Salvage Pathways
general (PRPP is back)

-Phosphoribosyl pyrophosphate (PRPP) provides a sugar.

-Di- and triphosphates are formed by kinases as discussed.

-Ribonucleotide reductase may be used to make dNTPs.

Salvage Pathways
Specific Enzymes

Adenosine phosphoribosyltransferase

Adenine + PRPP→ Adenylate + PPi

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Hypoxanthine + PRPP→  Innosinate + PPi

Guanine + PRPP→ Guanylate + PPi

Salvage Pathways
Lesch-Nyhan Syndrome

-Lesch-Nyhan syndrome results from HGPRT absence.

-Lesch-Nyhan is X-linked with a frequency of 1 in 100,000 males.

Syndrome is characterized by:

-Self-mutilation behaviors by age two

  -biting lips and fingers

  -head banging

-Self-mutilation may progress to attacks on caregivers

  -kicking, hitting, head butting, spitting and vomiting

-Mild mental retardation

-Hyperuricemia- high uric acid levels in blood.

  Results from purine breakdown and increased purine synthesis

Urate crystals form in urine, kidneys and tissues.

- Lowering urate does not alleviate neurological symptoms.

Purine Catabolism
uric acid

1.  Remove phosphate.

-5’-nucleotidase

  1a. Deaminate adenosine

  -Adenosine deaminase

2. Remove the ribose.

  -nucleosidase

3.  Generate xanthine.

  -oxidize hypoxanthine

  -deaminate guanine

  -xanthine oxidase

Purine Catabolism

Clinical Correlations

  Acute Gouty Arthritis

  Lithiasis (Kidney stones)

2.  Adenine Deaminase deficiency.

  Severe Combined Immunodeficiency

Biochemcial Basis of Hyperuricemia

-Increased Purine Production

  Elevated PRPP synthetase levels.

  Loss of feedback inhibition of PRPP amidotransferase.

-Increased Purine Degradation

  Decreased salvage pathway-HGPRT activity is low.

-  Increased adenine deaminase activity

-Secondary Hyperuricema

  Other pathologies such as leukemia.

Purine Catabolism
Gout-Treatment Chronic

Chronic:

  2.  Urate Lowering Drugs

A.  Allopurinol:

       A analogue of hypoxanthine. A suicide inhibitor of xanthine oxidase. (Xanthine oxidase converts xanthine to uric acid.)

Results in increased levels of the more soluble xanthine and hypoxanthine.

Purine Catabolism
Gout-Treatment Chronic
  Allopurinol ribonucleotide

-Allopurinol lowers purine synthesis. 

-Allopurinol is converted to the ribonucleotide and allopurinol ribonucleotide inhibits  the first committed step of purine biosynthesis. 

-Which we all remember is subject to feedback inhibition.

Purine Catabolism
Severe Combined Immunodeficiency (SCID)

-ADA deficiency accounts for about one-half of cases of autosomal recessive SCID.

-It is not understood why lymphocytes are sensitive to increased adenine levels.

-ADA deficient children were the subjects for the first human gene therapy trial.

Pyrimidine Catabolism

-Pyrimidine degradation leads to NH3 and

urea synthesis.

-Further degradation occurs through

propionyl-CoA and methylmalonyl-CoA to

succinyl-CoA.

Chemotherapeutics
  glutamine amidotransferase inhibitors

-Glutamine amidotransferases function in

  -first committed step of purine biosynthesis

    PRPP to 5-phosphoribosylamine provides

    one nitrogen of the imidazole ring.

  -also in the addition of second nitrogen

    of the imidazole ring of purines.

  -xanthylate-glutamine amidotransferase

    conversion of xanthylate to guanylate.

 -cytidylate synthetase

    makes CTP from UTP.

-Azaserine and acivicin are used as in cancer treatment.

Chemotherapeutics
Pro-drug Activated by Thymidine Kinase

-Acyclovir is a nucleotide analogue that functions as a substrate for the Herpes

virus thymidine kinase but not the cellular TK. 

-Thus, acyclovir is a prodrug that

is activated only in viral infected cells.

-Thus, viral infected cells produce an acyclovir triphosphate that can be

incorporated in polynucleotide but results in chain termination.

-Blocks viral replication and kills viral infected cells.