BMBC 310 Metabolism of Nucleic Acids and Nucleotides

Flashcards covering the de novo and salvage pathways of purine and pyrimidine nucleotides, key enzymes, regulatory mechanisms, and related clinical conditions like Lesch-Nyhan Syndrome from the BMBC 310 course at the University of Lusaka.

What are the primary metabolic sources that supply atoms to the purine ring during de novo synthesis?

Aspartate provides N1; respiratory $CO_2$ provides C6; Glycine provides C4, C5, and N7; Glutamine provides N3 and N9; and folate derivatives (Formyltetrahydrofolate) provide C2 and C8.

Where in the body and cell does de novo purine synthesis primarily occur?

It occurs primarily in the cytosol of the liver.

Which enzyme converts ribose-5-phosphate to 5-phosphoribosyl-1-pyrophosphate (PRPP), and what molecules inhibit it?

PRPP Synthetase catalyzes the reaction, and it is inhibited by the end-products AMP, GMP, and IMP.

What is the first committed and rate-limiting step in de novo purine nucleotide synthesis?

The conversion of PRPP to 5-phosphoribosyl-1-amine, catalyzed by Glutamine: PRPP Amidotransferase.

How is Glutamine: PRPP Amidotransferase regulated allosterically?

It is synergistically inhibited by AMP, GMP, and IMP, and feed-forward activated by high levels of PRPP.

What is the total energy cost in high-energy phosphate bonds (ATP) to form one molecule of Inosine Monophosphate (IMP) de novo?

It requires six high-energy phosphate bonds (ATP).

Which antimetabolite drug acts as a folate antagonist to inhibit steps in de novo purine synthesis and halt cell division?

Methotrexate.

What energy source and amino donor are required to synthesize AMP from IMP?

AMP synthesis requires Aspartate as the amino donor and uses GTP as the energy source.

What energy source and amino donor are required to synthesize GMP from IMP (via XMP)?

GMP synthesis requires Glutamine as the amino donor and uses ATP as the energy source.

How does cross-regulation between AMP and GMP synthesis help maintain balanced purine pools?

GTP is required for AMP synthesis and ATP is required for GMP synthesis. High GTP levels drive AMP production, while high ATP levels drive GMP synthesis, preventing an imbalance when one nucleotide is scarce.

What are the precursor molecules required for de novo pyrimidine synthesis?

Aspartate, Glutamine, and cytoplasmic Carbamoyl Phosphate.

What enzyme catalyzes the primary regulatory step of pyrimidine synthesis, and what molecule inhibits it?

Carbamoyl Phosphate Synthetase II (CPS-II), which is inhibited by UTP.

How does the assembly of the pyrimidine ring differ structurally from purine ring assembly regarding PRPP?

The pyrimidine ring is assembled as a free base first and then attached to PRPP, whereas the purine ring is built step-by-step directly on a ribose-5-phosphate molecule.

What is the initial pyrimidine nucleotide synthesized in the de novo pathway before it is converted to UMP?

Orotate Monophosphate (OMP).

Which enzyme reduces ribonucleotides to deoxyribonucleotides, and at what level of phosphorylation does this occur?

Ribonucleotide Reductase, which reduces ribonucleotides at the nucleoside diphosphate (NDP) level using Thioredoxin as a reducing agent.

Which enzyme synthesizes dTMP from dUMP, and what donor molecule is required for this reaction?

Thymidylate Synthase, which requires folate ($N^5,N^{10}\text{-methylene-THF}$) as a methyl donor.

Why are extrahepatic tissues such as the brain, erythrocytes, and leukocytes dependent on salvage pathways?

Because these peripheral tissues lack de novo synthesis pathways and rely entirely on salvage of free bases exported by the liver for their nucleotide supply.

What specific reactions are catalyzed by HGPRT and APRT in the purine salvage pathway?

HGPRT converts hypoxanthine to IMP and guanine to GMP; APRT converts adenine to AMP.

What percentage of daily purine nucleotide biosynthesis is accounted for by the salvage pathway?

The salvage pathway accounts for 90% of daily purine nucleotide biosynthesis.

What is the genetic and enzymatic cause of Lesch-Nyhan Syndrome?

It is an X-linked recessive disorder caused by a total deficiency of HGPRT (due to a defect in the HPRT1 gene).

Why do patients with Lesch-Nyhan Syndrome experience excessive de novo purine synthesis and hyperuricemia?

The failure to salvage hypoxanthine and guanine leads to their degradation into uric acid, while unused PRPP accumulates and stimulates the de novo purine synthesis pathway to massive levels.

What are the characteristic clinical features and neurological symptoms of Lesch-Nyhan Syndrome?

Self-injury (biting fingers/mouth, head banging), dystonia, chorea, hypotonia, ballismus, developmental delay, hyperuricemia, gouty arthritis, renal stones, and renal failure.

What causes the presence of orange 'sand-like' crystals in the diapers of infants with Lesch-Nyhan Syndrome?

Sodium urate crystals in the urine resulting from hyperuricemia.

What is the most common cause of death in individuals with Lesch-Nyhan Syndrome?

Renal failure.