Phomoxanthone A

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Phomoxanthone A
Phomoxanthone A structure.svg
Names
Preferred IUPAC name
rel-(5R,5′R,6R,6′R,10aR,10′aR)-10a,10′a-Bis[(acetyloxy)methyl]-1,1′,8,8′-tetrahydroxy-6,6′-dimethyl-9,9′-dioxo-5,5′,7,7′,9,9′,10a,10′a-octahydro-6H,6′H-[4,4′-bixanthene]-5,5′-diyl diacetate
Other names
PXA
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
  • InChI=ZCLZNQUALWMDDN-ACMZUNAXSA-N
  • CC1CC(=O)C2=C(C3=C(C=CC(=C3OC2(C1OC(=O)C)COC(=O)C)C4=C5C(=C(C=C4)O)C(=C6C(=O)CC(C(C6(O5)COC(=O)C)OC(=O)C)C)O)O)O
Properties
C38H38O16
Molar mass 750.70 g/mol
Appearanceyellow solid
Density ~1.53 g/cm3
not soluble
Solubility in DMSO good, but unstable [1]
Solubility in EtOH moderate [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

The mycotoxin phomoxanthone A, or PXA for short, is a toxic natural product that affects the mitochondria. It is the most toxic and the best studied of the naturally occurring phomoxanthones. PXA has recently been shown to induce rapid, non-canonical mitochondrial fission by causing the mitochondrial matrix to fragment while the outer mitochondrial membrane can remain intact. This process was shown to be independent from the mitochondrial fission and fusion regulators DRP1 and OPA1. [1]

Contents

Properties and structure

Xanthone (pictured) is the basis for the structure of phomoxanthone A (PXA), making PXA a xanthonoid. Xanthone.svg
Xanthone (pictured) is the basis for the structure of phomoxanthone A (PXA), making PXA a xanthonoid.

The phomoxanthones are named after the fungus Phomopsis , from which they were first isolated, and after their xanthonoid structure, which means they have structures similar to the compound xanthone (pictured on the left). Chemically, the phomoxanthones are dimers of two tetrahydroxanthones, meaning that they consist of two subunits of xanthonoids that have four hydroxy groups each. The two subunits of the phomoxanthones are covalently linked to each other. PXA itself is a homodimer, meaning that it consists of two identical subunits. Both of these subunits are diacetylated tetrahydroxanthones, so two of their hydroxy groups have been replaced by acetyl groups. The position of the link between the two dimer subunits is the only structural difference between PXA and its less toxic isomers phomoxanthone B (PXB) and dicerandrol C: In PXA, the two xanthonoid monomers are symmetrically linked at the position C-4,4’, while in PXB, they are asymmetrically linked at C-2,4’, and in dicerandrol C, they are symmetrically linked at C-2,2’. Otherwise, these three compounds are structurally identical. [2] [3] The phomoxanthones are structurally closely related to the secalonic acids, another class of dimeric tetrahydroxanthone mycotoxins, with which they share several properties. Notably, both the phomoxanthones and the secalonic acids are unstable when dissolved in polar solvents such as DMSO, with the covalent bond between the two monomers shifting between 2,2′-, 2,4′-, and 4,4′-linkage. [4] The two phomoxanthones PXA and PXB can thus slowly isomerise into each other as well as into the essentially non-toxic dicerandrol C, resulting in a loss of activity of PXA over time when dissolved in a polar solvent. [1]

Occurrence

As natural products, PXA and other phomoxanthones occur as secondary metabolites in fungi of the eponymous genus Phomopsis , most notably in the species Phomopsis longicolla . [2] [3] This fungus is an endophyte of the mangrove plant Sonneratia caseolaris . [5] [3] However, it has also been identified as a pathogen in other plants, such as the soybean plant in which it causes a disease called Phomopsis seed decay (PSD). [6] [7]

Preparation

Both PXA and PXB were discovered in 2001, and their preparation by isolation from Phomopsis fungal cultures was described in the corresponding publication. [2] Briefly, a MeOH extract of a Phomopsis culture is mixed with H2O and washed with hexane. The aqueous phase is then dried and the residue is dissolved in EtOAc, washed with H2O, concentrated and repeatedly purified by size-exclusion chromatography. The resulting mixture of PXA and PXB is separated by HPLC. A modified method, in which the initial extraction is done with EtOAc instead of MeOH and the drying step is skipped, was described in 2013. [3]

Uses

Phomoxanthone A was first identified in a screening for antimalarial compounds. [2] It showed strong antibiotic activity against a multidrug-resistant strain of the main causative agent of malaria, the protozoan parasite Plasmodium falciparum . The same study also reported antibiotic activity of PXA against Mycobacterium tuberculosis and against three animal cell lines, two of which were derived from human cancer cells. [2] These findings not only showed that PXA has antibiotic activity against very diverse organisms, but they also sparked further studies that investigated PXA as a potential antibiotic or anti-cancer drug. A later study also reported antibiotic activity for PXA against the alga Chlorella fusca , the fungus Ustilago violacea , and the bacterium Bacillus megaterium . [8] This broad range of activity disqualified it as a specific antibiotic that could be used in the treatment of infectious diseases, however the hope that it could be used as an anti-cancer drug remained. Preliminary results from a study in human cancer cells and non-cancer cells suggested that PXA might be more toxic to the former than to the latter, although results from in vivo studies have not yet been presented. [3] [9]

Aside from a potential medical use, recent findings indicate that PXA might have an application as a research tool in the study of mitochondrial membrane dynamics, particularly non-canonical mitochondrial fission and remodelling of the mitochondrial matrix. [1]

Biological activity

Time lapse video of mitochondrial membrane dynamics during the first 5 minutes after PXA treatment, showing the transformation of a tubular network into separated fragments.

Since PXA has antibiotic activity against organisms as diverse as bacteria, protozoans, fungi, plants and animal cells including human cancer cells, it has to affect a cellular feature that is evolutionarily highly conserved. A recent study has shown that PXA directly affects the mitochondria by disrupting both their biochemical functions and their membrane architecture. [1] The mitochondria are cellular organelles that are present in almost all eukaryotes. According to the theory of symbiogenesis, they are derived from bacteria and share many characteristics with them, including several properties of their membrane composition. [10] [11]

One of the main functions of the mitochondria is to produce the cellular energy currency ATP through the process of oxidative phosphorylation (OxPhos). OxPhos depends on the mitochondrial membrane potential, which is generated by the electron transport chain (ETC) via the consumption of oxygen. PXA was shown to interfere with all of these functions of the mitochondria: not only does it decrease ATP synthesis and depolarise the mitochondria, but it also inhibits the ETC and cellular oxygen consumption. This sets it apart from uncoupling agents such as protonophores. While these also decrease ATP synthesis and depolarise the mitochondria, they increase respiration at the same time due to increased ETC activity in an attempt to restore the membrane potential. [1]

In addition to this inhibition of the function of mitochondria, PXA also disrupts their membrane architecture. In many cell types, the mitochondria normally form an intricate tubular network that undergoes a constant process of balanced mitochondrial fission and mitochondrial fusion. Treatment with PXA or many other mitochondrial stressors, such as protonophores, causes excessive fission that results in mitochondrial fragmentation. In the case of PXA, however, this fragmentation process was shown to be different from canonical fragmentation, caused by other agents such as protonophores, in several ways: first, it is considerably faster, resulting in complete fragmentation within a minute as opposed to about 30–60 minutes for canonical fragmentation; second, it is independent from the mitochondrial fission and fusion regulators DRP1 and OPA1; and third, while PXA causes fragmentation of both the outer mitochondrial membrane (OMM) and the mitochondrial matrix in wild type cells, it causes exclusive fragmentation of the matrix in cells that lack DRP1. [1] This last feature is especially unusual since no active mechanism for exclusive matrix fission is known in higher eukaryotes. [12] Examination of the mitochondrial ultrastructure revealed that PXA causes cristae disruption and complete distortion of the mitochondrial matrix. It is probably through this effect that PXA induces programmed cell death in the form of apoptosis. [1]

Related Research Articles

Cell biology is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and functioning of organisms. Cell biology is the study of the structural and functional units of cells. Cell biology encompasses both prokaryotic and eukaryotic cells and has many subtopics which may include the study of cell metabolism, cell communication, cell cycle, biochemistry, and cell composition. The study of cells is performed using several microscopy techniques, cell culture, and cell fractionation. These have allowed for and are currently being used for discoveries and research pertaining to how cells function, ultimately giving insight into understanding larger organisms. Knowing the components of cells and how cells work is fundamental to all biological sciences while also being essential for research in biomedical fields such as cancer, and other diseases. Research in cell biology is interconnected to other fields such as genetics, molecular genetics, molecular biology, medical microbiology, immunology, and cytochemistry.

<span class="mw-page-title-main">Mitochondrion</span> Organelle in eukaryotic cells responsible for respiration

A mitochondrion is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name.

A proton pump is an integral membrane protein pump that builds up a proton gradient across a biological membrane. Proton pumps catalyze the following reaction:

<span class="mw-page-title-main">ATP synthase</span> Enzyme

ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP synthase is a molecular machine. The overall reaction catalyzed by ATP synthase is:

<span class="mw-page-title-main">Crista</span> Fold in the inner membrane of a mitochondrion

A crista is a fold in the inner membrane of a mitochondrion. The name is from the Latin for crest or plume, and it gives the inner membrane its characteristic wrinkled shape, providing a large amount of surface area for chemical reactions to occur on. This aids aerobic cellular respiration, because the mitochondrion requires oxygen. Cristae are studded with proteins, including ATP synthase and a variety of cytochromes.

<span class="mw-page-title-main">Inner mitochondrial membrane</span>

The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">MFN2</span> Protein-coding gene in the species Homo sapiens

Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.

<span class="mw-page-title-main">DNM1L</span> Protein-coding gene in humans

Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L gene and is part of the dynamin superfamily (DSP) family of proteins.

<span class="mw-page-title-main">FIS1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7. This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission. Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis. By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.

<span class="mw-page-title-main">YME1L1</span> Protein-coding gene in the species Homo sapiens

ATP-dependent metalloprotease YME1L1 is an enzyme that in humans is encoded by the YME1L1 gene. YME1L1 belongs to the AAA family of ATPases and mainly functions in the maintenance of mitochondrial morphology. Mutations in this gene would cause infantile-onset mitochondriopathy.

Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers. It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles. Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli, such as aerobic exercise.

Fission, in biology, is the division of a single entity into two or more parts and the regeneration of those parts to separate entities resembling the original. The object experiencing fission is usually a cell, but the term may also refer to how organisms, bodies, populations, or species split into discrete parts. The fission may be binary fission, in which a single organism produces two parts, or multiple fission, in which a single entity produces multiple parts.

<span class="mw-page-title-main">Mitochondrial fusion</span> Merging of two or more mitochondria within a cell to form a single compartment

Mitochondria are dynamic organelles with the ability to fuse and divide (fission), forming constantly changing tubular networks in most eukaryotic cells. These mitochondrial dynamics, first observed over a hundred years ago are important for the health of the cell, and defects in dynamics lead to genetic disorders. Through fusion, mitochondria can overcome the dangerous consequences of genetic malfunction. The process of mitochondrial fusion involves a variety of proteins that assist the cell throughout the series of events that form this process.

<span class="mw-page-title-main">Phomoxanthone</span> Class of chemical compounds

The phomoxanthones are a loosely defined class of natural products. The two founding members of this class are phomoxanthone A and phomoxanthone B. Other compounds were later also classified as phomoxanthones, although a unifying nomenclature has not yet been established. The structure of all phomoxanthones is derived from a dimer of two covalently linked tetrahydroxanthones, and they differ mainly in the position of this link as well as in the acetylation status of their hydroxy groups. The phomoxanthones are structurally closely related to other tetrahydroxanthone dimers such as the secalonic acids and the eumitrins. While most phomoxanthones were discovered in fungi of the genus Phomopsis, most notably in the species Phomopsis longicolla, some have also been found in Penicillium sp.

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

The mycotoxin phomoxanthone B, or PXB for short, is a toxic natural product. It is a less toxic isomer of phomoxanthone A and one of the two founding members of the class of phomoxanthone compounds. The phomoxanthones are named after the fungus Phomopsis, from which they were first isolated, and after their xanthonoid structure. Chemically, they are dimers of two tetrahydroxanthones that are covalently linked to each other. PXB itself is a homodimer of two identical diacetylated tetrahydroxanthones. The position of the link between the two tetrahydroxanthones is the only structural difference between PXB and its isomers PXA and dicerandrol C: In PXA, the two xanthonoid monomers are symmetrically linked at C-4,4’, while in PXB, they are asymmetrically linked at C-2,4’, and in dicerandrol C, they are symmetrically linked at C-2,2’.

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

Dicerandrol C is a natural product. It is a less toxic isomer of phomoxanthone A (PXA) and phomoxanthone B (PXB), all three of which are members of the class of phomoxanthone compounds. The phomoxanthones are named after the fungus Phomopsis, from which they were first isolated, and after their xanthonoid structure. Chemically, they are dimers of two tetrahydroxanthones that are covalently linked to each other. Dicerandrol C itself is a homodimer of two identical diacetylated tetrahydroxanthones. The position of the link between the two tetrahydroxanthones is the only structural difference between dicerandrol C and its isomers PXA and PXB: In PXA, the two xanthonoid monomers are symmetrically linked at C-4,4’, while in PXB, they are asymmetrically linked at C-2,4’, and in dicerandrol C, they are symmetrically linked at C-2,2’.

<span class="mw-page-title-main">Mitochondrial dynamics protein MID49</span> Protein-coding gene in the species Homo sapiens

Mitochondrial elongation factor 2 is a protein that in humans is encoded by the MIEF2 gene.

<span class="mw-page-title-main">GFER Syndrome</span> Rare disease

GFER Syndrome is a rare mitochondrial disease. GFER was first reported in 2009 and since exome sequencing became more available, few more cases were discovered. In all known cases, the disease progresses with conditions that include: congenital cataracts, loss of motor abilities, development delay, degeneration of organs, sometimes hearing loss, etc.

<span class="mw-page-title-main">SLC25A46</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 25 member 46 is a protein that in humans is encoded by the SLC25A46 gene. This protein is a member of the SLC25 mitochondrial solute carrier family. It is a transmembrane protein located in the mitochondrial outer membrane involved in lipid transfer from the endoplasmic reticulum (ER) to mitochondria. Mutations in this gene result in neuropathy and optic atrophy.

References

  1. 1 2 3 4 5 6 7 8 9 10 Böhler, Philip; Stuhldreier, Fabian; Anand, Ruchika; Kondadi, Arun Kumar; Schlütermann, David; Berleth, Niklas; Deitersen, Jana; Wallot-Hieke, Nora; Wu, Wenxian; Frank, Marian; Niemann, Hendrik; Wesbuer, Elisabeth; Barbian, Andreas; Luyten, Tomas; Parys, Jan B; Weidtkamp-Peters, Stefanie; Borchardt, Andrea; Reichert, Andreas S; Peña-Blanco, Aida; García-Sáez, Ana J; Itskanov, Samuel; Van Der Bliek, Alexander M; Proksch, Peter; Wesselborg, Sebastian; Stork, Björn (2018). "The mycotoxin phomoxanthone a disturbs the form and function of the inner mitochondrial membrane". Cell Death & Disease. 9 (3): 286. doi:10.1038/s41419-018-0312-8. PMC   5833434 . PMID   29459714.
  2. 1 2 3 4 5 Isaka, Masahiko; Jaturapat, Amonlaya; Rukseree, Kamolchanok; Danwisetkanjana, Kannawat; Tanticharoen, Morakot; Thebtaranonth, Yodhathai (2001). "Phomoxanthones A and B, Novel Xanthone Dimers from the Endophytic Fungus Phomopsis Species". Journal of Natural Products . 64 (8): 1015–8. doi:10.1021/np010006h. PMID   11520217. S2CID   32242541.
  3. 1 2 3 4 5 Rönsberg, David; Debbab, Abdessamad; Mándi, Attila; Vasylyeva, Vera; Böhler, Philip; Stork, Björn; Engelke, Laura; Hamacher, Alexandra; Sawadogo, Richard; Diederich, Marc; Wray, Victor; Lin, Wenhan; Kassack, Matthias U; Janiak, Christoph; Scheu, Stefanie; Wesselborg, Sebastian; Kurtán, Tibor; Aly, Amal H; Proksch, Peter (2013). "Pro-Apoptotic and Immunostimulatory Tetrahydroxanthone Dimers from the Endophytic Fungus Phomopsis longicolla". Journal of Organic Chemistry . 78 (24): 12409–25. doi:10.1021/jo402066b. PMID   24295452.
  4. ↑ Qin, Tian; Iwata, Takayuki; Ransom, Tanya T; Beutler, John A; Porco, John A (2015). "Syntheses of Dimeric Tetrahydroxanthones with Varied Linkages: Investigation of "Shapeshifting" Properties". Journal of the American Chemical Society . 137 (48): 15225–33. doi:10.1021/jacs.5b09825. PMC   4863954 . PMID   26544765.
  5. ↑ Xing, X.K; Chen, J; Xu, M.J; Lin, W.H; Guo, S.X (2011). "Fungal endophytes associated with Sonneratia (Sonneratiaceae) mangrove plants on the south coast of China". Forest Pathology . 41 (4): 334. doi:10.1111/j.1439-0329.2010.00683.x.
  6. ↑ Hobbs, Thomas W; Schmitthenner, A. F; Kuter, Geoffrey A (1985). "A New Phomopsis Species from Soybean". Mycologia . 77 (4): 535. doi:10.2307/3793352. JSTOR   3793352.
  7. ↑ Li, Shuxian; Darwish, Omar; Alkharouf, Nadim W; Musungu, Bryan; Matthews, Benjamin F (2017). "Analysis of the genome sequence of Phomopsis longicolla: A fungal pathogen causing Phomopsis seed decay in soybean". BMC Genomics . 18 (1): 688. doi: 10.1186/s12864-017-4075-x . PMC   5584002 . PMID   28870170.
  8. ↑ Elsässer, Brigitta; Krohn, Karsten; Flörke, Ulrich; Root, Natalia; Aust, Hans-Jürgen; Draeger, Siegfried; Schulz, Barbara; Antus, Sándor; Kurtán, Tibor (2005). "X-ray Structure Determination, Absolute Configuration and Biological Activity of Phomoxanthone A". European Journal of Organic Chemistry . 2005 (21): 4563. doi:10.1002/ejoc.200500265.
  9. ↑ Frank, M; Niemann, H; Böhler, P; Stork, B; Wesselborg, S; Lin, W; Proksch, P (2015). "Phomoxanthone A--From Mangrove Forests to Anticancer Therapy". Current Medicinal Chemistry . 22 (30): 3523–32. doi:10.2174/0929867322666150716115300. PMID   26179997.
  10. ↑ Martin, William F; Garg, Sriram; Zimorski, Verena (2015). "Endosymbiotic theories for eukaryote origin". Philosophical Transactions of the Royal Society B: Biological Sciences . 370 (1678): 20140330. doi:10.1098/rstb.2014.0330. PMC   4571569 . PMID   26323761.
  11. ↑ Mileykovskaya, E; Dowhan, W (2009). "Cardiolipin Membrane Domains in Prokaryotes and Eukaryotes". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1788 (10): 2084–2091. doi:10.1016/j.bbamem.2009.04.003. PMC   2757463 . PMID   19371718.
  12. ↑ Van Der Bliek, A. M; Shen, Q; Kawajiri, S (2013). "Mechanisms of Mitochondrial Fission and Fusion". Cold Spring Harbor Perspectives in Biology . 5 (6): a011072. doi:10.1101/cshperspect.a011072. PMC   3660830 . PMID   23732471.
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