Pyrimidine metabolism

Pyrimidine

  • These are 3 in number;

– Cytosine

– Thymine

– Uracil

  • Cytosine is present in DNA and RNA.
  • Thymine is present in DNA only, while Uracil is found in RNA only.

2 oxo, 4 amino pyrimidine

2 oxo, 4 amino pyrimidine
  • In living organisms, reduced nitrogen is incorporated first into amino acids and then into a variety of other molecules such as nucleotides.
  • The key entry point is amino acid glutamate. Glutamate and glutamine are nitrogen donors in different biosynthetic reactions.
  • During nucleotide synthesis, the purine ring system is built up in a stepwise manner on 5- phosphoribosylamine, glutamine, glycine and aspartate provide nitrogen atoms of purine.
  • Similarly, pyrimidines are synthesised from carbamoyl phosphate and aspartate. Ribose 5-phosphate is then attached to yield the pyrimidine ribonucleotides. Purine & Pyrimidine biosynthesis is regulated by feedback inhibition.
  • Nucleoside monophosphate are converted to triphosphate by phosphorylation reaction.
  • Ribonucleotides are converted to deoxyribonucleotide by the action of reductase enzyme.
  • Thymine nucleotides are derived from the dCDP and dUMP.
  • Uric acid and urea are end products of purine and pyrimidine degradation.
  • Free purines can be salvaged and rebuilt into nucleotide by different pathways.
  • Genetic deficiency in salvage enzymes causes diseases such as Lesch-Nyhan syndrome.
  • This syndrome is characterised by selfmutilation, mental retardation and gout. This is caused by absence of Hypoxanthine Guanine Phosphoribosyl Transferase (HGPRTase), an enzyme essential for the purine synthesis.
  • This is an inborn error of metabolism. It is compulsive self destructive behaviour. At theage of 2-3 years, children of this disease begin to bite their fingers & lips.
  • Elevated levels of urate lead to formation of kidney stone followed by gout in later years. The disease is inherited as sex linked recessive disorder.
  • Biochemical consequences of this syndrome are elevated concentration of PRPP & increased purine synthesis by de novo pathway.
  • Another genetic deficiency results in accumulation of uric acid crystals in joints, causing gout.
  • Gout is a joint disease leading to arthritis, associated with excessive production of urate.
  • Allopurinol, a suicide inhibitor of xanthine oxidase, is used to treat gout.
  • Enzymes of nucleotide biosynthesis pathway serve as therapeutic agents to treat cancer. Rapidly dividing cells require abundant supply of Deoxythymidylate for DNA synthesis.
  • The vulnerability of these cells to the inhibition of dTMP synthesis has been used in cancer chemotherapy.
  • Thymidylate synthase and dihydrofolate reductase are target enzymes.

Sources of C & N of Pyrimidines

Pyrimidine is a heterocyclic molecule or ring.

Sources of C & N of Pyrimidines

STEP-1 Synthesis of Carbamoyl Phosphate

The synthesis of pyrimidine ring begins with the formation of carbamoyl phosphate from glutamine, CO2 & ATP in a reaction catalysed by carbamoyl phosphate synthetase II. The reaction is feedback inhibited by UTP.

STEP-1 Synthesis of Carbamoyl Phosphate

In second step, aspartate transcarbamoylase transfers carbamoyl group to aspartic acid to form carbamoyl aspartic acid. This is the committed and rate limiting step. Enzyme can be feedback inhibited by CTP & UTP, however it can be reversed by ATP.

STEP-2 Synthesis of Carbamoyl Phosphate

Third step is catalysed by dihydro-orotase, to form dihydro-orotic acid by removing water molecule.

STEP-4 Synthesis of Carbamoyl Phosphate

In the next step, oxidation of dihydro-orotic acid takes place in presence of dihydroortate dehydrogenase to form orotic acid. In this reaction, NAD+ is required as coenzyme.

STEP-5 Synthesis of Carbamoyl Phosphate

Now, 5-phosphoribosyl group is transferred from 5-phosphoribosyl-1-pyrophosphate (PRPP) to produce orotidylic acid. The reaction is catalyzed by orotate phosphoribosyl transferase in presence of Mg++.

STEP-5 Synthesis of Carbamoyl Phosphate

Further, decarboxylation of orotidylic acid takes place to form uridylic acid (UMP) under influence of orotidylate decarboxylase.

STEP-6 Synthesis of Carbamoyl Phosphate

In this manner, UMP, the first pyrimidine nucleotide is formed. UMP is the feedback inhibitor of decarboxylase enzyme. Other pyrimidine nucleotide such as UDP, UTP, CTP & dUDP are the synthesized from UMP.

STEP-7 Synthesis of Carbamoyl Phosphate

Formation of UDP & UTP

UMP is phosphorylated by ATP to form UDP in presence of enzyme nucleoside monophosphokinase. This UDP is then phosphorylated by ATP to form UTP.

Formation of UDP & UTP

Formation of CTP

UTP is converted into CTP by addition of glutamine in the presence of enzyme CTP synthetase & ATP.

Formation of CTP

Formation of dUDP

UDP is converted into dUDP via reaction catalyzed by ribonucleoside reductase. The reaction requires thioredoxin and NADPH.

Formation of dUDP

FORMATION OF THYMINE DEOXYRIBONUCLEOTIDE (dTMP)

dUDP is first hydrolyzed by phosphatase to form dUMP, which is then converted into dTMP in the presence of enzyme Thymidylate synthetase.

FORMATION OF THYMINE DEOXYRIBONUCLEOTIDE (dTMP)

dTMP thus formed is converted into dTDP by transphosphorylation in the presence of ATP, Mg++, and enzyme Thymidylate kinase.

CATABOLISM OF PYRIMIDINES

Catabolism of pyrimidines starts with the dephosphorylation of nucleosides catalysed by 5′ nucleotidase, then pyrimidine nucleosides are phosphorolysed into free pyrimidines by nucleoside phosphorylase.

CATABOLISM OF CYTOSINE & URACIL

In the next reaction, cytosine undergoes deamination to form uracil by cytosine deaminase, uracil, is then reduced to 5,6-

dihydrouracil in presence of enzyme dihydrouracil dehydrogenase.

CATABOLISM OF CYTOSINE & URACIL

Dihydrouracil is now hydrolyzed to β-ureidopropionic acid by hydropyrimidine hydrase.

CATABOLISM OF CYTOSINE & URACIL

Ureidopropionic acid is then hydrolyzed to β-alanine, NH3 & CO2 in presence of enzyme β-Ureidopropinase.

CATABOLISM OF CYTOSINE & URACIL

This β-alanine then can be used for synthesis of carnosine or CoA or can be further oxidized to acetate, CO2 & NH3.

CATABOLISM OF CYTOSINE & URACIL

CATABOLISM OF THYMINE

Thymine is either released from thymidine or produced by deamination of 5-methylcytosine. Thymine is actually reduced to 5,6-dihydrothymine by thymine dehydrogenase.

CATABOLISM OF THYMINE

Dihydrothymine is now hydrolyzed to β-ureidoisobutyric acid by enzyme hydrase. This β-ureidoisobutyric acid is hydrolyzed to CO , NH & 23 β-aminoisobutyrate by β-ureidoisobutyrase.

CATABOLISM OF THYMINE

PYRIMIDINE SALVAGE

Enzyme Pyrimidine phosphoribosyl transferase catalyses the formation of pyrimidine nucleotide, in this reaction PRPP is used up as ribosyl donor.

PYRIMIDINE SALVAGE

Disorders of pyrimidine metabolism

Orotic aciduria type-I

  • An autosomal recessive genetic disorder with deficiency of either or both orotate phosphoribosyl transferase and OMP decarboxylase.
  • In this disorder, orotic acid accumulates in blood because it is not converted into uridylate. Disorder is characterized by growth retardation and megaloblastic anemia.
Disorders of pyrimidine metabolism

Orotic aciduria type-II

  • It is also an autosomal recessive genetic disorder due to OMP decarboxylase.
  • Disorder is characterized by megaloblastic anemia and excessive urinary excretion of asididine than orotic acid.
  • In both disorders, megaloblastic anemia occurs due to deficiency UMP synthase which cannot be cured by supplementation of Vitamin B12 or folic acid. There can be inhibition of RNA and DNA synthesis also.

Other Biochemistry Notes

Biochemistry of Proteins

Carbohydrate Metabolism

VITAMIN PYRIDOXINE AND BIOTIN

Vitamin A

Pyrimidine metabolism

Purine Metabolism

Cardiac Biomarkers

VITAMIN D

. Blood Metabolism (Heme synthesis and breakdown)

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