Pyrimidine biosynthesis occurs both in the body and through organic synthesis.
''De novo'' biosynthesis of pyrimidine
''De Novo'' biosynthesis of a
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
is catalyzed by three gene products CAD, DHODH and UMPS. The first three enzymes of the process are all coded by the same gene in
CAD
Computer-aided design (CAD) is the use of computers (or ) to aid in the creation, modification, analysis, or optimization of a design. This software is used to increase the productivity of the designer, improve the quality of design, improve co ...
which consists of
carbamoyl phosphate synthetase II,
aspartate carbamoyltransferase
Aspartate carbamoyltransferase (also known as aspartate transcarbamoylase or ATCase) catalyzes the first step in the pyrimidine biosynthetic pathway ().
In ''E. coli'', the enzyme is a multi- subunit protein complex composed of 12 subunits (300 ...
and
dihydroorotase
Dihydroorotase (, ''carbamoylaspartic dehydrase'', ''dihydroorotate hydrolase'') is an enzyme which converts carbamoyl aspartic acid into 4,5-dihydroorotic acid in the biosynthesis of pyrimidines. It forms a multifunctional enzyme with carbamoyl ...
.
Dihydroorotate dehydrogenase (DHODH) unlike
CAD
Computer-aided design (CAD) is the use of computers (or ) to aid in the creation, modification, analysis, or optimization of a design. This software is used to increase the productivity of the designer, improve the quality of design, improve co ...
and
UMPS is a mono-functional enzyme and is localized in the mitochondria. UMPS is a bifunctional enzyme consisting of
orotate phosphoribosyltransferase (OPRT) and
orotidine monophosphate decarboxylase (OMPDC). Both, CAD and UMPS are localized around the mitochondria, in the cytosol. In
Fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
, a similar protein exists but lacks the dihydroorotase function: another protein catalyzes the second step.
In other organisms (
Bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
,
Archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
and the other
Eukaryota
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
), the first three steps are done by three different enzymes.
Pyrimidine catabolism
Pyrimidines
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
are ultimately
catabolized
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
(degraded) to
CO2,
H2O, and
urea
Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid.
Urea serves an important r ...
.
Cytosine
Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...
can be broken down to
uracil
Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by ...
, which can be further broken down to
N-carbamoyl-β-alanine, and then to
beta-alanine, CO
2, and
ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...
by
beta-ureidopropionase.
Thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nu ...
is broken down into
β-aminoisobutyrate which can be further broken down into intermediates eventually leading into the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...
.
β-aminoisobutyrate acts as a rough indicator for rate of
DNA turnover.
Regulations of pyrimidine nucleotide biosynthesis
Through negative feedback inhibition, the end-products UTP ''and'' UDP prevent the enzyme CAD from catalyzing the reaction in animals. Conversely,
PRPP
Phosphoribosyl pyrophosphate (PRPP) is a pentose phosphate. It is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, as well as in pyrimidine nucleotide formation. Hence it is a building block for DNA ...
and
ATP act as positive effectors that enhance the enzyme's activity.
Pharmacotherapy
Modulating the pyrimidine metabolism pharmacologically has therapeutical uses, and could implement in cancer treatment.
''Pyrimidine synthesis inhibitors'' are used in active moderate to severe
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
and
psoriatic arthritis
Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Thi ...
, as well as in
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
. Examples include
Leflunomide
Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibito ...
and
Teriflunomide
Teriflunomide, sold under the brand name Aubagio, is the active metabolite of leflunomide. Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010. 2-ye ...
(the active metabolite of leflunomide).
Prebiotic synthesis of pyrimidine nucleotides
In order to understand how
life
Life is a quality that distinguishes matter that has biological processes, such as signaling and self-sustaining processes, from that which does not, and is defined by the capacity for growth, reaction to stimuli, metabolism, energ ...
arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausible
prebiotic conditions. The
RNA world
The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence ...
hypothesis holds that in the
primordial soup
Primordial soup, also known as, primordial goo, primordial ooze, prebiotic soup and prebiotic broth, is the hypothetical set of conditions present on the Earth around 3.7 to 4.0 billion years ago. It is an aspect of the heterotrophic theory (also k ...
there existed free-floating pyrimidine and purine
ribonucleotide
In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic m ...
s, the fundamental molecules that combine in series to form
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
. Complex molecules such as RNA must have emerged from relatively small molecules whose reactivity was governed by physico-chemical processes. RNA is composed of
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
and
purine
Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
nucleotides, both of which are necessary for reliable information transfer, and thus natural selection and Darwinian
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
. Becker et al. showed how pyrimidine
nucleoside
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
s can be synthesized from small molecules and
ribose
Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this compo ...
, driven solely by wet-dry cycles.
[Becker S, Feldmann J, Wiedemann S, Okamura H, Schneider C, Iwan K, Crisp A, Rossa M, Amatov T, Carell T. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science. 2019 Oct 4;366(6461):76-82. doi: 10.1126/science.aax2747. PMID 31604305]
References
External links
Overviewat
Queen Mary, University of London
, mottoeng = With united powers
, established = 1785 – The London Hospital Medical College1843 – St Bartholomew's Hospital Medical College1882 – Westfield College1887 – East London College/Queen Mary College
, type = Public researc ...
{{Purinergics
Pyrimidines
Metabolism