epoxyqueuosine - CAS 107865-20-3

Catalog number: BRB-001

Epoxyqueuosine is a crucial compound used in biomedical field for the development of drugs to study antibiotic-resistant bacterial infections. It plays a vital role in synthesizing modified queuosine, which enhances the efficacy of antibiotics against resistant pathogens.

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Synonyms
4H-Pyrrolo[2,3-d]pyrimidin-4-one, 2-amino-5-[[(3,4-dihydroxy-6-oxobicyclo[3.1.0]hex-2-yl) amino]methyl]-1,7-dihydro-7-b-D-ribofuranosyl-; 7-(5-((2,3-Epoxy-4,5-dihydroxycyclopent-1-yl)amino)methyl)-7-deazaguanosine; 6-Amino-3-(((3,4-dihydroxy-6-oxabicyclo(3.1.0)hex-2-yl)amino)methyl)-1,5-dihydro-1-beta-D-ribofuranosyl-4H-pyrrolo(2,3-d)pyrimidin-4-one
CAS
107865-20-3
IUPAC Name
2-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-[[(3,4-dihydroxy-6-oxabicyclo[3.1.0]hexan-2-yl)amino]methyl]-3H-pyrrolo[2,3-d]pyrimidin-4-one
Molecular Weight
425.4
Molecular Formula
C17H23N5O8
Canonical SMILES
C1=C(C2=C(N1C3C(C(C(O3)CO)O)O)N=C(NC2=O)N)CNC4C(C(C5C4O5)O)O
InChI
InChI=1S/C17H23N5O8/c18-17-20-14-6(15(28)21-17)4(1-19-7-9(25)10(26)13-12(7)30-13)2-22(14)16-11(27)8(24)5(3-23)29-16/h2,5,7-13,16,19,23-27H,1,3H2,(H3,18,20,21,28)/t5-,7?,8-,9?,10?,11-,12?,13?,16-/m1/s1
InChIKey
RRCFLRBBBFZLSB-MPMHWICOSA-N
Boiling Point
864ºC at 760mmHg
Purity
≥98%
Density
2.33g/cm3
Symbol
oQ

Chemical Structure:

Reference Reading

1. Epoxyqueuosine Reductase Structure Suggests a Mechanism for Cobalamin-dependent tRNA Modification
Karl A P Payne, Karl Fisher, Hanno Sjuts, Mark S Dunstan, Bruno Bellina, Linus Johannissen, Perdita Barran, Sam Hay, Stephen E J Rigby, David Leys. J Biol Chem. 2015 Nov 13;290(46):27572-81. doi: 10.1074/jbc.M115.685693.
Queuosine (Q) is a hypermodified RNA base that replaces guanine in the wobble positions of 5'-GUN-3' tRNA molecules. Q is exclusively made by bacteria, and the corresponding queuine base is a micronutrient salvaged by eukaryotic species. The final step in Q biosynthesis is the reduction of the epoxide precursor, epoxyqueuosine, to yield the Q cyclopentene ring. The epoxyqueuosine reductase responsible, QueG, shares distant homology with the cobalamin-dependent reductive dehalogenase (RdhA), however the role played by cobalamin in QueG catalysis has remained elusive. We report the solution and structural characterization of Streptococcus thermophilus QueG, revealing the enzyme harbors a redox chain consisting of two [4Fe-4S] clusters and a cob(II)alamin in the base-off form, similar to RdhAs. In contrast to the shared redox chain architecture, the QueG active site shares little homology with RdhA, with the notable exception of a conserved Tyr that is proposed to function as a proton donor during reductive dehalogenation. Docking of an epoxyqueuosine substrate suggests the QueG active site places the substrate cyclopentane moiety in close proximity of the cobalt. Both the Tyr and a conserved Asp are implicated as proton donors to the epoxide leaving group. This suggests that, in contrast to the unusual carbon-halogen bond chemistry catalyzed by RdhAs, QueG acts via Co-C bond formation. Our study establishes the common features of Class III cobalamin-dependent enzymes, and reveals an unexpected diversity in the reductive chemistry catalyzed by these enzymes.
2. Epoxyqueuosine Reductase QueH in the Biosynthetic Pathway to tRNA Queuosine Is a Unique Metalloenzyme
Qiang Li, Rémi Zallot, Brian S MacTavish, Alvaro Montoya, Daniel J Payan, You Hu, John A Gerlt, Alexander Angerhofer, Valérie de Crécy-Lagard, Steven D Bruner. Biochemistry. 2021 Oct 26;60(42):3152-3161. doi: 10.1021/acs.biochem.1c00164.
Queuosine is a structurally unique and functionally important tRNA modification, widely distributed in eukaryotes and bacteria. The final step of queuosine biosynthesis is the reduction/deoxygenation of epoxyqueuosine to form the cyclopentene motif of the nucleobase. The chemistry is performed by the structurally and functionally characterized cobalamin-dependent QueG. However, the queG gene is absent from several bacteria that otherwise retain queuosine biosynthesis machinery. Members of the IPR003828 family (previously known as DUF208) have been recently identified as nonorthologous replacements of QueG, and this family was renamed QueH. Here, we present the structural characterization of QueH from Thermotoga maritima. The structure reveals an unusual active site architecture with a [4Fe-4S] metallocluster along with an adjacent coordinated iron metal. The juxtaposition of the cofactor and coordinated metal ion predicts a unique mechanism for a two-electron reduction/deoxygenation of epoxyqueuosine. To support the structural characterization, in vitro biochemical and genomic analyses are presented. Overall, this work reveals new diversity in the chemistry of iron/sulfur-dependent enzymes and novel insight into the last step of this widely conserved tRNA modification.
3. Spectroscopic and Computational Investigation of the Epoxyqueuosine Reductase QueG Reveals Intriguing Similarities with the Reductive Dehalogenase PceA
Elizabeth D Greenhalgh, William Kincannon, Vahe Bandarian, Thomas C Brunold. Biochemistry. 2022 Feb 1;61(3):195-205. doi: 10.1021/acs.biochem.1c00644.
Queuosine (Q) is a highly modified nucleoside of transfer RNA that is formed from guanosine triphosphate over the course of eight steps. The final step in this process, involving the conversion of epoxyqueuosine (oQ) to Q, is catalyzed by the enzyme QueG. A recent X-ray crystallographic study revealed that QueG possesses the same cofactors as reductive dehalogenases, including a base-off Co(II)cobalamin (Co(II)Cbl) species and two [4Fe-4S] clusters. While the initial step in the catalytic cycle of QueG likely involves the formation of a reduced Co(I)Cbl species, the mechanisms employed by this enzyme to accomplish the thermodynamically challenging reduction of base-off Co(II)Cbl to Co(I)Cbl and to convert oQ to Q remain unknown. In this study, we have used electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) spectroscopies in conjunction with whole-protein quantum mechanics/molecular mechanics (QM/MM) computations to further characterize wild-type QueG and select variants. Our data indicate that the Co(II)Cbl cofactor remains five-coordinate upon substrate binding to QueG. Notably, during a QM/MM optimization of a putative QueG reaction intermediate featuring an alkyl-Co(III) species, the distance between the Co ion and coordinating C atom of oQ increased to >3.3 Å and the C-O bond of the epoxide reformed to regenerate the oQ-bound Co(I)Cbl reactant state of QueG. Thus, our computations indicate that the QueG mechanism likely involves single-electron transfer from the transient Co(I)Cbl species to oQ rather than direct Co-C bond formation, similar to the mechanism that has recently been proposed for the tetrachloroethylene reductive dehalogenase PceA.
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