Swinholide

Last updated
Swinholide
Swinholide 2 copy.gif
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
Properties
C78H132O20
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Swinholides are dimeric 42 carbon-ring polyketides that exhibit a 2-fold axis of symmetry. Found mostly in the marine sponge Theonella, swinholides encompass cytotoxic and antifungal activities via disruption of the actin skeleton. [1] Swinholides were first described in 1985 [2] and the structure and stereochemistry were updated in 1989 [3] and 1990, [4] respectively. Thirteen swinholides have been described in the literature, including close structural compounds such as misakinolides/bistheonellides, [5] ankaraholides, [6] and hurgholide A [7] It is suspected that symbiotic microbes that inhabit the sponges rather than the sponges themselves produce swinholides since the highest concentration of swinholides are found in the unicellular bacterial fraction of sponges and not in the sponge fraction or cyanobacteria fraction that also inhabit the sponges. [4] [8] [9]

Contents

From a marine field sample containing the cyanobacterium Symploca sp, Swinholide A has also been reported in literature. [6] The structural analogs of swinholides, ankaraholides, were also found from the cyanobacterium Geitlerinema sp. in the same experimental study. [6] Since sponges host a range of bacteria, including symbiotic cyanobacteria, it is often wondered how swinholides are produced. [1] A study of the production of misakinolide revealed that it was attributed to the Theonella symbiont bacterium Candidatus Entotheonella via the discovery of a trans-AT polyketides synthase (PKS) biosynthesis gene cluster. [1] This demonstrates that the true origin of swinholides is symbiotic bacteria that inhabit sponges. [1]

History

Cyanobacteria are known to have a wide application scope due to their structurally varied secondary metabolites they produce. [1] Among many of the secondary metabolites, polyketides have demonstrated vital bioactivities that can be applied to a number of fields. For example, many antifungal, antitumor, and antibiotic polyketides are found from plants, bacteria, and fungi. [1] The synthesis of polyketides is well known: small monomeric compounds frame polyketides via elongation on multidomain PKS complexes. [1] The PKSs can add either a malonyl, acyl, or derivative unit to the chain and they are classified into types 1-3, which are dependent on factors such as functionality and domain architecture. [1] Type I PKSs include cis- and trans-acyltransferase (trans-AT) PKSs where each section of the cis-AT PKSs encodes a dedicated AT domain and the trans-AT PKSs have distinct ATs that are used in place of the cis-encoded AT domains. [1]

Structure

The structures of swinholide, misakinolide, and luminaolide are shown below. (Figure 1 and Figure 2). [1]

Figure 1. Structure of Swinholide and Misakinolide. Swinholide 1.gif
Figure 1. Structure of Swinholide and Misakinolide.
Figure 2. Structure of Luminaolide. Luminaolide.gif
Figure 2. Structure of Luminaolide.

Biosynthesis

The swinholide biosynthesis gene cluster (swi) was located on a single scaffold by BLASTp searches against misakinolide biosynthesis cluster genes. This was chosen because of the close structural resemblance of these compounds. [10]

The swinholide biosynthesis gene cluster (85-kb) encodes for five PKS proteins, including SwiC to SwiG. [1] This includes an AT enzyme, SwiG, which is an characteristic of trans-PKSs (Figure 3). [1]

Figure 3. Swinholide Biosynthesis. Swinholide Biosynthesis.gif
Figure 3. Swinholide Biosynthesis.

The swinholide biosynthesis gene cluster codes for a trans-AT PKS and does not integrate AT domains similar to the phormidolide (phm), miskinolide (mis), tolytoxin (tto), luminaolide (lum), and nosperin (nsp) gene clusters. [1] The swinholide biosynthesis gene cluster is also similar to the tto and lum gene clusters. [1] The swi and mis clusters both include four large genes encoding PKS enzymes and a gene encoding for the AT protein, but the order of the genes differs (Figure 4). [1]

In the swi biosynthesis gene cluster, first gene, SwiC, is on the reverse strand and the other four genes are facing the forward direction. [1] In the mis biosynthesis gene cluster, all genes are oriented in the same direction. [1] Although this is different, both swi and mis biosynthesis gene clusters are composed of similar catalytic domains. [1]

One distinct characteristic of the swi biosynthesis enzymes are its domain order, nonelongating domains, and split modules. [1] These are common features found in trans-PKSs. [1] There are four nonelongating ketosynthases in the swi cluster that are not a factor of the polyketide chain synthesis. [1] Three ketosynthases function to bind with modification enzymes and the fourth ketosynthase is found in the terminal section of SwiF. [1] There are only minor differences between swi and mis: two acyl carrier proteins (ACPs) in the middle of the SwiC protein, instead of a single ACP in the found in the MisC protein (Figure 4). [1]

Figure 4. Domains of Swinholide and its Structural Variants. Domains of Swinholide and its Structural Variants.gif
Figure 4. Domains of Swinholide and its Structural Variants.

In their monomeric structures, swi and mis have two varying ring structures. [1] In SwiF, the second and third dehydrotases (DHs) are located side-by-side (Figure 4). [1] For mis, the same DH-like domains were identified, but the third DH is pyran synthase (PS), which creates the dihydropyran ring in the structure of mis. [1] Further investigation revealed third DH in swi was a PS (Figure 3 and 5). [1] The other ring formation in mis was hypothesized to be catalyzed by either accessory enzymes or DH in MisC. [1] MisC and SwiC code for similar, but different DHs, but lack an overall PS domain in the dihydropyran ring formation. [1] The DH domains from MisC and SwiC were found to lack the glycine in a specific motif. [1] This, therefore, could indicate that a varying DH domain plays a vital role in ring formation. [1]

Despite the structural differences between swi and mis, the sequence identities of the genes differed from 73 to 85% even though there are structural similarities. [1] Scytophycin, tolytoxin, and luminaolide biosynthesis cluster genes also encompassed high sequence identity to swi and mis. [1] Although there is high sequence identity, SwiC and MisC proteins differ from alternative gene clusters, as shown in their chemical structures (Figure 1). [1]

Phylogenic analysis

The structural variants of the swinholide biosynthesis gene clusters origins were elucidate through phylogenic studies. [1] A phylogenetic tree of trans-encoded AT proteins showed that all six biosynthesis gene clusters were similar and assembled their own group. [1] Scytophycin, luminaolide, and tolytoxin biosynthesis gene clusters were arranged together based on ketosynthase domains, and the misakinolide and swinholide biosynthesis gene clusters constituted their own category (Figure 5). [1]

Figure 5. Phylogenic Analysis of Swinholide and Structural Variants. Phylogenic Analysis of Swinholide and Structural Variants.gif
Figure 5. Phylogenic Analysis of Swinholide and Structural Variants.

Related Research Articles

Oxytetracycline Antibiotic

Oxytetracycline was the second of the broad-spectrum tetracycline group of antibiotics to be discovered.

Mycolactone chemical compound

Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related pathogenic Mycobacteria species that have been assigned a variety of names including, M. ulcerans, M. liflandii, M. pseudoshottsii, and some strains of M. marinum. These mycobacteria are collectively referred to as mycolactone-producing mycobacteria or MPM.

Polyketide synthases (PKSs) are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share striking similarities with fatty acid biosynthesis.

Biosynthesis of doxorubicin

Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of streptomyces. In contrast, only one known non-wild type species, streptomyces peucetius subspecies cesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin. This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of streptomyces can produce doxorubicin. His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR. By 1999, they produced recombinant Dox A, a Cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin. This was significant because it became clear that all daunorubicin producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing Dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides. Some triple mutants, that also over-expressed Dox A, were able to double the yield of DXR. This is of more than academic interest because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum. More efficient production techniques have brought the price down to $1.1 million per kg for the non-liposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps and the yield is poor. Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.

Psymberin chemical compound

Psymberin, also known as irciniastatin A, is a cytotoxin derived from sea sponges. It was discovered by two independent research groups in 2004. Psymberin was found to be highly bioactive as it showed LC50s at nanomolar concentrations against various types of tumors.

Streptogramin A is a group of antibiotics within the larger family of antibiotics known as streptogramins. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone and peptide bonds while group B antibiotics are depsipeptides. While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.

6-Deoxyerythronolide B Synthase or DEBS has been identified as a Type 1 polyketide synthase. DEBS is found in Saccharopolyspora erythraea and responsible for the synthesis of the macrolide ring which is the precursor of the antibiotic erythromycin. There have been three categories of polyketide synthases identified to date, type 1, 2 and 3. Type one synthases involve large multidomain proteins containing all the sites necessary for polyketide synthesis. Type two synthases contain active sites distributed among several smaller polypeptides, and type three synthases are large multi-protein complexes containing modules which have a single active site for each and every step of polyketide synthesis. In the case of DEBS, there are three large multi-functional proteins, DEBS 1,2, and 3, that each exist as a dimer of two modules. Each module consists of a minimum of a Ketosynthase (KS), Acyl carrier protein (ACP) site, and acyltransferase (AT), but may also contain a Ketoreductase (KR), Dehydrotase (DH), and Enol Reductase (ER) for additional reduction reactions. The DEBS complex also contains a Loading Domain on module 1 consisting of an acyl carrier protein and an acyltransferase. The terminal Thioesterase acts solely to terminate DEBS polyketide synthesis and cyclize the macrolide ring.

Pikromycin chemical compound

Pikromycin was studied by Brokmann and Hekel in 1951 and was the first antibiotic macrolide to be isolated. Pikromycin is synthesized through a type I polyketide synthase system in Streptomyces venezuelae, a species of Gram-positive bacterium in the genus Streptomyces. Pikromycin is derived from narbonolide, a 14-membered ring macrolide. Along with the narbonolide backbone, pikromycin includes a desosamine sugar and a hydroxyl group. Although Pikromycin is not a clinically useful antibiotic, it can be used as a raw material to synthesize antibiotic ketolide compounds such as ertythromycins and new epothilones.

Callystatin A chemical compound

Callystatin A is a polyketide natural product from the leptomycin family of secondary metabolites. It was first isolated in 1997 from the marine sponge Callyspongia truncata which was collected from the Goto Islands in the Nagasaki Prefecture of Japan by the Kobayashi group. Since then its absolute configuration has been elucidated and callystatin A was discovered to have anti-fungal and anti-tumor activities with extreme potency against the human epidermoid carcinoma KB cells (IG50 = 10 pg/ml) and the mouse lymphocytic leukemia Ll210 cells (IG50 = 20 pg/ml).

Apratoxin A chemical compound

Apratoxin A - is a cyanobacterial secondary metabolite, known as a potent cytotoxic marine natural product. It is a derivative of the Apratoxin family of cytotoxins. The mixed peptide-polyketide natural product comes from a polyketide synthase/non-ribosomal peptide synthase pathway (PKS/NRPS). This cytotoxin is known for inducing G1-phase cell cycle arrest and apoptosis. This natural product's activity has made it a popular target for developing anticancer derivatives.

Tirandamycin

The tirandamycins are a small group of natural products that contain a bicyclic ketal system and a tetramic acid moiety, the latter of which is found in different natural products from a variety of sources and which is characterized by a 2,4-pyrrolidinedione ring system. Members of this structural family have shown a wide range of biological activities like in antiparasitic, antifungal and anti-HIV evaluations, and furthermore, have shown potential usefulness because of their potent antibacterial properties. Streptolydigin, an analogue of the tirandamycins, is known to function as an antibacterial agent through inhibiting the chain initiation and elongation steps RNA polymerase transcription. The structural diversity in the tirandamycin family originates from the different oxidation patterns observed in the bicycic ketal system, and these modifications are determinant features for the bioactivity associated with these molecules.

Curacin A is a hybrid polyketide synthase (PKS)/nonribosomal peptide synthase (NRPS) derived natural product produced isolated from the cyanobacterium Lyngbya majuscula. Curacin A belongs to a family of natural products including jamaicamide, mupirocin, and pederin that have an unusual terminal alkene. Additionally, Curacin A contains a notable thiazoline ring and a unique cyclopropyl moiety, which is essential to the compound's biological activity. Curacin A has been characterized as potent antiproliferative cytotoxic compound with notable anticancer activity for several cancer lines including renal, colon, and breast cancer. Curacin A has been shown to interact with colchicine binding sites on tubulin, which inhibits microtubule polymerization, an essential process for cell division and proliferation.

Onnamide A chemical compound

Onnamide A is a bioactive natural product found in Theonella swinhoei, a species of marine sponge whose genus is well known for yielding a diverse set of biologically active natural products, including the swinholides and polytheonamides. It bears structural similarities to the pederins, a family of compounds known to inhibit protein synthesis in eukaryotic cells. Onnamide A and its analogues have attracted academic interest due to their cytotoxicity and potential for combating the growth and proliferation of cancer cells.

Gephyronic acid vvv bg

Gephyronic acid is a polyketide that exists as an equilibrating mixture of structural isomers. In nature, gephyronic acid is produced by slow growing myxobacterium: Archangium gephyra strain Ar3895 and Cystobacter violaceus strain Cb vi76. It is the first antibiotic in myxobacteria that was reported to specifically inhibit eukaryotic protein synthesis.

<i>BY1</i> species of fungus

BY1 is a taxonomically unidentified basidiomycete fungus. ITS sequencing has placed it in the Russulales and is referred to as a stereaceous basidiomycete. Chemotaxonomically supporting its placement in this group, it produces fomannoxins and vibralactones. The fungus' mycelia were isolated from dead aspen in Minnesota, USA. It is presumed to decompose wood by white rot.

Borrelidin chemical compound

Borrelidin is an 18-membered polyketide macrolide derived from several Streptomyces species. First discovered in 1949 from Streptomyces rochei, Borrelidin shows antibacterial activity by acting as an inhibitor of threonyl-tRNA synthetase and features a nitrile moiety, a unique functionality in natural products., Borrelidin also exhibits potent angiogenesis inhibition, which was shown in a rat aorta matrix model. Other studies have been performed to show that low concentrations of borrelidin can suppress growth and induce apoptosis in malignant acute lymphoblastic leukemia cells. Borredlidin’s antimalarial activity has also been shown in vitro and in vivo.

Annimycin chemical compound

Annimycin is a polyenoic acid amide natural product produced by Streptomyces calvus. Annimycin inhibits the sporulation of several actinobacterial genera.

Tylactone synthase or TYLS is a Type 1 polyketide synthase. TYLS is found in strains of Streptomyces fradiae and responsible for the synthesis of the macrolide ring, tylactone, the precursor of an antibiotic, tylosin. TYLS is composed of five large multi-functional proteins, TylGI-V. Each protein contains either one or two modules. Each module consists of a minimum of a Ketosynthase (KS), an Acyltransferase (AT), and an Acyl carrier protein (ACP) but may also contain a Ketoreductase (KR), Dehydrotase (DH), and Enoyl Reductase (ER) for additional reduction reactions. The domains of TYLS have similar activity domains to those found in other Type I polyketide synthase such as 6-Deoxyerythronolide B synthase (DEBS). The TYLS system also contains a loading module consisting of a ketosynthase‐like decarboxylase domain, an acyltransferase, and acyl carrier protein. The terminal Thioesterase terminates tylactone synthesis by cyclizing the macrolide ring. After the TYLS completes tylactone synthesis, the tylactone molecule is modified by oxidation at C-20 and C-23 and glycosylation of mycaminose, mycinose, and mycarose to produce tylosin.

Phoslactomycin B chemical compound

Phoslactomycin (PLM) is a natural product from the isolation of Streptomyces species. This is an inhibitor of the protein serine/threonine phosphatase which is the protein phosphate 2A (PP2A). The PP2A involves the growth factor of the cell such as to induce the formation of mitogen-activated protein interaction and playing a role in cell division and signal transduction. Therefore, PLM is used for the drug that prevents the tumor, cancer, or bacteria. There are nowsaday has 7 kinds of different PLM from PLM A to PLM G which differ the post-synthesis from the biosynthesis of PLM.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 Humisto A, Jokela J, Liu L, Wahlsten M, Wang H, Permi P, Machado JP, Antunes A, Fewer DP, Sivonen K (November 2017). "Nostoc sp. UHCC 0450". Applied and Environmental Microbiology. 84 (3): e02321–17. doi:10.1128/AEM.02321-17. PMC   5772238 . PMID   29150506.
  2. ↑ Carmely S, Kashman Y (January 1985). "Structure of swinholide-a, a new macrolide from the marine sponge". Tetrahedron Letters. 26 (4): 511–514. doi:10.1016/s0040-4039(00)61925-1.
  3. ↑ Kobayashi M, Tanaka J, Katori T, Matsuura M, Kitagawa I (January 1989). "Structure of swinholide A, a potent cytotoxic macrolide from the Okinawan marine sponge". Tetrahedron Letters. 30 (22): 2963–2966. doi:10.1016/s0040-4039(00)99170-6.
  4. 1 2 Kitagawa I, Kobayashi M, Katori T, Yamashita M, Tanaka J, Doi M, Ishida T (April 1990). "Absolute stereostructure of swinholide A, a potent cytotoxic macrolide from the Okinawan marine sponge Theonella swinhoei". Journal of the American Chemical Society. 112 (9): 3710–2. doi:10.1021/ja00165a094.
  5. ↑ Sakai R, Higa T, Kashman Y (September 1986). "Misakinolide-A, an Antitumor Macrolide from the Marine Sponge Theonella Sp". Chemistry Letters. 15 (9): 1499–1502. doi:10.1246/cl.1986.1499.
  6. 1 2 3 Andrianasolo EH, Gross H, Goeger D, Musafija-Girt M, McPhail K, Leal RM, Mooberry SL, Gerwick WH (March 2005). "Isolation of swinholide A and related glycosylated derivatives from two field collections of marine cyanobacteria". Organic Letters. 7 (7): 1375–8. doi:10.1021/ol050188x. PMID   15787510.
  7. ↑ Youssef DT, Mooberry SL (January 2006). "Hurghadolide A and swinholide I, potent actin-microfilament disrupters from the Red Sea sponge Theonella swinhoei". Journal of Natural Products. 69 (1): 154–7. doi:10.1021/np050404a. PMID   16441091.
  8. ↑ Tsukamoto S, Ishibashi M, Sasaki T, Kobayashi J (1991). "New congeners of swinholides from the okinawan marine sponge Theonella sp". Journal of the Chemical Society, Perkin Transactions 1 (12): 3185–8. doi:10.1039/p19910003185.
  9. ↑ Bewley CA, Holland ND, Faulkner DJ (July 1996). "Two classes of metabolites from Theonella swinhoei are localized in distinct populations of bacterial symbionts". Experientia. 52 (7): 716–22. doi:10.1007/bf01925581. PMID   8698116. S2CID   25812491.
  10. ↑ Ueoka R, Uria AR, Reiter S, Mori T, Karbaum P, Peters EE, Helfrich EJ, Morinaka BI, Gugger M, Takeyama H, Matsunaga S, Piel J (September 2015). "Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms". Nature Chemical Biology. 11 (9): 705–12. doi:10.1038/nchembio.1870. PMC   7116039 . PMID   26236936.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.