Neucleotid Metabolism

Functions :

Ribonucleosides and deoxyribonucleoside phosphates (nucleotides) are essential for all cells. Without them, neither DNA nor RNA can be produced and, therefore, proteins cannot be synthesized or cells proliferate.

  1. Nucleotides serve as carriers of activated intermediates in the synthesis of some carbohydrates, lipids, and proteins.

2. They are structural components of several essential coenzymes, for example, coenzyme A,FAD.

3. Nucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), serve as second messengers in signal transduction pathways.

4. Nucleotides play an important role as "energy currency" in the cell.

5. Nucleotides are important regulatory compounds for many of the pathways of intermediary metabolism, inhibiting or activating key enzymes.

Synthesis of purine nucleotide :

-ribose-5-phosphate is the initiation step in the synthesis of nucleotide

ribose-5-phosphate + ATP ------> PRPP + AMP

prpp is activator for synthesis of nucleotide because it activate amidotrasferase..

-The major site of purine synthesis is in the liver. Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, inosine 5'-monophosphate (IMP).

-inosine 5'-monophosphate (IMP) either become GMP or AMP.

-Synthesis of GMP require ATP.

Regulation of purine nucleotide synthesis

1. Cross regulation: GMP formation from IMP needs the presence

of ATP (ATP is synthesized from AMP). And AMP formation

from IMP needs the presence of GTP (GTP is synthesized from

GMP).

2. Feedback mechanism: When GMP is synthesized in high

amounts, that will inhibit the enzyme, IMP dehydrogenase. And

when AMP is present in high amounts, that will inhibit the

enzyme, adenylsuccinatesynthetase.

Summary of the regulation of purine synthesis:

PRPP will activate this process by the activating of the second

step enzyme, amidotransferase while AMP, GMP, & IMP will

cause a feedback inhibition of the same step enzyme.

Salvage pathway :

There are 2 enzymes to convert free nitrogen base to

nucleotide. :

Adeninphosphoribosyltransferase( APRT) and hypoxanthine guanine phsphoribosyltransferase(HGPRT) .

-It need PRPP to give Ribose and Phosphate because nucleotide need 3 things :

1-Free nitrogen.

2-Ribose sugar.

3-Phosphate.

Catabolism of the purine nucleotides:

leads ultimately to the production of uric acid which is insoluble and is excreted in the urine as sodium urate crystals.

Gout:

In the case of increased concentration of uric acid ( hyperuricemia)

1. Primary gout: It is an inborn (genetic) error of metabolism due

to overproduction of uric acid. This is mostly related to

increased synthesis of purine nucleotides. The following

metabolic defects ( enzymes ) associated with primary gout:

a. PRPP synthetase: so this will activate more formation of

purine, which will be degraded into uric acid

b. PRPP glutamylamidotransferase: will produce more and

more purine

c. HGPRT deficiency: in this case PRPP will accumulate

(HGPRT use PRPP to convert hypoxanthine into IMP. In

this case no PRPP is used so it will accumulate).

d. Glucose -6- phosphatase deficiency: in this case glucose -6-

phosphate will enter the pentose pathway instead of being

converted into glucose. So there will be more formation of

ribose 5-phosphate which in turn will be converted into

PRPP.

e. Elevation of glutathione reductase.

2. Secondary gout: due to other disease such as cancer, trauma,

starvation, etc which cause the raise of uric acid formation.

Tow enzymes are important in catabolism of nucleotide into uric

acid :

1. Adenosine deaminase: which convert adenosine into inosine , which lead to acute amino deficiency disease.

2. Xanthineoxidase: which convert hypoxanthine into xanthine

then into uric acid. This is important in treatment of gout , by Allopurinolwe can inhibit this enzyme.

Lesch-Nyhan syndrome :

-This disorder is due to the deficiency of hypoxanthine- guanine phosphoribosyltransferase( HGPRT) Which convert hypoxanthine and guanine to IMP and GMP.

-It is genetic disease and located in x-chromosome , the symptoms will be hyperruricemia and neurological disorder

Severe combined immuno deficiency disease :

. SCID is caused by a deficiency in the enzyme adenosine deaminase

(ADA). This is the compound responsible for converting adenosine to

inosine in the catabolism of the purines.

So adenosine will accumulated in lymphocyte , then converted to

dATP whiche inhibit ribonucleotidereductase thereby preventing other dNTPsfrom being produced. The net effect is to inhibit DNA synthesis.

So the number of lymphocyte will decrease and any invasion from parasite will lead to death.

Pyrimidine nucleotide biosynthesis:

Synthesis of the pyrimidines is less complex than that of the purines.

Synthesis of the pyrimidines is less complex than that of the purines. The

first completed base is derived from 1 mole of glutamine, one mole of

ATP and one mole of CO2 (which form carbamoyl phosphate) and one

mole of aspartate. An additional mole of glutamine and ATP are required

in the conversion of UTP to CTP.

Then we need carbamoyl phosphate 11 .

Degradation of pyrimidine gives:

1. β –alanine.

2. β – aminoisobutyric acid.

Clinical Significances of Pyrimidine Metabolism:

Degradation of pyrimidine gives:

1. β –alanine.

2. β – aminoisobutyric acid.

Because the products of pyrimidine catabolism aresoluble, few disordersresult from excess levels of their synthesis or catabolism

Two inherited disorders affecting pyrimidine biosynthesis are the result of deficiencies in the bifunctional enzyme catalyzing the last two steps of UMP

synthesis, orotatephosphoribosyltransferase and OMP decarboxylase.

These deficiencies result in oroticaciduria that causes retarded growth,

and severe anemia . Leukopeniais also common in oroticacidurias.

Anti-cancer drugs:

1. FdUMP

2. Methotrexateaminopterintrimethoprim.

FdUMP / Methotrexate
Inhibit thymidylatesynthetaseby
binding with it. / Inhibit dihydrofolatereductaseby
binding with it.
Stop conversion of dUMP into
dTMP so no more formation of
DNA which stop cell divition / Stop conversion of dihydrofolate
into tetrahydrofolte
Specific. / Not specific, so it would attack
even normal cells and it would
cause hair loss
Used in treatment of uterine and
gastric cancers. / Used in treatment of leukemia.