Nucleic acid metabolism

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Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which

enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.[1]

Composition of nucleotides, which make up nucleic acids.

Synthesis of nucleotides

Nucleotides are the monomers which polymerize into nucleic acids. All nucleotides contain a sugar, a phosphate, and a nitrogenous base. The bases found in nucleic acids are either purines or pyrimidines. In the more complex multicellular animals, they are both primarily produced in the liver but the two different groups are synthesized in different ways. However, all nucleotide synthesis requires the use of phosphoribosyl pyrophosphate (PRPP) which donates the ribose and phosphate necessary to create a nucleotide.

Purine synthesis

The origin of atoms that make up purine bases.

glutamate.[1] AMP and GMP can then be converted into ATP and GTP, respectively, by kinases
that add additional phosphates.

ATP stimulates production of GTP, while GTP stimulates production of ATP. This cross regulation keeps the relative amounts of ATP and GTP the same. Excess of either nucleotide could increase the likelihood of DNA mutations, where the wrong purine nucleotide is inserted.[1]

Lesch–Nyhan syndrome is caused by a deficiency in hypoxanthine-guanine phosphoribosyltransferase or HGPRT, the enzyme that catalyzes the reversible reaction of producing guanine from GMP. This is a sex-linked congenital defect that causes overproduction of uric acid along with mental retardation, spasticity, and an urge to self-mutilate.[1][2][3]

Pyrimidine synthesis

Uridine-triphosphate (UTP), at left, reacts with glutamine and other chemicals to form cytidine-triphosphate (CTP), on the right.

Pyrimidine nucleosides include

PRPP which provides ribose-monophosphate. Unlike in purine synthesis, the sugar/phosphate group from PRPP is not added to the nitrogenous base until towards the end of the process. After synthesizing uridine-monophosphate, it can react with 2 ATP to form uridine-triphosphate or UTP. UTP can be converted to CTP (cytidine-triphosphate) in a reaction catalyzed by CTP synthetase. Thymidine synthesis first requires reduction of the uridine to deoxyuridine (see next section), before the base can be methylated to produce thymidine. [1][5]

ATP, a purine nucleotide, is an activator of pyrimidine synthesis, while CTP, a pyrimidine nucleotide, is an inhibitor of pyrimidine synthesis. This regulation helps to keep the purine/pyrimidine amounts similar, which is beneficial because equal amounts of purines and pyrimidines are required for DNA synthesis.[1][6]

Deficiencies of enzymes involved in pyrimidine synthesis can lead to the genetic disease Orotic aciduria which causes excessive excretion of orotic acid in the urine.[1][7]

Converting nucleotides to deoxynucleotides

Nucleotides are initially made with

2'-hydroxyl (-OH group) on the ribose. The reaction to remove this -OH is catalyzed by ribonucleotide reductase. This enzyme converts NDPs (nucleoside-diphosphate) to dNDPs (deoxynucleoside-diphosphate). The nucleotides must be in the diphosphate form for the reaction to occur.[1]

In order to synthesize thymidine, a component of DNA which only exists in the deoxy form, uridine is converted to deoxyuridine (by ribonucleotide reductase), and then is methylated by thymidylate synthase to create thymidine.[1]

Degradation of nucleic acids

General outline of nucleic acid degradation for purines.

The breakdown of DNA and RNA is occurring continuously in the cell. Purine and pyrimidine nucleosides can either be degraded to waste products and excreted or can be salvaged as nucleotide components.[5]

Pyrimidine catabolism

Cytosine and uracil are converted into

beta-alanine and later to malonyl-CoA which is needed for fatty acid synthesis, among other things. Thymine, on the other hand, is converted into β-aminoisobutyric acid which is then used to form methylmalonyl-CoA. The leftover carbon skeletons such as acetyl-CoA and Succinyl-CoA can then be oxidized by the citric acid cycle. Pyrimidine degradation ultimately ends in the formation of ammonium, water, and carbon dioxide. The ammonium can then enter the urea cycle which occurs in the cytosol and the mitochondria of cells.[5]

Pyrimidine bases can also be salvaged. For example, the uracil base can be combined with ribose-1-phosphate to create uridine monophosphate or UMP. A similar reaction can also be done with thymine and deoxyribose-1-phosphate.[8]

Deficiencies in enzymes involved in pyrimidine catabolism can lead to diseases such as Dihydropyrimidine dehydrogenase deficiency which has negative neurological effects.[9]

Purine catabolism

Purine degradation takes place mainly in the liver of humans and requires an assortment of enzymes to degrade purines to uric acid. First, the nucleotide will lose its phosphate through 5'-nucleotidase. The nucleoside, adenosine, is then deaminated and hydrolyzed to form hypoxanthine via adenosine deaminase and nucleosidase respectively. Hypoxanthine is then oxidized to form xanthine and then uric acid through the action of xanthine oxidase. The other purine nucleoside, guanosine, is cleaved to form guanine. Guanine is then deaminated via guanine deaminase to form xanthine which is then converted to uric acid. Oxygen is the final electron acceptor in the degradation of both purines. Uric acid is then excreted from the body in different forms depending on the animal.[5]

Free purine and pyrimidine bases that are released into the cell are typically transported intercellularly across membranes and salvaged to create more nucleotides via nucleotide salvage. For example, adenine +

PRPP --> AMP + PPi. This reaction requires the enzyme adenine phosphoribosyltransferase. Free guanine is salvaged in the same way except it requires hypoxanthine-guanine phosphoribosyltransferase
.

Defects in purine catabolism can result in a variety of diseases including gout, which stems from an accumulation of uric acid crystals in various joints, and adenosine deaminase deficiency, which causes immunodeficiency.[10][11][12]

Interconversion of nucleotides

Once the nucleotides are synthesized they can exchange phosphates among one another in order to create mono-, di-, and tri-phosphate molecules. The conversion of a nucleoside-diphosphate (NDP) to a nucleoside-triphosphate (NTP) is catalyzed by

nucleoside-monophosphate kinase carries out the phosphorylation of nucleoside-monophosphates. Adenylate kinase is a specific nucleotide kinase used for regulating cellular energy fluctuations by the interconversion of 2ADP ⇔ ATP + AMP.[1][8]

See also

References

  1. ^
    ISBN 9780470129302
    .
  2. PMID 4575865
    .
  3. ^ "Lesch-Nyhan". Lesch-Nyhan.org. Retrieved 31 October 2014.
  4. PMID 35893264
    .
  5. ^
    ISBN 978-0716771081
    .
  6. ^ "Nucleotide Metabolism II". Oregon State. Archived from the original on 11 February 2017. Retrieved 20 October 2014.
  7. S2CID 13215215
    .
  8. ^ a b "Nucleotide Metabolism". The Medical Biochemistry Page. Retrieved 20 October 2014.
  9. ^ "Dihydropyrimidine dehydrogenase deficiency". Genetics Home Reference. Retrieved 31 October 2014.
  10. ^ "Nucleotides: Their Synthesis and Degradation". Molecular Biochemistry II. Retrieved 20 October 2014.
  11. PMID 24365355
    .
  12. ^ "Adenosine deaminase (ADA) deficiency". Learn.Genetics. Archived from the original on 3 November 2014. Retrieved 31 October 2014.

External links

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