This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Nucleosides and Nucleotides Biosynthesis → 2'-Deoxyribonucleotides Biosynthesis → Pyrimidine Deoxyribonucleotides De Novo Biosynthesis|
|Biosynthesis → Nucleosides and Nucleotides Biosynthesis → Pyrimidine Nucleotide Biosynthesis → Pyrimidine Nucleotides De Novo Biosynthesis → Pyrimidine Deoxyribonucleotides De Novo Biosynthesis|
Some taxa known to possess this pathway include
Aquifex aeolicus VF5,
Campylobacter jejuni jejuni NCTC 11168 = ATCC 700819,
Pyrimidine and purine nucleoside triphosphates are the activated precursors of DNA and RNA. The pyrimidine deoxyribonucleoside triphosphates dCTP and dTTP are incorporated into DNA while the ribonucleoside triphosphates CTP and UTP are incorporated into RNA. In addition, their diphosphates form activated derivatives of other molecules, such as UDP-α-D-glucose, CMP-3-deoxy-β-D-manno-octulosonate and dTDP-α-D-fucopyranose, for use in biosynthesis of polysaccharides, glycoproteins and phospholipids [Zhou98a, Giermann02, Schroder05, Zrenner06].
In addition to de novo biosynthesis, salvage pathways reutilize exogenous free bases and nucleosides and some of the resulting pyrimidine nucleotides can enter the de novo biosynthesis pathways (see pyrimidine ribonucleosides salvage I, pyrimidine nucleobases salvage I and pyrimidine deoxyribonucleosides salvage). The de novo biosynthetic pathways consume relatively large amounts of high energy phosphate and reducing power, and thus organisms prefer to use salvage pathways when possible. However, the de novo biosynthetic pathways are necessary when exogenous precursors are limiting. In order to conserve resources, the de novo pathways are regulated both by allosteric enzymes and at the gene expression level. These essential, evolutionarily conserved biosynthetic and salvage pathways are found in both prokaryotes and eukaryotes.
The pyrimidine nucleotide de novo biosynthetic pathway derives in part from the central metabolic precursors oxaloacetate and D-ribose 5-phosphate. L-aspartate, a precursor of pyrimidine ribonucleotides, is derived from oxaloacetate, which is generated in the TCA cycle.
About This Pathway
The pathway shown here is similar to pathway pyrimidine deoxyribonucleotides de novo biosynthesis I with the exception of the flavin-dependent thymidylate synthase reaction EC 22.214.171.124 (catalyzed by ThiX), which substitutes for the more common thymidylate synthase reaction EC 126.96.36.199 (catalyzed by ThiA).
In 2002 it was discovered that some organisms do not posses the thyA gene (named TYMS in animals), and instead have an alternate, novel flavin-dependent thymidylate synthase encoded by gene thyX.
Both thymidylate synthases catalyze a reductive methylation involving the transfer of the methylene group of 5,10-methylenetetrahydropteroyl mono-L-glutamate to the C5-position of dUMP and a two electron reduction of the methylene group to a methyl group. However, the reductive mechanisms of ThyA and ThyX are distinctly different. The ThyA reductive mechanism uses folate as both a 1-carbon donor and a source of reducing equivalents, producing dUMP and 7,8-dihydrofolate monoglutamate as products, and does not involve a flavin coenzyme or a third substrate. In contrast, the ThyX mechanism uses a flavin coenzyme as a source of reducing equivalents, which are derived from NADPH. This NAD(P)H oxidase uses FAD to mediate hydride transfer in a methylation reaction that results in tetrahydropteroyl mono-L-glutamate as a product, rather than the 7,8-dihydrofolate monoglutamate that is produced by ThyA. The chemical and kinetic mechanisms of ThyX and progress in the design of specific inhibitors are reviewed in [Koehn10]. Inhibitor design has been specifically addressed in [Chernyshev07, Esra08].
Homologs of the thyX gene have been identified in some eubacterial, archaeal, slime mold and viral genomes [Myllykallio02]. The genomes of some of these organisms contain only thyX, while others, such as those of Mycobacterium and Corynebacterium species, including Mycobacterium tuberculosis, Mycobacterium bovis and Corynebacterium glutamicum ATCC 13032 contain both thyA and thyX. The two proteins may function under different phases of the growth cycle (in [Park10a, Myllykallio02, Lesley02, Graziani06, Leduc07] and reviewed in [Murzin02, Leduc04, Koehn10]).
Because ThyX is found in some important human and animal pathogens, it is of interest as a drug target
[Chernyshev07]. Some of the bacterial pathogens that appear to posses only ThyX include
Some archaea apparently posses only ThyX and others only ThyA. Those with only ThyX include Aeropyrum pernix, Pyrobaculum aerophilum, Pyrococcus abyssi, Pyrococcus furiosus, Pyrococcus horikoshii, Thermoplasma acidophilum, Thermoplasma volcanium, Sulfolobus solfataricus and Sulfolobus tokodaii [Myllykallio02, Leduc04], and Halobacterium salinarum [Giladi02]. Conversely, archaea that possess only ThyA include Archaeoglobus fulgidus, Methanocaldococcus jannaschii, Methanopyrus kandleri, and Methanothermobacter thermautotrophicus [Leduc04]. It should be noted that many archaea do not contain the substrate tetrahydrofolate as shown in these pathways, and utilize chemically modified tetrahydromethanopterins instead [Leduc04].
ThyX shows no sequence homology with ThyA and substantially differs from ThyA in crystal structure and reaction mechanism. Evidence has been presented that ThyX is less catalytically efficient than ThyA and it may limit chromosomal replication in bacteria and archaea that posses it [Escartin08].
Variants: pyrimidine deoxyribonucleotides de novo biosynthesis I, pyrimidine deoxyribonucleotides de novo biosynthesis II, pyrimidine deoxyribonucleotides de novo biosynthesis IV, superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis, superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis (E. coli)
Relationship Links: KEGG:PART-OF:map00240
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