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Structures of purines and

pyrimidines

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Purine Synthesis

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Purine Synthesis

Purine synthesis is critical to fetaldevelopment, therefore defects inenzymes will result in a nonviable fetus.

PRPP synthetase defects are known andhave severe consequences (next slide)

PRPP synthetase superactivity has been

documented, resulting in increased PRPP,elevated levels of nucleotides, andincreased excretion of uric acid.

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Phosphoribosyl Pyrophosphate

(PRPP) Synthetase Defects

PRPP deficiency results in convulsions,

autistic behavior, anemia, and severe

mental retardation.

Excessive PRPP activity causes gout

(deposition of uric acid crystals), along

with various neurological symptoms, such

as deafness.

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Pyrimidine Synthesis

Production of Uridine

5-monophosphate

(UMP) from orotate

is catalyzed by the

enzyme UMP

synthase

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Pyrimidine Synthesis

Pyrimidine Synthesis is critical to fetal

development just as purine metabolism is

critical. Therefore an absolute deficiency

of an enzyme of pyrimidine synthesiswould be fatal.

A very low level of the enzyme UMP

synthase has been documented, resultingin the condition orotic aciduria.

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Orotic Aciduria

Deficiency in UMP synthetase activity

Due to the demand for nucleotides in the

process of red blood cell synthesis, patients

develop the condition of megaloblastic anemia,

a deficiency of red blood cells.

Pyrimidine synthesis is decreased and excess

orotic acid is excreted in the urine (hence the

name orotic aciduria)

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Purine Degradation

Purine Nucleotides from ingested nucleic

acids or turnover of cellular nucleic acids

is excreted by humans as uric acid.

Humans excrete about 0.6 g uric acid

every 24 hours.

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Purine

Degradation

The enzyme

nucleotidase is also

known as purine

nucleotide

phosphorylase (PNP)

Ad i D i (ADA) d P i

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Adenosine Deaminase (ADA) and Purine

Nucleoside Phosphorylase (PNP) Deficiency.

A deficiency of either ADA or PNP causes a

moderate to complete lack of immune function.

Affected children cannot survive outside a

sterile environment.

They may also have moderate neurological

problems, including partial paralysis of the

limbs.

When a compatible donor can be found, bone

marrow transplant is an effective treatment.

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Pyrimidine Degradation

Pyrimidines are generally degraded to intermediates

of carbon metabolism (for example, succinyl-CoA) and

ammonia (NH4+).

NH4+is packaged as urea throughthe urea cycle and excreted by humans

Defects in enzymes of pyrimidine degradation have

been documented, resulting in increased levels of

pyrimidines and neurological disorders.

No treatments are available and mechanisms are

unknown

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Pyrimidine and Purine Salvage

Free Purine and Pyrimidine bases are

constantly released in cells during the metabolic

degradation of nucleotides.

Free Purine and Pyrimidine bases are in large

part salvaged and reused to make nucleotides.

Salvage of free nucleotides consumes much

less energy than de novo nucleotide synthesis

and is the energetically preferred source of

nucleotides for nucleic acid synthesis.

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Purine Salvage

Salvage of the free purine bases guanine andhypoxanthine (the deamination product of

adenine) often involves the enzyme

hypoxanthine-guaninephosphoribosyltransferase (HGPRT)

Salvage of free adenine is accomplished by the

enzyme adenine phosphoribosyltransferase(APRT), converting free adenine and PRPP to

adenosine monophosphate (AMP)

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Purine Salvage

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Lesch-Nyhan Syndrome

Hypoxanthine Guanine Phosphoribosyltransferase(HGPRT) deficiency

X-linked genetic condition

Severe neurologic disease, characterized by self-mutilating behaviors such as lip and finger bitingand/or head banging

Up to 20 times the uric acid in the urine than in normalindividuals. Uric acid crystals form in the urine.

Untreated condition results in death within the firstyear due to kidney failure.

Treated with allopurinol, a competitive inhibitor ofxanthine oxidase.

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Allopurinol and Hypoxanthine

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Gout Elevated uric acid levels in

the blood Uric acid crystals will formin the extremities with asurrounding area of

inflammation. This is calleda tophusand is oftendescribed as an arthriticgreat toe.

Can be caused by a defectin an enzyme of purinemetabolism or by reducedsecretion of uric acid intothe urinary tract.

tophus

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Pyrimidine Salvage

Pyrimidine salvage defects have not been clinically documented