Cobalamin Riboswitches Are Broadly Sensitive to Corrinoid Cofactors to Enable an Efficient Gene Regulatory Strategy

Kennedy, Kristopher J.; Widner, Florian J.; Sokolovskaya, Olga M.; Innocent, Lina Victoria; Procknow, Rebecca; Mok, Kenny C.; Taga, Michiko E.

doi:10.1128/mbio.01121-22

Cited by 13 publications

(18 citation statements)

References 129 publications

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“…Complementary to the class-II Cbl riboswitch findings is the observation that an increase in AdoCbl selectivity, integral to class-I Cbl riboswitches, appears to be deleterious to plasticity. It has been hypothesized that class-I Cbl riboswitches are incapable of discriminating between AdoCbl and similar antivitamin B 12 forms, and some evidence supports this. ,, However, we show that the E. coli btuB Cbl riboswitch did not bind any of the Cbl derivatives tested through SHAPE and fluorescent methods.…”

Section: Discussionmentioning

confidence: 41%

“…It has been hypothesized that class-I Cbl riboswitches are incapable of discriminating between AdoCbl and similar antivitamin B 12 forms, and some evidence supports this. 24,26,53 However, we show that the E. coli btuB Cbl riboswitch did not bind any of the Cbl derivatives tested through SHAPE and fluorescent methods. This suggests that displacement of the equivalent A20 position in this riboswitch is disallowed.…”

Section: ■ Summary and Outlookmentioning

confidence: 99%

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Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

et al. 2023

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RNA-targeting small-molecule therapeutics is an emerging field hindered by an incomplete understanding of the basic principles governing RNA–ligand interactions. One way to advance our knowledge in this area is to study model systems where these interactions are better understood, such as riboswitches. Riboswitches bind a wide array of small molecules with high affinity and selectivity, providing a wealth of information on how RNA recognizes ligands through diverse structures. The cobalamin-sensing riboswitch is a particularly useful model system, as similar sequences show highly specialized binding preferences for different biological forms of cobalamin. This riboswitch is also widely dispersed across bacteria and therefore holds strong potential as an antibiotic target. Many synthetic cobalamin forms have been developed for various purposes including therapeutics, but their interaction with cobalamin riboswitches is yet to be explored. In this study, we characterize the interactions of 11 cobalamin derivatives with three representative cobalamin riboswitches using in vitro binding experiments (both chemical footprinting and a fluorescence-based assay) and a cell-based reporter assay. The derivatives show productive interactions with two of the three riboswitches, demonstrating simultaneous plasticity and selectivity within these RNAs. The observed plasticity is partially achieved through a novel structural rearrangement within the ligand binding pocket, providing insight into how similar RNA structures can be targeted. As the derivatives also show in vivo functionality, they serve as several potential lead compounds for further drug development.

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Section: Discussionmentioning

confidence: 41%

Section: ■ Summary and Outlookmentioning

confidence: 99%

Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

et al. 2023

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“…As observed with AdoRhbl , [9] the bioassay indicated that AcRhbl was actively imported by the bacteria and produced inhibitory growth effects. These observations indicate that AcRhbl interferes with bacterial metabolism, most likely by impairing the B 12 ‐riboswitch regulated import of CNCbl [55,56] . In this scenario AcRhbl may regulate the riboswitch either directly, or indirectly as a possible metabolic precursor [57] to AdoRhbl , the structural AdoCbl ‐mimic.…”

Section: Discussionmentioning

confidence: 94%

“…These observations indicate that AcRhbl interferes with bacterial metabolism, most likely by impairing the B 12 -riboswitch regulated import of CNCbl. [55,56] In this scenario AcRhbl may regulate the riboswitch either directly, or indirectly as a possible metabolic precursor [57] to AdoRhbl, the structural AdoCbl-mimic. Further studies are planned to elucidate more precisely the inhibitory mechanism considered here.…”

Section: Discussionmentioning

confidence: 99%

Solution, Crystal and in Silico Structures of the Organometallic Vitamin B₁₂‐Derivative Acetylcobalamin and of its Novel Rhodium‐Analogue Acetylrhodibalamin

Wiedemair

Kieninger

Wurst

et al. 2023

Helvetica Chimica Acta

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The natural vitamin B 12 -derivatives are intriguing complexes of cobalt that entrap the metal within the strikingly skewed and ring-contracted corrin ligand. Here, we describe the synthesis of the Rh(III)-corrin acetylrhodibalamin (AcRhbl) from biotechnologically produced metal-free hydrogenobyric acid and analyze the effect of the replacement of the cobalt-center of the organometallic vitamin B 12 -derivative acetylcobalamin (AcCbl) with its group-IX homologue rhodium, to give AcRhbl. The structures of AcCbl and AcRhbl were thoroughly analyzed in aqueous solution, in crystals and by in silico methods, in order to gain detailed insights into the structural adaptations to the two homologous metals. Indeed, the common, nucleotide-appended corrin-ligand in these two metal corrins features extensive structural similarity. Thus, the rhodium-corrin AcRhbl joins the small group of B 12 -mimics classified as 'antivitamins B 12 ', isostructural metal analogues of the natural cobalt-corrins that hold significant potential in biological and biomedical applications as selective inhibitors of key cellular processes.

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“…It has been hypothesized that class-I Cbl riboswitches are incapable of discriminating between AdoCbl and similar antivitamin B12 forms and some evidence supports this. 25,27,52 However, we show that the E. coli btuB Cbl riboswitch did not bind any of the Cbl derivatives tested through either SHAPE or fluorescent methods. This suggests that displacement of the equivalent A20 position in this riboswitch is disallowed, which may be a result of the plasticity of the nucleotide on the opposite strand in J6/3 that is required to accommodate the Ado.…”

Section: Discussionmentioning

confidence: 99%

Targeting riboswitches with beta-axial substituted cobalamins

Lennon

Wierzba

Siwik

et al. 2022

Preprint

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RNA-targeting small molecule therapeutics an emerging field hindered by an incomplete understanding of the basic principles governing RNA-ligand interactions. One way to advance our knowledge in this area is to study model systems where these interactions are better understood, such as riboswitches. Riboswitches bind a wide array of small molecules with high affinity and selectivity, providing a wealth of information on how RNA recognizes ligands through diverse structures. The cobalamin-sensing riboswitch is a particularly useful model system as similar sequences show highly specialized binding preferences for different biological forms of cobalamin. This riboswitch is also widely dispersed across bacteria and therefore holds strong potential as an antibiotic target. Many synthetic cobalamin forms have been developed for various purposes including therapeutics, but their interaction with cobalamin riboswitches is yet to be explored. In this study, we characterize the interactions of eleven cobalamin derivatives with three representative cobalamin riboswitches using in vitro binding experiments (both chemical footprinting and a fluorescence-based assay) and a cell-based reporter assay. The derivatives show productive interactions with two of the three riboswitches, demonstrating simultaneously plasticity and selectivity within these RNAs. The observed plasticity is partially achieved through a novel structural rearrangement within the ligand binding pocket, providing insight into how similar RNA structures can be targeted in the future. As the derivatives also show in vivo functionality, they serve as several potential lead compounds for further drug development.

show abstract

Cobalamin Riboswitches Are Broadly Sensitive to Corrinoid Cofactors to Enable an Efficient Gene Regulatory Strategy

Abstract: Some bacterial mRNAs contain a region called a riboswitch which controls gene expression by binding to a metabolite in the cell. Typically, riboswitches sense and respond to a limited range of cellular metabolites, often just one type.

Cited by 13 publications

References 129 publications

Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

Solution, Crystal and in Silico Structures of the Organometallic Vitamin B₁₂‐Derivative Acetylcobalamin and of its Novel Rhodium‐Analogue Acetylrhodibalamin

Targeting riboswitches with beta-axial substituted cobalamins

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Cobalamin Riboswitches Are Broadly Sensitive to Corrinoid Cofactors to Enable an Efficient Gene Regulatory Strategy

Abstract: Some bacterial mRNAs contain a region called a riboswitch which controls gene expression by binding to a metabolite in the cell. Typically, riboswitches sense and respond to a limited range of cellular metabolites, often just one type.

Cited by 13 publications

References 129 publications

Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

Solution, Crystal and in Silico Structures of the Organometallic Vitamin B12‐Derivative Acetylcobalamin and of its Novel Rhodium‐Analogue Acetylrhodibalamin

Targeting riboswitches with beta-axial substituted cobalamins

Contact Info

Product

Resources

About

Solution, Crystal and in Silico Structures of the Organometallic Vitamin B₁₂‐Derivative Acetylcobalamin and of its Novel Rhodium‐Analogue Acetylrhodibalamin