Reductase

Thioredoxin Reductase

Replenishes the -SH groups of Thioredoxin

Substrate Specificity Sites on Ribonucleotide Reductase

ATP, dATP, dTTP, anf dGTP regulate the reduction of specific ribonucleotides

Activator of Ribonucleotide Reductase

ATP

Inhibitor of Ribonucleotide Reductase

dATP

hydroxyurea

inhibits Ribonucleotide Reductase, inhibiting the generation of substrates for DNA synthesis

Used in the treatment of cancers such as melanoma

Thymidylate synthase

Enxyme responsible for the conversion of Uracil to Thymine

5-Fluorouracil

thymine analog that serves as a suicide inhibitor of Thymidylate synthase

antitumor agent

CMP and UMP are degraded to

Beta-alanine

TMP is degraded to

ammonia and CO2

Salvage of Pyrimidine bases

Can be salvaged to nucleosides, which are phosphorylated to nucleotides

Xanithine Oxidase

Degrades Xanthine from purine nucleotides to Uric Acid

Uric Acid

Final product of purine degredation

Where is the (small) salvage of Purine Nucleotides important?

in the Brain, T-cells, intracellular microbes

HGPRT

Key Enzyme in Purine Salvage Pathway; generates IMP and GMP

Lesch-Nyhan Syndrome

• XLR

• Deficiency of HGPRT

• Results:

  • increase of PRPP

  • decrease of IMP, GMP

  • increase de novo purine synthesis

  • accumulation of large amounts of uric acid

Clinical Presentation of Lesch-Nyhan Syndrome

• Hyperuricemia

  • uric acid stones in kidneys

• Motor Dysfunction

• Cognitive deficits and behavior disturbances

  • Self Mutilation (lip and finger biting)

SCID (Severe Combined Immunodeficiency)

• AR

• Deficiency of Adenosine Deaminase

  • converts adenosine to inosine

• Causes issues in the differentiation and function of immunocompotent cells (B cells, T cells, NK cells)

• Patients usually die before the age of 2

Can also have deficiency of PNP (even rarer), which is less severe, only affecting T cell development

Causes of Gout

• underexcretion of uric acid

• overproduction of uric acid (less common)

Gout

• Disorder characterized by hyperuricemia with recurrent attacks of acute arthritic joint inflammation caused by deposition of sodium urate crystals

Allopurinol

Inhibitor of Xanthine Oxidase, resulting in the accumulation of hypoxanthine and xanthine instead of uric acid, which are more soluble compounds that can be excreted

Used in the treatment of gout