Purine Metabolism

Introduction to Purine

  • Purine is a molecule which is a product of fusion of pyrimidine ring with an imidazole ring.
  • Adenine and Guanine are 2 purines found in both DNA & RNA.

Purine ring

Purine ring

Major Purines

  • Adenine– 6-amino purine
  • Guanine—2 amino, 6-oxo purine
Major Purines

Sources of C & N atoms in purine

Sources of C & N atoms in purine

METABOLISM OF PURINES

Synthesis of purines (Buchanan & Green berg – 1950)

  • Synthesis of purines takes place in liver as nucleotides.
  • These are first synthesized as inosinic acid (Inosinate / hypoxanthine ribose 5 phosphate) which is further converted into Adenine & Guanine nucleotide.
METABOLISM OF PURINES
  • Purine ring is built on ribose 5 phosphate. 5-phosphoribosyl 1 pyrophosphate is the starting material. Synthesis of PRPP takes place from Dribose 5 phosphate (obtained from HMP shunt), by the action of enzyme PRPP synthase and ATP is utilized.
METABOLISM OF PURINES
  • In the next step, which is committed one, an amino group donated by glutamine is attached to C-1 of PRPP. The resulting 5-phosphoribosylamine is unstable compound.
METABOLISM OF PURINES
  • The purine ring is subsequently built up on this structure. The next step is the addition of 3 atoms from the amino acid glycine. An ATP is consumed to activate the carboxyl group of glycine for this condensation reaction.
METABOLISM OF PURINES
  • The added glycine amino group is then formylated by N10-formyltetrahydrofolate, and a nitrogen is contributed by glutamine, before dehydration and ring closure yield the 5-membered imidazole ring of the purine nucleus as 5-aminoimidazole ribonucleotide.
METABOLISM OF PURINES
METABOLISM OF PURINES
  • Now at this point, 3 of the 6 atoms needed for the second ring in the purine structure are in place. To complete the process, a carboxyl group is first added. This carboxylation is unusual because it does not require biotin, but uses bicarbonate present in aqueous solution.
METABOLISM OF PURINES
  • Aspartate then donates its amino group to the imidazole ring in 2 steps; formation of an amide bond is followed by elimination of carbon skeleton of aspartate.
5-aminoimidazole-N-succinyl Carboxamide ribotide
  • The final carbon is contributed by N10-formyltetrahydrofolate, and a second ring closure takes place to yield the second of the two fused rings of the purine nucleus.
formamidoimidazole-4 carboxamide ribotide
  • Thus the first complete purine ring is Inosinate (IMP).
formamidoimidazole-4 carboxamide ribotide

FORMATION OF ADENYLATE (AMP)

This requires the insertion of an amine group derived from aspartate, this occurs by a series of 2 reactions to introduce another nitrogen atom. Key point is that GTP is used as source of high energy phosphate in synthesizing adenylosuccinate.

Adenylosuccinate
  • Adenylosuccinate is converted into adenylate in the presence of enzyme lyase and release of fumarate.
Adenylate

FORMATION OF GUANYLATE (GMP)

Guanylate is formed by the oxidation of Inosinate at C-2 using NAD+, followed by the addition of an amino group derived from glutamine. ATP is cleaved to AMP and PPi finally.

REGULATION OF PURINE SYNTHESIS

Level-1

  • By PRPP synthase. It is allosterically inhibited by the feedback effects of ADP & GDP.
  • By PRPP amidotransferase. It is feedback inhibited by AMP, ADP, ATP, GMP, GDP & GTP, while PRPP enhances the activity of enzyme.

Level-2

  • Both AMP & GMP are competitive inhibitor of IMP.
AMP & GMP are competitive inhibitor of IMP.
  • ATP & GTP stimulates the conversion of IMP into AMP & GMP
ATP & GTP stimulates the conversion of IMP into AMP & GMP

SALVAGE PATHWAY FOR PURINE

  • There are 2 types of pathways described for nucleotides; the de novo pathway and salvage pathway.
  • De novo synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose 5-phosphate, CO2 and NH3.
  • All tissues are not capable of de novo synthesis eg. RBC, neutrophils, brain cells etc, because these lack the enzyme PRPP amido transferase.
  • Salvage pathway recycle the free bases and nucleosides released from nucleic acid breakdown.

Features:

  • Simple, cost effective,
  • Prevents wastage of starting raw material

Two types

  • one step synthesis & two step synthesis

ONE STEP SYNTHESIS : FORMATION OF GMP

Guanine is converted into GMP by enzyme Hypoxanthine Guanine Phosphoribosyl Transferase (HGPRTase). In this reaction ribosyl moiety is donated by PRPP

FORMATION OF GMP

FORMATION OF AMP

Adenine is converted into AMP by enzyme Adenine Phosphoribosyl Transferase (APRTase). In this reaction ribosyl moiety is donated by PRPP.

FORMATION OF AMP

TWO STEP SYNTHESIS

  • Also known as Nucleoside phosphorylasenucleoside kinase pathway.
  • Adenine is the only purine which is salvaged by this pathway.
  • Actually, Nucleoside phosphorylase is responsible for nucleoside breakdown but the reaction is reversible & can result in the formation of nucleoside. Here comes the action of enzyme kinase which phosphorylate it to 5′-nucleotide.

PURINE SALVAGE GYCLE

  • By this cycle, GMP and IMP and their deoxyribonucleotides are converted to respective nucleotide by the action of enzyme Purine 5′-nucleotidase. The nucleosides thus formed are hydrolytically cleaved to produce corresponding sugar phosphates & free N-base are released.
  • The Guanine & hypoxanthine, then can be phosphoribosylated again to complete the cycle.

CATABOLISM OF PURINE

  • Purine nucleotides are degraded by the action of 5′ nucleotidase and a phosphate is released.
  • Adenylate yields adenosine which is deaminated to Inosine by adenosine deaminase. Inosine is hydrolyzed to yield its purine base hypoxanthine and D-ribose.
  • Hypoxanthine is oxidized successively to xanthine and then uric acid by xanthine oxidase, in this reaction electron acceptor is molecular oxygen.
CATABOLISM OF PURINE
CATABOLISM OF PURINE
  • GMP also degrades to yield uric acid as end product.
  • GMP is first hydrolyzed to yield nucleoside guanosine which is then cleaved to guanine.
  • Guanine undergoes hydrolytic removal of its amino group to yield xanthine, which is further converted into uric acid by xanthine oxidase.
  • Uric acid is the excreted as end product of purine catabolism in primates, birds and several animals.
  • In some vertebrates, uric acid is further degraded to allantoin by the action of urate oxidase.
  • The rate of uric acid excretion by an adult is approximately 0.6g/day, from the ingested purines and turnover of the purine nucleotides.
  • Actually, the main site of uric acid formation is liver from where, it is carried to kidneys.
  • Uric acid is present in body water, on an average about 1130 mg.
  • Plasma contains higher concentration of uric acid as compared to other body compartments containing water.
  • All the uric acid is not excreted in urine, some is excreted in bile, some is converted to urea and ammonia by intestinal bacteria.
  • Normal serum levels of uric acid is 3-6 mg/dl.
  • Consumption of foods high in nucleoproteins such as glandular organs produces a marked increase in urinary uric acid.
  • Administration of glucocorticoids hormones & ACTH increases the excretion of UA in urine.
  • Lactic acid competes with uric acid in its excretion, thus during lactic acidosis uric acid is retained & results in gout.
    • Solubility: uric acid 15mg/dL
    • urate 200mg/dL
    • Sod urate 7mg/dL

GOUT

GOUT
  • It is a chronic disorder characterised by; excess uric acid in blood (Hyperuricemia), deposition of monosodium urate in alveolar & non alveolar structures (tophi), recurring attacks of acute arthritis, deposition of monosodium urate in joints.
  • It is of 2 types; primary & secondary
GOUT

PRIMARY GOUT

  • It is due to increased formation of uric acid from simple carbon & nitrogen compounds without intermediary incorporation into nucleic acids.
  • Increased production of purines results in increased degradation because purine nucleotides cannot be stored in body

PRIMARY RENAL GOUT

  • It is due to failure in uric acid excretion.
  • It is inherited metabolic defect in purine metabolism, which leads to high rate of conversion of glycine to uric acid. Actually, X-linked recessive defect enhances the de novo synthesis of purine, thus catabolism results in hyperuricemia.
  • On the other hand, x-linked recessive defect of HGPRTase reduces utilization of PRPP, thus increased levels of PRPP also enhances de novo synthesis of purines.

SECONDARY GOUT

SECONDARY METABOLIC GOUT

  • It is due to secondary increase in purine catabolism during conditions like leukemia, prolonged fasting, multiple myeloma & polycythemia.

SECONDARY RENAL GOUT

  • Due to defective glomerular filtration of urate due to chronic renal failure.

DURING VON GIERKES DISEASE

  • Deficiency of G-6 Phosphatase results in accumulation of glucose 6-phosphate in turn high concentration of pentose phosphates are formed, which act as a good substrate for PRPP synthetase & enhances the purine synthesis thus leading to uric acid formation.

Genetic deficiency in Purine salvage enzyme : Lesch-Nyhan syndrome

  • This syndrome is characterised by selfmutilation, mental mutilation, 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 the age 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.

Other Biochemistry Notes

Biochemistry of Proteins

Carbohydrate Metabolism

VITAMIN PYRIDOXINE AND BIOTIN

Vitamin A

Pyrimidine metabolism

Cardiac Biomarkers

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