Nucleotide Synthesis And Degradation 😆 Flashcards
Purine ring is constructed by adding carbons and nitrogens to a preformed ribose-5-phosphate
Source of atoms:
- Aspartic acid
- Glycine
- Glutamine
- Carbon dioxide
- N10-formyltetahydrofolate and N5, N10-methenyltetrahydrofolate
Purine synthesis
pyrimidine ring is synthesized before being attached to ribose -5-phosphate
Source of atoms:
- Glutamine
- Aspartic acid
- Carbon dioxide
Pyrimidine synthesis
Important steps in DE NOVO PURINE SYNTHESIS
- Synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)
- Synthesis of 5’-phosphoribosylamine
- Synthesis of inosine monophosphate
- Synthesis of IMP to AMP and GMP
Synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)
PRPP is an activated pentose that participates in the synthesis of purines and pyrimidines, and in the salvage of purine bases
Substrates: ATP and ribose 5-phosphate
Enzyme: PRPP synthetase
Regulation:
- activated by inorganic phosphate (Pi)
- inhibited by purine nucleotides
Synthesis of 5’-phosphoribosylamine
This is committed step in purine nucleotide biosynthesis
Enzyme: glutamyl PRPP amidotransferase
Inhibited by 5’-nucleotides AMP, GMP and IMP
Synthesis of inosine monophosphate
9 steps that lead to the synthesis of IMP (whose base is hypoxanthine)
“Parent” purine nucleotide
Conversion of IMP to AMP and GMP
Requires a two-step energy-requiring pathway
AMP synthesis requires GTP, while GMP synthesis requires ATP
Salvage pathways for PURINES
Purines that result from the normal turnover of cellular nucleic acids or that are obtained from the diet and not degraded, can be converted into nucleoside triphosphates and used by the body
Irreversible enzymes:
- adenine phosphoribosyltransferase (APRT)
- hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
PRPP is the source of the ribose 5-P
Important steps in DE NOVO PYRIMIDINE synthesis
- Synthesis of carbamoyl phosphate
- Synthesis of orotic acid
- Formation of pyrimidine nucleotide
- Synthesis of UTP and CTP
- Synthesis of dTMP from dUMP
Synthesis of carbamoyl phosphate
This is the regulated and rate-limiting step
Enzyme: carbamoyl phosphate synthetase II
Inhibited by UTP
Activated ATP and PRPP
Synthesis of orotic acid
Dihydroorotate reductase is located inside the mitochondria
All the rest are cytosolic
Formation of pyrimidine nucleotide
The “parent” pyrimidine nucleotide is orotidine monophosphate (OMP)
OMP is then converted to uridine monophosphate (UMP) by OMP decarboxylase
Synthesis of UTP and CTP
Enzyme: CTP synthetase
Synthesis of dTMP from dUMP
Enzyme: Thymidylate synthase
N5N10 methyltetrahydrofolate is the source of the methyl group
Salvage Pathway for Pyrimidines
Few pyrimidine bases are salvaged in human cells
However the following can be salvaged:
- Uridine and Cytidine (uridine-cytidine kinase)
- Deoxycytidine (deoxycitine kinase)
- Thymidine (Thymidine kinase)
Synthesis of Diphosphates and Triphosphates
Conversion of nucleoside monophosphates to nucleoside diphosphates and triphosphates
- nucleoside diphosphates are synthesized from the corresponding nucleoside monophosphates using base-specific nucleoside monophosphate kinases
- ATP is generally the source of the transferred phosphate
- Diphosphates kinases, in contrast, have broad specificity
Synthesis of DEOXYRIBONUCLEOTIDES
Enzyme: Ribonucleotide reductase
It is multi subunit enzyme that is specific for the reduction of nucleoside diphosphates to their deoxy forms
The enzyme thioredoxin regenerates the reduced form of ribonucleotide reductase
On the other hand, NADPH reconvers thioredoxin to its reduced form
Purine degradation
Degradation of dietary nucleic acids occurs in the small intestines where a family of pancreatic enzymes hydrolyze the nucleotides to nucleosides and free bases
Dietary purines are generally converted to serum uric acid
Pyrimidine degradation
The pyrimidine ring can be opened and degraded to highly soluble structures
Products:
- B-alanine (precursor for acetyl-CoA)
- B-aminoisobutyrate (precursor for succinyl-CoA)
Pyrimidine overproduction rarely with significant abnormalities
Drugs that inhibit purine synthesis
PABA analogs
- sulfonamide are structural analogs of PABA that competitively inhibit bacterial synthesis of folic acid
- purine synthesis requires THF as a coenzyme, the sulfa drugs slow down this pathway in bacteria
Folic acid analogs
- Methotrexate and TMP inhibit the reduction of dihydrofolate to tetrahydrofolate, catalyzed by dihydrofolate reductase
Hyperuricemia with recurrent attacks of acute arthritis, caused by deposition of uric acid crystals
Primary: no known cause of ⬆️ UA
Secondary: with causes for ⬆️ UA (⬆️ cell turnover, ⬆️ uric acid production, ⬆️ uric acid secretion)
Management:
- Acute phase: manage the inflammation, NSAIDs, steroids, colchicine
- intercritical phase: manage the ⬆️ uric acid, allopurinol for overproducers, Probevocine for underexcretors
Gouty arthritis
X-linked recessive deficiency in HGPRT that causes a rise in intracellular PRPP and hyperuricemia
Triad of: hyperuricemia, mental retardation, self-mutilation
Lesch-Nyhan Syndrome
Purine overproduction and hyperuricemia occurs secondary to enhanced generation of PRPP precursor ribose 5-phosphate
Von Gierke’s disease
Leads to severe combined immunodeficiency (both T and B lymphocytes affected)
Pathophysiology:
- adenosine deaminated is necessary for conversion of adenosine to inosine
- deficiency leads to very high dATP
- dATP inhibits ribonucleotide reductase and inhibits formation of deoxyribonucleotides
Tx: Gene therapy
Adenosine deaminase deficiency
Metabolically converted to 5-FdUMP which becomes permanently bound to the inactivated thymidylate synthase
5-Flurouracil
Low activities of orotidine phosphate decarboxylase and orotate phosphoribosyltransferase result in:
- abnormal growth
- Megaloblastic anemia
- excretion of large amounts of orotate in urine
Treatment: diet rich in uridine results in improvement of the anemia and decreased excretion of orotate
Orotate Aciduria
