Lactic Acidosis and Deoxythymidine Monophosphate Synthesis

Study Notes

Lactic acidosis can be influenced by environmental factors such as drug use and lead exposure.

ADA deficiency leads to adenosine accumulation, converted to ribonucleotide or deoxyribonucleotide forms by kinases.
Elevated dATP inhibits ribonucleotide reductase, hindering deoxyribose nucleotide synthesis.
Inability to synthesize DNA can result in developmental arrest and apoptosis.
Severe forms cause severe combined immunodeficiency (SCID), reducing T cells, B cells, and natural killer cells.

Pyrimidine ring forms before attachment to ribose 5-phosphate from PRPP.
Ring atoms derived from glutamine, CO2, and aspartate.
First three enzymes in the pathway are functional domains of the single polypeptide CAD.
Key steps include:
- Step 1: Carbamoyl phosphate synthesis from glutamine and CO2, regulated by CPS II, inhibited by uridine triphosphate (UTP), activated by PRPP.
- Step 2: Carbamoyl aspartate formation by aspartate transcarbamoylase.
- Step 3: Dihydroorotate formed by the closure of the pyrimidine ring.

Both GMP and AMP contribute to uric acid production, essential for purine metabolism.
ADA deficiency may contribute to SCID, affecting uric acid levels.

A nucleotide consists of a pentose monosaccharide, a nitrogenous base, and phosphate group/s.

Two main synthesis pathways:
- De novo synthesis: Involves constructing bases from simple precursors.
- Salvage pathways: Assembling bases from recycled pre-existing purines and pyrimidines.

Synthesis of IMP involves multiple steps, serving as a precursor to AMP and GMP.
Four steps necessitate ATP, while two require N10-formyl-THF.

IMP conversion to AMP or GMP occurs in two steps, each inhibited by the respective end product.
AMP synthesis utilizes GTP as an energy source and aspartate as a nitrogen source.