If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
|Superclasses:||Biosynthesis → Nucleosides and Nucleotides Biosynthesis → Purine Nucleotide Biosynthesis → Purine Nucleotides De Novo Biosynthesis|
De novo biosynthesis of purines starts with the synthesis of IMP which can be converted to all other purines. In E. coli IMP is synthesized in a total of 11 enzymatic reactions in which the purine ring is formed by stepwise addition of small molecules to 5-phospho-α-D-ribose-1-phosphate (PRPP). The first five reactions are shown in pathways 5-aminoimidazole ribonucleotide biosynthesis I and 5-aminoimidazole ribonucleotide biosynthesis II which illustrate the alternative use of two phosphoribosylglycinamide formyltransferases encoded by purN and purT. The last six reactions leading to IMP are shown in pathway inosine-5'-phosphate biosynthesis I. IMP can then be converted to guanosine nucleotides as shown in this pathway, or adenosine nucleotides as shown in pathway superpathway of guanosine nucleotides de novo biosynthesis II.
About This Pathway
The conversion of IMP to GMP is catalyzed by the consecutive action of IMP dehydrogenase and GMP synthetase encoded by guaB and guaA, respectively. The former enzyme is the first committed step in GMP synthesis. The latter enzyme catalyzes the replacement of an oxygen atom at the 2-position of XMP with an amino group, utilizing either L-glutamine or ammonia. The specific kinase product of gene gmk converts GMP to GDP. GMP can also be supplied by a salvage pathway as indicated by the pathway link. However, rapidly growing cells may require more GMP than can be supplied by the salvage pathway (reviewed in [Hedstrom09]).
Both GDP and GTP can be converted to the deoxy forms of the nucleotide. GTP is converted to dGTP by ribonucleoside-triphosphate reductase, while GDP can be converted to dGDP by either ribonucleoside diphosphate reductase 1 or ribonucleoside-diphosphate reductase 2. Finally, nucleoside diphosphate kinase can also convert dGDP to dGTP.
In bacteria, genetic studies have indicated that the majority of de novo purine biosynthetic genes are unlinked, but may act as a single unit of regulation controlled by the PurR repressor protein [Meng90].
Review: Jensen, K.F., G. Dandanell, B. Hove-Jensen, and M. Willemoes (2008) "Nucleotides, Nucleosides and Nucleobases" EcoSal 3.6.2 [ECOSAL]
Meng90: Meng LM, Kilstrup M, Nygaard P (1990). "Autoregulation of PurR repressor synthesis and involvement of purR in the regulation of purB, purC, purL, purMN and guaBA expression in Escherichia coli." Eur J Biochem 1990;187(2);373-9. PMID: 2404765
Abbott06: Abbott JL, Newell JM, Lightcap CM, Olanich ME, Loughlin DT, Weller MA, Lam G, Pollack S, Patton WA (2006). "The Effects of Removing the GAT Domain from E. coli GMP Synthetase." Protein J 25;483-491. PMID: 17103135
Allard92: Allard P, Kuprin S, Shen B, Ehrenberg A (1992). "Binding of the competitive inhibitor dCDP to ribonucleoside-diphosphate reductase from Escherichia coli studied by 1H NMR. Different properties of the large protein subunit and the holoenzyme." Eur J Biochem 1992;208(3);635-42. PMID: 1396671
Andersson99: Andersson ME, Hogbom M, Rinaldo-Matthis A, Andersson KK, Sjoberg BM, Nordlund P (1999). "The Crystal Structure of an Azide Complex of the Diferrous R2 Subunit of Ribonucleotide Reductase Displays a Novel Carboxylate Shift with Important Mechanistic Implications for Diiron-Catalyzed Oxygen Activation." J. Am. Chem. Soc. 121: 2346-2352.
Artin09: Artin E, Wang J, Lohman GJ, Yokoyama K, Yu G, Griffin RG, Bar G, Stubbe J (2009). "Insight into the mechanism of inactivation of ribonucleotide reductase by gemcitabine 5'-diphosphate in the presence or absence of reductant." Biochemistry 48(49);11622-9. PMID: 19899770
Assarsson01: Assarsson M, Andersson ME, Hogbom M, Persson BO, Sahlin M, Barra AL, Sjoberg BM, Nordlund P, Graslund A (2001). "Restoring proper radical generation by azide binding to the iron site of the E238A mutant R2 protein of ribonucleotide reductase from Escherichia coli." J Biol Chem 276(29);26852-9. PMID: 11328804
Bennett04: Bennett SE, Chen CY, Mosbaugh DW (2004). "Escherichia coli nucleoside diphosphate kinase does not act as a uracil-processing DNA repair nuclease." Proc Natl Acad Sci U S A 101(17);6391-6. PMID: 15096615
Brignole12: Brignole EJ, Ando N, Zimanyi CM, Drennan CL (2012). "The prototypic class Ia ribonucleotide reductase from Escherichia coli: still surprising after all these years." Biochem Soc Trans 40(3);523-30. PMID: 22616862
Brown69a: Brown NC, Canellakis ZN, Lundin B, Reichard P, Thelander L (1969). "Ribonucleoside diphosphate reductase. Purification of the two subunits, proteins B1 and B2." Eur J Biochem 1969;9(4);561-73. PMID: 4896737
Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043
Cotruvo08: Cotruvo JA, Stubbe J (2008). "NrdI, a flavodoxin involved in maintenance of the diferric-tyrosyl radical cofactor in Escherichia coli class Ib ribonucleotide reductase." Proc Natl Acad Sci U S A 105(38):14383-8. PMID: 18799738
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