Team:Wageningen UR/Secondary metabolites

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<h1>Secondary metabolites</h1>
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<h2>An infinity field</h2>
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        <ul>
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            <li id="li_tab1" onclick="tab('tab1')"><a>Introduction</a></li>
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            <li id="li_tab2" onclick="tab('tab2')" class="active"><a>Secondary metabolites</a></li>
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            <li id="li_tab3" onclick="tab('tab3')"><a>Toolbox</a></li>
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            <li id="li_tab4" onclick="tab('tab4')"><a>Host engineering</a></li>
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            <li id="li_tab5" onclick="tab('tab5')"><a>Summary</a></li>
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         <li class="fillfirst"><a href="https://2013.igem.org/Team:Wageningen_UR/Why_Aspergillus_nigem">Why Aspergillus nigem?</a></li>
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         <li class="firstbgsm fill"><a href="https://2013.igem.org/Team:Wageningen_UR/Why_Aspergillus_nigem">Why <i>Aspergillus nigem</i>?</a></li>
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         <li class="current">Aspergillus introduction</li>
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         <li class="smbgsm current">Secondary metabolites</li>
         <li><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin">Lovastatin</a></li>
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         <li><a href="https://2013.igem.org/Team:Wageningen_UR/Applications">Applications</a></li>
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         <li class="last"><a href="https://2013.igem.org/Team:Wageningen_UR/Summary">Summary</a></li>
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        <li class="first fill"><a href="https://2013.igem.org/Team:Wageningen_UR/Why_Aspergillus_nigem">Why <i>Aspergillus nigem</i>?</a></li>
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        <li class="smbg current">Secondary metabolites</li>
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        <li class="bgbg"><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin">Lovastatin</a></li>
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        <li class="bgsm"><a href="https://2013.igem.org/Team:Wageningen_UR/Modeling">Modeling</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Biosensors">Biosensors</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Infrastructure">Infrastructure</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Chromoproteins">Chromoproteins</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Host_engineering">Host engineering</a></li>
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        <li class="last"><a href="https://2013.igem.org/Team:Wageningen_UR/Summary">Summary</a></li>
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        <li class="first fill"><a href="https://2013.igem.org/Team:Wageningen_UR/Why_Aspergillus_nigem">Why <i>Aspergillus nigem</i>?</a></li>
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        <li class="smbgsm current">Secondary metabolites</li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin">Lovastatin</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Modeling">Modeling</a></li>
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        <li class="smbg"><a href="https://2013.igem.org/Team:Wageningen_UR/Biosensors">Biosensors</a></li>
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        <li class="bgbg"><a href="https://2013.igem.org/Team:Wageningen_UR/Infrastructure">Infrastructure</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Host_engineering">Host engineering</a></li>
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        <li class="last"><a href="https://2013.igem.org/Team:Wageningen_UR/Summary">Summary</a></li>
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        <li class="first fill"><a href="https://2013.igem.org/Team:Wageningen_UR/Why_Aspergillus_nigem">Why <i>Aspergillus nigem</i>?</a></li>
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        <li class="smbgsm current">Secondary metabolites</li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin">Lovastatin</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Modeling">Modeling</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Biosensors">Biosensors</a></li>
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        <li class="smbgsm"><a href="https://2013.igem.org/Team:Wageningen_UR/Host_engineering">Host engineering</a></li>
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        <li class="last"><a href="https://2013.igem.org/Team:Wageningen_UR/Summary">Summary</a></li>
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        <li class="first fill"><a href="https://2013.igem.org/Team:Wageningen_UR/Why_Aspergillus_nigem">Why <i>Aspergillus nigem</i>?</a></li>
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        <li class="smbgsm current">Secondary metabolites</li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin">Lovastatin</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Modeling">Modeling</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Biosensors">Biosensors</a></li>
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        <li><a href="https://2013.igem.org/Team:Wageningen_UR/Infrastructure">Infrastructure</a></li>
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        <li class="last bg"><a href="https://2013.igem.org/Team:Wageningen_UR/Summary">Summary</a></li>
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    <h1>Aspergillus introduction</h1>
 
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== Exploiting the therapeutic potential of secondary metabolites from fungi ==
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== Natural Products ==
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      <p>Secondary metabolites are the products of metabolism not essential for normal growth, development or reproduction of an organism. They meet the secondary requirements of the producing organisms, empower them to survive interspecies competition, provide defensive mechanisms and facilitate reproductive processes. Well known sources of secondary metabolites are plants, bacteria, fungi and marine organisms such as sponges, tunicates, corals and snails.</p>
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    <p>Biotechnology has brought about a revolution in drug manufacturing since its inception. Many life-saving drugs have spun out of biotech companies over the past few decades. However, there is still a vast body of unexplored compounds such as the fungal secondary metabolites that have the potential to prolong human lifespan. The production of these secondary metabolites in most cases involves a large backbone enzyme that contains multiple catalytic domains. One of the goals is to establish a modular system of domain shuffling to generate a plethora of novel enzymes with new and improved functionalities. The possibilities are endless as there is a myriad of different domains from many fungi that can be added, removed, reordered or exchanged in this synthetic biology approach. The production of lovastatin, a drug used in lowering LDL cholesterol for patients suffering from cardiovascular disease, has been chosen as a proof of principle. Currently, it is produced in the fungi Aspergillus terreus, which also produces less desirable toxins. The aim is to transfer the entire lovastatin metabolic pathway from A. terreus into a GRAS organism like Aspergillus niger, which is closely related. A. niger is amenable to genetic engineering, has a high protein secretion capacity and produces high amounts of organic acids. One of the main enzymes involved in the production of lovastatin is the 277kDa LovB enzyme, which contains 7 different catalytic domains. Prior studies on this pathway provide a good insight into the catalytic mechanisms of these individual domains. The individual domains have been mapped by homology modeling and are found to be well defined as well as often in a sequential order, which makes the modular approach more feasible.</p>
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<p>In addition to the modularity approach, a toolkit for A. niger is also being created, consisting of an ATP and a pH biosensor that can be targeted to specific compartments with the use of signal peptides, actin and septa GFP fusions to visualize the cytoskeleton and the junctions between adjacent cells, and chromoproteins that can serve as secondary selection markers. These tools allow one to obtain insight in cellular economy, physiology and architecture, which can be used to optimize the production processes in A. niger.</p>
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== Well-known Medical Uses==
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    <p>Secondary metabolites are well-known as antimicrobials. Currently, many secondary metabolites have been proven to be effective as antibacterial or antifungal agents, anticancer drugs, cholesterol-lowering agents, immunosuppressants, antiparasitic agents, herbicides, diagnostics, and even tools for other researches.</p>
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<h3>Cholesterol-lowering agents</h3>
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    <p>Compactin was first reported as a cholesterol-lowering drug by Endo in 1985. The fungal fermentation products lovastatin produced by <i>Aspergillus terreus</i> and <i>Monascus ruber</i> was found to be highly effective in reducing serum cholesterol in humans, especially cholesterol LDL levels. Lovastatin is a potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase and blocks formation of all products of the mammalian polyisoprenoid pathway, thus reducing the risk of cardiovascular disease. </p>
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== Extensive Applications ==
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  <h3>Exploiting the therapeutic potential of fungi</h3>
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<p>In addition to their known roles in combating disease, secondary metabolites reveal surprising additional activities, which may be possible solutions to other treatment lacking diseases. Many antibiotics, bacterial pigments and plant terpenoids, are also found to have anti-HIV, antitumor, anti-ageing, immunosuppressant, antiprotozoal and antihelminth activities, thus exhibiting multifarious applications in the sphere of medicine.</p>
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<p>Unraveling the novel applications of known secondary metabolites and exploiting a myriad of sources as microbes, plants and higher animals for screening new secondary metabolites are paving the way to treat “untreatable diseases”, and help reduce mortality rates. The study of those useful activities of secondary metabolites against life-threatening diseases may catalyze further efforts to apply them against other forms of human disease.</p>
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Latest revision as of 22:11, 4 October 2013

Secondary metabolites

An infinity field

Natural Products

Secondary metabolites are the products of metabolism not essential for normal growth, development or reproduction of an organism. They meet the secondary requirements of the producing organisms, empower them to survive interspecies competition, provide defensive mechanisms and facilitate reproductive processes. Well known sources of secondary metabolites are plants, bacteria, fungi and marine organisms such as sponges, tunicates, corals and snails.

Well-known Medical Uses

Secondary metabolites are well-known as antimicrobials. Currently, many secondary metabolites have been proven to be effective as antibacterial or antifungal agents, anticancer drugs, cholesterol-lowering agents, immunosuppressants, antiparasitic agents, herbicides, diagnostics, and even tools for other researches.

Cholesterol-lowering agents

Compactin was first reported as a cholesterol-lowering drug by Endo in 1985. The fungal fermentation products lovastatin produced by Aspergillus terreus and Monascus ruber was found to be highly effective in reducing serum cholesterol in humans, especially cholesterol LDL levels. Lovastatin is a potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase and blocks formation of all products of the mammalian polyisoprenoid pathway, thus reducing the risk of cardiovascular disease.

Extensive Applications

Exploiting the therapeutic potential of fungi

In addition to their known roles in combating disease, secondary metabolites reveal surprising additional activities, which may be possible solutions to other treatment lacking diseases. Many antibiotics, bacterial pigments and plant terpenoids, are also found to have anti-HIV, antitumor, anti-ageing, immunosuppressant, antiprotozoal and antihelminth activities, thus exhibiting multifarious applications in the sphere of medicine.

Unraveling the novel applications of known secondary metabolites and exploiting a myriad of sources as microbes, plants and higher animals for screening new secondary metabolites are paving the way to treat “untreatable diseases”, and help reduce mortality rates. The study of those useful activities of secondary metabolites against life-threatening diseases may catalyze further efforts to apply them against other forms of human disease.

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