Cobalamin riboswitch

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Cobalamin riboswitch
RF00174-rscape.svg
Predicted secondary structure and sequence conservation of Cobalamin
Identifiers
SymbolCobalamin
Rfam RF00174
Other data
RNA type Cis-reg; riboswitch
Domain(s) Bacteria
SO SO:0000035
PDB structures PDBe 6VMY

Cobalamin riboswitch is a cis-regulatory element which is widely distributed in 5' untranslated regions of vitamin B12 (Cobalamin) related genes in bacteria. [1]

Contents

Cobalamin (vitamin B12, coenzyme B12 ) riboswitches are structured RNA elements that regulate adjacent genes related to cobalamin metabolism in response to cobalamin binding. Riboswitches are RNA-based genetic regulatory elements present in the 5’ untranslated region (5'UTR) of primarily bacterial RNA. These switches bind to a ligand, which is generally a metabolite, with high affinity and specificity.  Ligand binding mediates allosteric rearrangement of mRNA structure, and this results in modulation of gene expression or translation of mRNA to yield a protein. The cobalamin riboswitch, along with most other riboswitches, are cis-regulatory. This means they regulate genes involved in the same metabolic pathways as the metabolite they bind, which creates regulation through a negative feedback loop. Riboswitches are grouped into classes by the ligand that they bind because the ligand-binding or aptamer domain is highly conserved across species. Riboswitches, including the cobalamin riboswitch, have garnered a lot of attention recently due to their therapeutic and synthetic potential, [2] as well as their interesting structural properties. [3] [4] [5] As of 2019, cobalamin riboswitches have been identified in over 5000 species of bacteria. [2]

Ligand selectivity

Cobalamin riboswitches bind cobalamin (vitamin B12), which is a complex enzyme cofactor composed of a corrin ring coordinated to a cobalt (III) ion. In the alpha-axial position, the cobalt is coordinated to a dimethylbenzimidazole moiety attached to the corrin ring via a flexible aminopropanol linker. [6] [7] The active portion of the cofactor is in the beta-axial position. Methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are the biologically active forms of cobalamin, containing a methyl group and an adenosyl moiety in the beta-axial position, respectively. [6] Hydroxocobalamin (HyCbl), with a hydroxyl group in the beta-axial position, is produced as a result of cobalamin photolysis, and is present in biological conditions but is not in an active form. Cyanocobalamin (CyCbl) is an artificial form of cobalamin found in supplements, which can be converted to active forms of cobalamin. Cobalamin riboswitches can exhibit selectivity toward different forms of cobalamin. [6]

Structure and classes

Riboswitches, including the cobalamin riboswitch, are generally composed of a ligand-binding or aptamer domain and an expression platform. Ligand binding induces an allosteric structural rearrangement in the expression platform that results in the regulation of gene expression via transcriptional or translational mechanisms. [4] [8]

Class I (Cbl-I)

Cobalamin riboswitches are broadly classified by the identity of the aptamer, but can be further classified into Class I (Cbl-I) and Class II (Cbl-II) based on cobalamin analogue selectivity and peripheral structural elements. [6] Cbl-I and Cbl-II riboswitches share a conserved receptor domain composed of a four-way junction and regulatory domain. Cbl-I riboswitches are selective for AdoCbl, with a variable peripheral stem loop structure facilitating ligand specificity. [6] [9] Over 90% of cobalamin riboswitches identified before 2003 are Cbl-I riboswitches. [10]

Class IIa (Cbl-IIa)

VB12-bound Riboswitches with PDB codes: a) 4FRN b) 6VMY c) 4FRG d) 4GMA Riboswitch Crystal Structures.png
VB12-bound Riboswitches with PDB codes: a) 4FRN b) 6VMY c) 4FRG d) 4GMA

Cbl-II can be further divided into two classes (Cbl-IIa and Cbl-IIb). Cbl-IIa riboswitches are specific to cobalamin analogues with smaller β-axial ligands including MeCbl and HyCbl. [6] [9] This selectivity is determined by peripheral element variations. [6]

Class IIb (Cbl-IIb)

Cbl-IIb riboswitches are also selective for AdoCbl, [6] [9] but they differ significantly in structure from Cbl-I riboswitches. The structural basis for AdoCbl selectivity has not yet been determined. [6] Cbl-IIb riboswitches also differ in terms of the nature of the genes they regulate, with Cbl-IIb riboswitches primarily associated with genes involved in ethanolamine utilization. [6] Ethanolamine is abundant in the human intestinal tract as it is the product of the breakdown of the phosphatidylethanolamine from cell membranes and is also present in processed food. Most bacteria that inhabit the intestinal tract can utilize ethanolamine as a carbon and nitrogen source by upregulating the expression of the ethanolamine utilization genes; this may have a survival advantage. [11] The expression of the ethanolamine utilization genes (eutG) is influenced by two different mechanisms. The first is a two component regulatory system that senses the presence of ethanolamine and the second mechanism is an AdoCbl riboswitch that senses the presence of AdoCbl, a cofactor needed for the breakdown of ethanolamine. A study showed that both these regulatory elements need to be activated for the bacteria to grow efficiently on medium containing ethanolamine. [12] Bioinformatic studies were initially unsuccessful in identifying AdoCbl riboswitches within the bacteria genomes, but subsequent studies of the intergenic regions of the eutG locus using Ribex identified an RNA element between the eutT and eutG genes. [1] [13]

In addition, some cobalamin riboswitches exhibit promiscuous ligand binding, such as the B. subtilis yvrC riboswitch, which can adopt different structural conformations in order to bind cobalamin analogues with smaller β-axial ligands such as MeCbl and HyCbl in addition to AdoCbl, which has a much bulker β-axial moiety. [9] This riboswitch is also capable of binding CyCbl. [9]

Discovery

Before proof of riboswitch function, a conserved sequence motif called the B12 box [14] was identified that corresponds to a part of the cobalamin riboswitch, [1] and a more complete conserved structure was identified. [10] [8] Variants of the riboswitch consensus have been identified. [15] Before a broader range of cobalamin riboswitches were identified, it was believed that only AdoCbl riboswitches existed. [10]

Mechanism

The mechanisms of individual cobalamin riboswitches can vary and many have not yet been elucidated. [16] The four canonical mechanisms for riboswitches include transcriptional activation or repression and translational activation or repression. [17] [16] In transcriptional activation, a terminator loop, which blocks the RNA polymerase binding site, is present in the absence of ligand and upon ligand binding, an anti-terminator loop forms and the terminator hairpin is removed. Transcriptional termination occurs when the terminator stem loop forms in the presence of a ligand. Regulation via translational activation occurs when the Shine-Dalgarno (SD) sequence, necessary for the ribosome to bind to the mRNA and initiate translation, is sequestered within tertiary structural elements when the ligand is unbound and is made accessible after the riboswitch undergoes a ligand-induced conformational change. In translational repression, the SD is sequestered upon ligand binding. [18] [16] The E. coli btuB AdoCbl riboswitch and  confirmed to regulate gene expression via a translational repression mechanism, as well as the env8 HyCbl riboswitch. [16]

Regulated Genes

The cobalamin riboswitch is known to regulate a broad range of genes involved in cobalamin metabolism, including those genes coding for proteins involved in cobalamin biosynthesis and transport. [19] Examples include regulation of the btuB gene in E. coli which codes for a cobalamin transport protein, [1] regulation of CobA, an enzyme which converts uroporphyrinogen III to precorrin-2 during cobalamin biosynthesis in P. freudenreichiii, [20] and the cobalamin biosynthesis (cob) operon in S. typhimurium [21] among others.

Applications

As drug targets

The emerging threat of antibiotic resistance highlights the need for novel antibiotic development. [17] riboswitches, including cobalamin riboswitches, are currently being investigated as potential targets for novel antibiotics. [2] Not only do they regulate essential metabolic processes, they are also primarily found in prokaryotes. Only one riboswitch (the TPP riboswitch) has been identified in some plant cells to date, and no riboswitches have been identified in mammalian cells. [2] [3] By targeting bacteria-specific regulatory mechanisms, the risk of host side-effects is minimized. [4] Furthermore, the mechanism in which a ligand binds to its riboswitch is inherently different from how a protein binds that same ligand, thus minimizing interference between the two systems. [16]

A basic schematic is shown here where the purple stars indicate the metabolite and the yellow arrow shows the reporter gene. The cells with a lower concentration of the metabolite have more riboswitches in the unbound state. The unbound conformation has an unstructured interaction between the ribosome binding site (RBS) and the blue and green segments. This unstructured interaction allows for the reporter gene to be translated efficiently downstream and produce a high signal output. At a higher metabolite concentration, the riboswitches form a bound conformation where the blue segment of the riboswitch interacts with the target RNA. This allows the green segment to interact with the RBS instead, and this allows the RBs to inhibit translation initiation of the reporter gene. Because of this, the signal output is lower than with the low concentration of the metabolite. Riboswitch-Based Intracellular Metabolite Sensor.jpg
A basic schematic is shown here where the purple stars indicate the metabolite and the yellow arrow shows the reporter gene. The cells with a lower concentration of the metabolite have more riboswitches in the unbound state. The unbound conformation has an unstructured interaction between the ribosome binding site (RBS) and the blue and green segments. This unstructured interaction allows for the reporter gene to be translated efficiently downstream and produce a high signal output. At a higher metabolite concentration, the riboswitches form a bound conformation where the blue segment of the riboswitch interacts with the target RNA. This allows the green segment to interact with the RBS instead, and this allows the RBs to inhibit translation initiation of the reporter gene. Because of this, the signal output is lower than with the low concentration of the metabolite.

A bioinformatic study performed in 2019, which analyzed eight different riboswitch classes for suitability as antibacterial drug targets, classified the cobalamin riboswitch as being partially suitable for targeting with antibiotics. [2] As of 2019, cobalamin riboswitches were found in 5174 bacterial species, 7% of which are human pathogens. [2] The development of antibiotics targeting the cobalamin riboswitch is hindered due to the fact that not all cobalamin biosynthetic pathways are regulated by riboswitches, meaning that antibiotics targeting the riboswitch would need to be used in conjunction with additional drugs targeting alternative synthetic pathways in order to be effective. [2] As of 2021, no therapeutics targeting the cobalamin riboswitch are being developed. [5]

As biosensors

Riboswitches are ideally suited to be engineered into biosensors due to their ability to undergo a conformational switch upon binding to specific ligands. [4] These sensors are constructed with a cobalamin riboswitch upstream of a gene encoding for a reporter molecule. The nature of the reporter molecule can vary depending on the desired detection method. For example, the reporter gene can encode for green fluorescent protein (GFP) when fluorescence-based detection methods are desired. [22] In the presence of ligand, the riboswitch undergoes a conformational change which blocks the ribosomal binding site, halting transcription of the reporter gene.

In 2010, researchers designed the first riboswitch-based AdoCbl sensor in E. coli. [4]   This sensor was also used to detect vitamin B12 biosynthetic precursors such as cobinamide and confirm the involvement of specific genes in cobalamin metabolism. [4] More recently, this sensor was used to screen Ensifer meliloti mutants for their ability to synthesize large quantities of Vitamin B12. [22] Riboswitch sensors can be utilized outside of a cellular environment. For example, a biosensor developed from a Propionibacterium freudenreichii cobalamin riboswitch was used to determine the vitamin B12 concentration in fermented food with high sensitivity. [23]

Related Research Articles

<span class="mw-page-title-main">Riboswitch</span>

In molecular biology, a riboswitch is a regulatory segment of a messenger RNA molecule that binds a small molecule, resulting in a change in production of the proteins encoded by the mRNA. Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, in response to the concentrations of its effector molecule. The discovery that modern organisms use RNA to bind small molecules, and discriminate against closely related analogs, expanded the known natural capabilities of RNA beyond its ability to code for proteins, catalyze reactions, or to bind other RNA or protein macromolecules.

<span class="mw-page-title-main">Methionine synthase</span> Mammalian protein found in Homo sapiens

Methionine synthase (MS, MeSe, MTR) is primarily responsible for the regeneration of methionine from homocysteine in most individuals. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase</span> Mammalian protein found in Homo sapiens

Methylmalonyl-CoA mutase (EC 5.4.99.2, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.

<span class="mw-page-title-main">Adenosylcobalamin</span> Biologically active form of vitamin B12

Adenosylcobalamin (AdoCbl), also known as coenzyme B12, cobamamide, and dibencozide, is, along with methylcobalamin (MeCbl), one of the biologically active forms of vitamin B12.

<span class="mw-page-title-main">FMN riboswitch</span> Highly conserved RNA element

The FMN riboswitch is a highly conserved RNA element which is naturally occurring, and is found frequently in the 5'-untranslated regions of prokaryotic mRNAs that encode for flavin mononucleotide (FMN) biosynthesis and transport proteins. This element is a metabolite-dependent riboswitch that directly binds FMN in the absence of proteins, thus giving it the ability to regulate RNA expression by responding to changes in the concentration of FMN. In Bacillus subtilis, previous studies have shown that this bacterium utilizes at least two FMN riboswitches, where one controls translation initiation, and the other controls premature transcription termination. Regarding the second riboswitch in Bacilius subtilis, premature transcription termination occurs within the 5' untranslated region of the ribDEAHT operon, precluding access to the ribosome-binding site of ypaA mRNA. FMN riboswitches also have various magnesium and potassium ions dispersed throughout the nucleotide structure, some of which participate in binding of FMN.

<span class="mw-page-title-main">Lysine riboswitch</span>

The Lysine riboswitch is a metabolite binding RNA element found within certain messenger RNAs that serve as a precision sensor for the amino acid lysine. Allosteric rearrangement of mRNA structure is mediated by ligand binding, and this results in modulation of gene expression. Lysine riboswitch are most abundant in Bacillota and Gammaproteobacteria where they are found upstream of a number of genes involved in lysine biosynthesis, transport and catabolism. The lysine riboswitch has also been identified independently and called the L box.

<span class="mw-page-title-main">PreQ1 riboswitch</span>

The PreQ1-I riboswitch is a cis-acting element identified in bacteria which regulates expression of genes involved in biosynthesis of the nucleoside queuosine (Q) from GTP. PreQ1 (pre-queuosine1) is an intermediate in the queuosine pathway, and preQ1 riboswitch, as a type of riboswitch, is an RNA element that binds preQ1. The preQ1 riboswitch is distinguished by its unusually small aptamer, compared to other riboswitches. Its atomic-resolution three-dimensional structure has been determined, with the PDB ID 2L1V.

<span class="mw-page-title-main">Purine riboswitch</span>

A purine riboswitch is a sequence of ribonucleotides in certain messenger RNA (mRNA) that selectively binds to purine ligands via a natural aptamer domain. This binding causes a conformational change in the mRNA that can affect translation by revealing an expression platform for a downstream gene, or by forming a translation-terminating stem-loop. The ultimate effects of such translational regulation often take action to manage an abundance of the instigating purine, and might produce proteins that facilitate purine metabolism or purine membrane uptake.

<span class="mw-page-title-main">SAM riboswitch (S-box leader)</span>

The SAM riboswitch is found upstream of a number of genes which code for proteins involved in methionine or cysteine biosynthesis in Gram-positive bacteria. Two SAM riboswitches in Bacillus subtilis that were experimentally studied act at the level of transcription termination control. The predicted secondary structure consists of a complex stem-loop region followed by a single stem-loop terminator region. An alternative and mutually exclusive form involves bases in the 3' segment of helix 1 with those in the 5' region of helix 5 to form a structure termed the anti-terminator form. When SAM is unbound, the anti-terminator sequence sequesters the terminator sequence so the terminator is unable to form, allowing the polymerase to read-through the downstream gene. When S-Adenosyl methionine (SAM) is bound to the aptamer, the anti-terminator is sequestered by an anti-anti-terminator; the terminator forms and terminates the transcription. However, many SAM riboswitches are likely to regulate gene expression at the level of translation.

<span class="mw-page-title-main">TPP riboswitch</span> RNA secondary structure

The TPP riboswitch, also known as the THI element and Thi-box riboswitch, is a highly conserved RNA secondary structure. It serves as a riboswitch that binds thiamine pyrophosphate (TPP) directly and modulates gene expression through a variety of mechanisms in archaea, bacteria and eukaryotes. TPP is the active form of thiamine (vitamin B1), an essential coenzyme synthesised by coupling of pyrimidine and thiazole moieties in bacteria. The THI element is an extension of a previously detected thiamin-regulatory element, the thi box, there is considerable variability in the predicted length and structures of the additional and facultative stem-loops represented in dark blue in the secondary structure diagram Analysis of operon structures has identified a large number of new candidate thiamin-regulated genes, mostly transporters, in various prokaryotic organisms. The x-ray crystal structure of the TPP riboswitch aptamer has been solved.

ykkC-yxkD leader Conserved RNA structure in bacteria

The ykkC/yxkD leader is a conserved RNA structure found upstream of the ykkC and yxkD genes in Bacillus subtilis and related genes in other bacteria. The function of this family is unclear for many years although it has been suggested that it may function to switch on efflux pumps and detoxification systems in response to harmful environmental molecules. The Thermoanaerobacter tengcongensis sequence AE013027 overlaps with that of purine riboswitch suggesting that the two riboswitches may work in conjunction to regulate the upstream gene which codes for TTE0584 (Q8RC62), a member of the permease family.

<span class="mw-page-title-main">Cyclic di-GMP-I riboswitch</span>

Cyclic di-GMP-I riboswitches are a class of riboswitch that specifically bind cyclic di-GMP, which is a second messenger that is used in a variety of microbial processes including virulence, motility and biofilm formation. Cyclic di-GMP-I riboswitches were originally identified by bioinformatics as a conserved RNA-like structure called the "GEMM motif". These riboswitches are present in a wide variety of bacteria, and are most common in Clostridia and certain varieties of Pseudomonadota. The riboswitches are present in pathogens such as Clostridium difficile, Vibrio cholerae and Bacillus anthracis. Geobacter uraniumreducens is predicted to have 30 instances of this riboswitch in its genome. A bacteriophage that infects C. difficile is predicted to carry a cyclic di-GMP-I riboswitch, which it might use to detect and exploit the physiological state of bacteria that it infects.

The Magnesium responsive RNA element, not to be confused with the completely distinct M-box riboswitch, is a cis-regulatory element that regulates the expression of the magnesium transporter protein MgtA. It is located in the 5' UTR of this gene. The mechanism for the potential magnesium-sensing capacity of this RNA is still unclear, though a recent report suggests that the RNA element targets the mgtA transcript for degradation by RNase E when cells are grown in high Mg2+ environments.

<span class="mw-page-title-main">Mesoplasma florum riboswitch</span>

Riboswitches are cis-acting regulatory elements located within the 5’UTR of mRNA transcripts. These regulatory elements bind small molecules which results in a conformational change within the 5’UTR of the mRNA. The changes in the mRNA secondary structure subsequently result in changes in the expression of the adjacent open reading frame.

<span class="mw-page-title-main">SAM–SAH riboswitch</span> Bacterial RNA structure

The SAM–SAH riboswitch is a conserved RNA structure in certain bacteria that binds S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) and is therefore presumed to be a riboswitch. SAM–SAH riboswitches do not share any apparent structural resemblance to known riboswitches that bind SAM or SAH. The binding affinities for both compounds are similar, but binding for SAH is at least somewhat stronger. SAM–SAH riboswitches are exclusively found in Rhodobacterales, an order of alphaproteobacteria. They are always found in the apparent 5' untranslated regions of metK genes, which encode the enzyme that synthesizes SAM.

<span class="mw-page-title-main">Fluoride riboswitch</span> Fluoride-binding RNA structure

The fluoride riboswitch is a conserved RNA structure identified by bioinformatics in a wide variety of bacteria and archaea. These RNAs were later shown to function as riboswitches that sense fluoride ions. These "fluoride riboswitches" increase expression of downstream genes when fluoride levels are elevated, and the genes are proposed to help mitigate the toxic effects of very high levels of fluoride.

<span class="mw-page-title-main">Glutamine riboswitch</span> Glutamine-binding RNA structure

The glutamine riboswitch is a conserved RNA structure that was predicted by bioinformatics. It is present in a variety of lineages of cyanobacteria, as well as some phages that infect cyanobacteria. It is also found in DNA extracted from uncultivated bacteria living in the ocean that are presumably species of cyanobacteria.

<span class="mw-page-title-main">Pfl RNA motif</span>

The pfl RNA motif refers to a conserved RNA structure present in some bacteria and originally discovered using bioinformatics. pfl RNAs are consistently present in genomic locations that likely correspond to the 5' untranslated regions of protein-coding genes. This arrangement in bacteria is commonly associated with cis-regulatory elements. Moreover, they are in presumed 5' UTRs of multiple non-homologous genes, suggesting that they function only in these locations. Additional evidence of cis-regulatory function came from the observation that predicted rho-independent transcription terminators overlap pfl RNAs. This overlap suggests that the alternate secondary structures of pfl RNA and the transcription terminator stem-loops compete with each other, and this is a common mechanism for cis gene control in bacteria.

<span class="mw-page-title-main">Tetrahydrofolate riboswitch</span> Class of homologous RNAs

Tetrahydrofolate riboswitches are a class of homologous RNAs in certain bacteria that bind tetrahydrofolate (THF). It is almost exclusively located in the probable 5' untranslated regions of protein-coding genes, and most of these genes are known to encode either folate transporters or enzymes involved in folate metabolism. For these reasons it was inferred that the RNAs function as riboswitches. THF riboswitches are found in a variety of Bacillota, specifically the orders Clostridiales and Lactobacillales, and more rarely in other lineages of bacteria. The THF riboswitch was one of many conserved RNA structures found in a project based on comparative genomics. The 3-d structure of the tetrahydrofolate riboswitch has been solved by separate groups using X-ray crystallography. These structures were deposited into the Protein Data Bank under accessions 3SD1 and 3SUX, with other entries containing variants.

SAM-V riboswitch is the fifth known riboswitch to bind S-adenosyl methionine (SAM). It was first discovered in the marine bacterium Candidatus Pelagibacter ubique and can also be found in marine metagenomes. SAM-V features a similar consensus sequence and secondary structure as the binding site of SAM-II riboswitch, but bioinformatics scans cluster the two aptamers independently. These similar binding pockets suggest that the two riboswitches have undergone convergent evolution.

References

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