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0

pyrimidine ring is synthesized before being attached to ribose -5-phosphate

Source of atoms:
- Glutamine
- Aspartic acid
- Carbon dioxide

Pyrimidine synthesis

1

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

2

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

3

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

4

Synthesis of 5'-phosphoribosylamine

This is committed step in purine nucleotide biosynthesis

Enzyme: glutamyl PRPP amidotransferase

Inhibited by 5'-nucleotides AMP, GMP and IMP

5

Synthesis of inosine monophosphate

9 steps that lead to the synthesis of IMP (whose base is hypoxanthine)

"Parent" purine nucleotide

6

Conversion of IMP to AMP and GMP

Requires a two-step energy-requiring pathway

AMP synthesis requires GTP, while GMP synthesis requires ATP

7

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

8

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

9

Synthesis of carbamoyl phosphate

This is the regulated and rate-limiting step

Enzyme: carbamoyl phosphate synthetase II

Inhibited by UTP

Activated ATP and PRPP

10

Synthesis of orotic acid

Dihydroorotate reductase is located inside the mitochondria

All the rest are cytosolic

11

Formation of pyrimidine nucleotide

The "parent" pyrimidine nucleotide is orotidine monophosphate (OMP)

OMP is then converted to uridine monophosphate (UMP) by OMP decarboxylase

12

Synthesis of UTP and CTP

Enzyme: CTP synthetase

13

Synthesis of dTMP from dUMP

Enzyme: Thymidylate synthase

N5N10 methyltetrahydrofolate is the source of the methyl group

14

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)

15

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

16

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

17

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

18

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

19

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

20

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

21

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

22

Purine overproduction and hyperuricemia occurs secondary to enhanced generation of PRPP precursor ribose 5-phosphate

Von Gierke's disease

23

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

24

Metabolically converted to 5-FdUMP which becomes permanently bound to the inactivated thymidylate synthase

5-Flurouracil

25

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