3 ms·

The impressive thing about this is not the size -- making long peptide chains is easy -- it's the fact that this can be consistently folded into a useful struct

• _yb2s 2y ago
  Essentially 100% of it is functional! What you have here is a repetitive pattern of small simple protein domains, all connected together in a long "assembly line." As this is a polyketide synthase (PKS), it is a long assembly line of "modules" that are like individual fatty acid synthase complexes, made from a bunch of small domains that each do a single chemical step as part of a massively complex many-step chemical synthesis. So we're talking about a huge number of individual domains (140 of them) that each fold separately into a "blob" from this massive peptide, and then they have "linkers" which are not folded, but connect from one domain to the next, and are just long enough so they are each in the proper spot.
  • biofox 2y ago
    Fascinating! This is a completely new area to me. Can I ask what the advantage of this over "classical" biosynthesis pathways, where precursors float from one enzyme to another?
    • _yb2s 2y ago
      They have different strengths and weaknesses, and natural product pathways often naturally combine steps from both. I'm not sure how technical to make this, but from your username and comments I will assume I can make it pretty technical. Some of the advantages of PKSs (both for bioengineering, and for the microbes using them to make molecules): -Rapid evolution and/or engineering modifications: the predictable relationship between the DNA and resulting chemical structure means you can reliably change the DNA and know what will happen to the chemical structure. This reconfigurability is also useful for microbes- they can duplicate or delete regions of DNA to create new variants, such as new antibiotics when their competition develops resistance. -You can change a part of the molecule without having to have anything unique in that region that an enzyme will recognize to act in the right spot- because a specific region of the assembly line relates to a specific part of the final product. -Avoids a lot of the issues of enzyme promiscuity in engineered pathways, to make something really different from what exists naturally while reusing natural domains. Although PKS domains can be selective, can be promiscuous and still work (and many natural ones are), because the physical configuration of the PKS will only present them with the right substrate at the right time -Overcomes lots of issues with reactant concentrations, and thermodynamics. Because the substrate is physically tethered, it is channeled right to the reaction site, and then snatched away afterwards- effectively simulating a very high reactant concentration, and a low product concentration, allowing reactions to occur in the right direction, that wouldn't otherwise be favorable/spontaneous -Precise control over stereochemistry There are also NRPSs, which are similar to PKSs, but make peptides instead of polyketides...
      • biofox 2y ago
        Thank you!
  • Terr_ 2y ago
    I'm imagining something a bit like a paint roller with a bunch of patterns around the rim, or an IBM Selectric ball, where the raw materials keep rolling around on the outside until the finished product hits a special protrusion that causes it to fall away.
    • _yb2s 2y ago
      That is a fairly accurate concept of how a single PKS "module" works- which extends a growing carbon chain by 2 carbons, plus whatever side groups or modifications it makes to those 2 carbons. Then the entire thing is passed to the next module to repeat, and so on down a long linear "assembly line" that you can think of like the conveyor belt that moves a car down a factory one station at a time.