Fungal ribotoxin

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Three-dimensiona structure of a-sarcin (PDB: 1DE3), a fungal ribotoxin produced by Aspergillus giganteus A-sarcina.png
Three-dimensiona structure of α-sarcin (PDB: 1DE3), a fungal ribotoxin produced by Aspergillus giganteus

Fungal ribotoxins are a group of extracellular ribonucleases (RNases) secreted by fungi. [1] [2] Their most notable characteristic is their extraordinary specificity. They inactivate ribosomes by cutting a single phosphodiester bond of the rRNA that is found in a universally conserved sequence. [3] [4] This cleavage leads to cell death by apoptosis. [5] However, since they are extracellular proteins, they must first enter the cells that constitute their target to exert their cytotoxic action. This entry constitutes the rate-determining step of their action.

Contents

No protein receptor has been found. Thus, in order to penetrate the cells, they must take advantage of changes in permeability and the biophysical properties of the membranes, produced by phenomena such as tumour transformation or a viral infection. This is why α-sarcin, the most representative member of the group, was originally discovered as an antitumoural agent. [6] However, it turned out not to be as safe as needed and the research in this field was temporarily abandoned. One of the determining factors in this process of entry into cells appears to be their ability to interact with phospholipids whose polar headgroup shows a net negative electrical charge. [7]

Today it is known that ribotoxins constitute a broad family, produced by many types of fungi, with common characteristics that make them optimal candidates to be used for biotechnological purposes, such as pest control, and for the development of anti-cancer drugs in the form of immunotoxins. [1] [8] [9]

Distribution

Ribotoxins have been detected in many different fungi, [10] including entomopathogenic [11] [12] and edible species, [13] but the three-dimensional structure has only been resolved for three of them: α-sarcin, [14] restrictocin, [15] and hirsutellin A (HtA). [16] The first two, produced by Aspergillus giganteus and Aspergillus restrictus , respectively, are nearly identical. HtA, produced by the entomopathogenic fungus Hirsutella thompsonii , is much smaller and only shows 25% sequence identity with the other larger ribotoxins. Even so, it retains all the functional characteristics of the family. A second ribotoxin similar to HtA, anisoplin, is known (70% sequence identity). It is produced by the fungus Metarhizium anisopliae , another insect pathogen. [12]

Structural features

All known ribotoxins are proteins of between 130 and 150 amino acids that share at least two different elements of ordered secondary structure: a β-sheet, where the active center is located, and a short α-helix. The structural arrangement is very similar to that of other extracellular fungal RNases, which are not toxic, and constitute a family whose best known representative is the RNase T1 of Aspergillus oryzae . [17] This explains why ribotoxins are considered the toxic representatives of the group. The observation of their three-dimensional structures reveals their functional differences in terms of toxicity, since ribotoxins present unordered, positively charged long loops, which are much shorter, and negatively charged, in their non-toxic "relatives". These ribotoxin bonds are responsible for recognition of both the negatively charged acid phospholipids that facilitate their entry into cells, and the ribosome-specific features that allow them to cause inactivation. [18] [19] [20]

Enzymatic mechanism

Ribotoxins cleave RNA following a general acid-base mechanism shared by all the extracellular fungal RNases so far characterized, regardless of their toxicity. Using dinucleosides, such as GpA, it has been demonstrated that the breakage of the phosphodiester bond 3′-5′ of the substrate takes place through the formation of a cyclic intermediate that becomes the corresponding derivative 3′-monophosphate, the final product of the reaction. It is a transphosphorylation reaction, followed by the hydrolysis of this cyclic intermediate. For this reason, these proteins are knows as cyclant RNases. [17] [21]

Sarcin/ricin loop (SRL)

Ribotoxins specifically cut a single phosphodiester bond within the preserved sequence found in the sarcin/ricin loop (SRL). It is a segment of rRNA that adopts a loop structure. It is known as SRL precisely because it is the target of both α-sarcin and ricin. Ricin is the best known representative of the ribosomal inactivating protein (RIP) family. [22] RIPs are also highly specialized toxic proteins produced by plants and fungi that inactivate ribosomes acting as N-glycosidases. Its target is found in the same singular structure of the rRNA that is attacked by ribotoxins. [23] [24] They also depurinate a single nucleotide, contiguous to the phosphodiester bond that constitutes the target of the ribotoxins, producing the same inactivating effect of the ribosome. According to this criterion, ribotoxins are also RIPs. However, there is a fairly general consensus to use this name only for plant N-glycosidases, whereas the term ribotoxins refers only to toxic fungal RNases.

In both cases, both ribotoxins and RIPs produce complete inactivation of the ribosome by causing the SRL loop to be unable to interact with the elongation factors of the translation. [25] It has been precisely determined, using E. coli , that the binding of the elongation factor G (EF-G) is the most disturbed event by the catalytic action of these toxins. [26]

The positively charged ribotoxin surface allows them to establish favourable electrostatic interactions between the residues of their active site and the rRNA, explaining why they can carry out this highly specific recognition of the SRL. [19] [20] [27]

Role of biological membranes

The toxicity of ribotoxins results from the combination of their specific catalytic activity and their ability to cross lipid membranes. Since no protein receptor has been found, the lipid composition of these membranes is a determining factor of their cytotoxic activity. Using phospholipid model systems it has been demonstrated that α-sarcin is able to bind to lipid vesicles enriched in acid phospholipids, promoting their aggregation, leading to fusion, and altering their permeability. [7] [28] This allows the protein to be translocated through certain lipid bilayers in absence of any other protein. [29] The outer leaflet of cancer cell membranes appears to be enriched with negatively charged phospholipids, which seems to explain the antitumor properties of ribotoxins.

Biological function in the wild

It is not clear why some fungi secrete ribotoxins. At least in the case of Aspergillus , it appears that they occur during the maturation of conidia, most likely as a defense mechanism against predators. [30] The discovery that the entomopathogenic fungus Hirsutella thompsonii synthesized HtA, [11] followed by the recent characterization of anisopline, [12] suggests the possibility that ribotoxins behave as insecticidal proteins. This function has already been tested, using larvae from Galeria mellonella in laboratory experiments, for α-sarcina and some other ribotoxins such as HtA itself. [8] [9] [12]

Biotechnological and biomedical applications

The presumed insecticidal function of ribotoxins enables biotechnological possibilities to use them as a basis for the design of new, environmentally friendly bioinsecticides. In fact, extracts of H. thompsonii and M. anisopliae are marketed as pest control agents for different crops, [31] although it is not yet known if their effect is due to the presence of ribotoxins. However, ribotoxins could be used, either independently or as part of bio-pesticide formulations, and this would be a more controlled and reproducible product than the complete fungal extract now in use. [8] [9] [12] The potential toxicity of ribotoxins against vertebrates could be overcome by the design of new variants with reduced non-specific toxicity. [32] Their combination with insect pathogenic viruses, such as some baculoviruses, represents another promising approach to this biological control. Natural baculoviruses are already used as effective biopesticides, but their genetic modification to supply ribotoxins could be an effective and safe alternative for pest control. [1]

Interest in ribotoxins has also been revived by the prospect of their use as components of antitumor immunotoxins. [33] These immunotoxins are chimeric molecules composed of a fragment of a specific antibody, responsible for targeting a surface antigen present only in certain tumor cells, fused with a ribotoxin that promotes the death of the recognized cell. These immunotoxin designs based on the use of ribotoxins have been shown to be highly effective, although in laboratory experiments, with mice and tumour cells in culture. They have not yet been tested in humans. The additional benefit of not showing any detectable undesirable side effects, most likely due to the highly specific recognition of the antigen by the antibody used, [1] [33] [34] makes them attractive for the therapeutic treatment of certain solid tumors. This approach has recently been improved with the incorporation of different artificial variants of ribotoxins, such as one that cannot cross the membranes on its own, but retains the ribosome inactivating activity, [35] or a de-immunized version of α-sarcin which, in vitro, has been proven incapable of triggering a T-lymphocyte response. [34] Since the antibody fragment used is humanized, this last construction would then be practically invisible to the immune system, thus increasing the time window of its action.

Related Research Articles

<span class="mw-page-title-main">Ricin</span> Type of toxic lectin

Ricin ( RY-sin) is a lectin (a carbohydrate-binding protein) and a highly potent toxin produced in the seeds of the castor oil plant, Ricinus communis. The median lethal dose (LD50) of ricin for mice is around 22 micrograms per kilogram of body weight via intraperitoneal injection. Oral exposure to ricin is far less toxic. An estimated lethal oral dose in humans is approximately one milligram per kilogram of body weight.

<span class="mw-page-title-main">Ribonuclease</span> Class of enzyme that catalyzes the degradation of RNA

Ribonuclease is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within the EC 2.7 and 3.1 classes of enzymes.

<span class="mw-page-title-main">Ribonuclease H</span> Enzyme family

Ribonuclease H is a family of non-sequence-specific endonuclease enzymes that catalyze the cleavage of RNA in an RNA/DNA substrate via a hydrolytic mechanism. Members of the RNase H family can be found in nearly all organisms, from bacteria to archaea to eukaryotes.

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Transfer-messenger RNA</span>

Transfer-messenger RNA is a bacterial RNA molecule with dual tRNA-like and messenger RNA-like properties. The tmRNA forms a ribonucleoprotein complex (tmRNP) together with Small Protein B (SmpB), Elongation Factor Tu (EF-Tu), and ribosomal protein S1. In trans-translation, tmRNA and its associated proteins bind to bacterial ribosomes which have stalled in the middle of protein biosynthesis, for example when reaching the end of a messenger RNA which has lost its stop codon. The tmRNA is remarkably versatile: it recycles the stalled ribosome, adds a proteolysis-inducing tag to the unfinished polypeptide, and facilitates the degradation of the aberrant messenger RNA. In the majority of bacteria these functions are carried out by standard one-piece tmRNAs. In other bacterial species, a permuted ssrA gene produces a two-piece tmRNA in which two separate RNA chains are joined by base-pairing.

<span class="mw-page-title-main">Abrin</span> Chemical compound

Abrin is an extremely toxic toxalbumin found in the seeds of the rosary pea, Abrus precatorius. It has a median lethal dose of 0.7 micrograms per kilogram of body mass when given to mice intravenously. The median toxic dose for humans ranges from 10 to 1000 micrograms per kilogram when ingested and is 3.3 micrograms per kilogram when inhaled.

<span class="mw-page-title-main">Angiogenin</span> Protein-coding gene in the species Homo sapiens

Angiogenin (ANG) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene. Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular RNA, resulting in modulated levels of protein synthesis and interacts with DNA causing a promoter-like increase in the expression of rRNA. Ang is associated with cancer and neurological disease through angiogenesis and through activating gene expression that suppresses apoptosis.

<span class="mw-page-title-main">Ribonuclease P</span> Class of enzymes

Ribonuclease P is a type of ribonuclease which cleaves RNA. RNase P is unique from other RNases in that it is a ribozyme – a ribonucleic acid that acts as a catalyst in the same way that a protein-based enzyme would. Its function is to cleave off an extra, or precursor, sequence of RNA on tRNA molecules. Further, RNase P is one of two known multiple turnover ribozymes in nature, the discovery of which earned Sidney Altman and Thomas Cech the Nobel Prize in Chemistry in 1989: in the 1970s, Altman discovered the existence of precursor tRNA with flanking sequences and was the first to characterize RNase P and its activity in processing of the 5' leader sequence of precursor tRNA. Recent findings also reveal that RNase P has a new function. It has been shown that human nuclear RNase P is required for the normal and efficient transcription of various small noncoding RNAs, such as tRNA, 5S rRNA, SRP RNA and U6 snRNA genes, which are transcribed by RNA polymerase III, one of three major nuclear RNA polymerases in human cells.

Ribonuclease T<sub>1</sub> Class of enzymes

Ribonuclease T1 (EC 4.6.1.24, guanyloribonuclease, Aspergillus oryzae ribonuclease, RNase N1, RNase N2, ribonuclease N3, ribonuclease U1, ribonuclease F1, ribonuclease Ch, ribonuclease PP1, ribonuclease SA, RNase F1, ribonuclease C2, binase, RNase Sa, guanyl-specific RNase, RNase G, RNase T1, ribonuclease guaninenucleotido-2'-transferase (cyclizing), ribonuclease N3, ribonuclease N1) is a fungal endonuclease that cleaves single-stranded RNA after guanine residues, i.e., on their 3' end; the most commonly studied form of this enzyme is the version found in the mold Aspergillus oryzae. Owing to its specificity for guanine, RNase T1 is often used to digest denatured RNA prior to sequencing. Similar to other ribonucleases such as barnase and RNase A, ribonuclease T1 has been popular for folding studies.

<span class="mw-page-title-main">5S ribosomal RNA</span> RNA component of the large subunit of the ribosome

The 5S ribosomal RNA is an approximately 120 nucleotide-long ribosomal RNA molecule with a mass of 40 kDa. It is a structural and functional component of the large subunit of the ribosome in all domains of life, with the exception of mitochondrial ribosomes of fungi and animals. The designation 5S refers to the molecule's sedimentation velocity in an ultracentrifuge, which is measured in Svedberg units (S).

<span class="mw-page-title-main">Pancreatic ribonuclease family</span> Class of enzymes

Pancreatic ribonuclease family is a superfamily of pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles.

Saporin is a protein that is useful in biological research applications, especially studies of behavior. Saporins are so-called ribosome inactivating proteins (RIPs), due to its N-glycosidase activity, from the seeds of Saponaria officinalis. It was first described by Fiorenzo Stirpe and his colleagues in 1983 in an article that illustrated the unusual stability of the protein.

<span class="mw-page-title-main">EF-G</span> Prokaryotic elongation factor

EF-G is a prokaryotic elongation factor involved in mRNA translation. As a GTPase, EF-G catalyzes the movement (translocation) of transfer RNA (tRNA) and messenger RNA (mRNA) through the ribosome.

Beetin is a ribosome-inactivating protein found in the leaves of sugar beets, Beta vulgaris L, specifically attacking plant ribosomes. Sugar beet, beetins, that have been isolated meet all the criteria to be classified as single chain ribosome inactivating proteins that are highly toxic to mammalian ribosomes but non-toxic to intact cultured mammalian cells. Beetin expression occurs when there is a viral infection of the plant. The different levels of glycosylation of the same polypeptide chain result in the two forms of beetin. Beetin exhibits these two primary forms with apparent Mr values of 27 000 (BE27) and 29 000 (BE29) along with possessing glycan chains. Beetins are a type-I (single-chain) proteins with N-glycoside activity. Since it has been discovered that beetin is mostly concentrated in the intercellular fluid, its presence in the remaining parts of the leaf may be below the limit of detection rather than being nonexistent. The expression of beetin is only found in mature plants, but is present in all developing stages.

<span class="mw-page-title-main">Ribosome-inactivating protein</span> Protein synthesis inhibitor

A ribosome-inactivating protein (RIP) is a protein synthesis inhibitor that acts at the eukaryotic ribosome. This protein family describes a large family of such proteins that work by acting as rRNA N-glycosylase. They inactivate 60S ribosomal subunits by an N-glycosidic cleavage, which releases a specific adenine base from the sugar-phosphate backbone of 28S rRNA. RIPs exist in bacteria and plants.

<span class="mw-page-title-main">Antifungal protein family</span>

The antifungal proteinfamily is a protein family, with members sharing a structure consisting of five antiparallel beta strands which are highly twisted creating a beta barrel stabilised by four internal disulphide bridges. A cationic site adjacent to a hydrophobic stretch on the protein surface may constitute a phospholipid binding site.

rRNA endonuclease is an enzyme that catalyses the hydrolysis of the phosphodiester linkage between guanosine and adenosine residues at one specific position in the 28S rRNA of rat ribosomes. This enzyme also acts on bacterial rRNA.

Internal-loops in RNA are found where the double stranded RNA separates due to no Watson-Crick-Franklin base pairing between the nucleotides. Internal-loops differ from Stem-loops as they occur in middle of a stretch of double stranded RNA. The non-canonicoal residues result in the double helix becoming distorted due to unwinding, unstacking and kinking.

The SraL RNA, also known as RyjA, is a small non-coding RNA discovered in E. coli, and later in Salmonella Tiphimurium. This ncRNA was found to be expressed only in stationary phase. It may possibly play a role in Salmonella virulence. The major stationary phase regulator RpoS is transcriptionally regulating SraL and directly binds to the sraL gene promoter. SraL down-regulates the expression of the ribosome-associated chaperone Trigger Factor (TF), which is involved in the folding of the newly synthesised cystolic proteins.

Aspergillus giganteus is a species of fungus in the genus Aspergillus that grows as a mold. It was first described in 1901 by Wehmer, and is one of six Aspergillus species from the Clavati section of the subgenus Fumigati. Its closest taxonomic relatives are Aspergillus rhizopodus and Aspergillus longivescia.

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  28. ↑ Gavilanes, J. G.; Thomas, P. G.; Oñaderra, M.; Gasset, M. (1990-02-01). "Fusion of phospholipid vesicles produced by the anti-tumour protein α-sarcin". Biochemical Journal. 265 (3): 815–822. doi:10.1042/bj2650815. ISSN   0264-6021. PMC   1133705 . PMID   2306215.
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  31. ↑ Kanga, L. H. B.; James, R. R.; Boucias, D. G. (2002). "Hirsutella thompsonii and Metarhizium anisopliae as potential microbial control agents of Varroa destructor, a honey bee parasite". Journal of Invertebrate Pathology. 81 (3): 175–184. Bibcode:2002JInvP..81..175K. doi:10.1016/S0022-2011(02)00177-5. PMID   12507487.
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  34. 1 2 Gehlsen, Kurt R.; Lacadena, Javier; Baker, Matthew P.; Carr, Francis J.; Fogg, Mark H.; Kozub, Dorota; Holgate, Robert G. E.; Hearn, Arron R.; Jones, Tim D. (2016-11-01). "A deimmunised form of the ribotoxin, α-sarcin, lacking CD4+ T cell epitopes and its use as an immunotoxin warhead". Protein Engineering, Design and Selection. 29 (11): 531–540. doi:10.1093/protein/gzw045. ISSN   1741-0126. PMC   5081043 . PMID   27578884.
  35. ↑ Tomé-Amat, Jaime; Herrero-Galán, Elías; Oñaderra, Mercedes; Martínez-del-Pozo, Álvaro; Gavilanes, José G.; Lacadena, Javier (2015). "Preparation of an engineered safer immunotoxin against colon carcinoma based on the ribotoxin hirsutellin A". The FEBS Journal. 282 (11): 2131–2141. doi: 10.1111/febs.13262 . ISSN   1742-4658. PMID   25752204. S2CID   39750333.
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