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Bioretrosynthesis

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Title: Bioretrosynthesis  
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Subject: Chemical synthesis, Genetic engineering, Biomimetic synthesis, Direct process, Biosynthesis
Collection: Chemical Synthesis, Genetic Engineering, Organic Chemistry
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Bioretrosynthesis

Bioretrosynthesis is a technique for synthesizing enzymes.[1] The technique builds on the retro-evolution hypothesis proposed in 1945 by geneticist Norman Horowitz.[2]

Contents

  • Technique 1
  • Didanosine 2
  • References 3
  • External links 4

Technique

The technique works backwards from the target to identify a precursor molecule and an enzyme that converts it into the target, and then a second precursor that can produce the first and so on until a simple, inexpensive molecule becomes the beginning of the series.[1]

For each precursor, the enzyme is evolved using induced mutations and natural selection to produce a more productive version. The evolutionary process can be repeated over multiple generations until acceptable productivity is achieved.[1]

The process does not require high temperature, high pressure, the use of exotic catalysts or other elements that can increase costs.[1]

The enzyme "optimizations" that increase the production of one precursor from another are cumulative in that the same precursor productivity improvements can potentially be leveraged across multiple target molecules.[1]

Didanosine

In 2014 the technique was used to produce the HIV drug didanosine.[2]

A simpler molecule was identified that can be converted into didanosine when subjected to a specific chemical transformation in the presence of a specific enzyme.[2]

The gene that creates the enzyme was then "copied", adding random mutations to each copy using ribokinase engineering.[2]

The mutant genes were inserted into Escherichia coli bacteria and used to produce (now-mutant) enzymes. The enzymes were then mixed with the precursor and the mutant enzymes that produced the greatest amount of didanosine were retained and replicated. One mutant stimulated a 50x increase in didanosine production.[2]

The first step was repeated, using the first precursor in place of didanosine, finding a yet simpler precursor and an enzyme to produce it. One mutated enzyme produced a 9,500x increase in nucleoside production.[2]

A third retrogression allowed them to start with the simple and inexpensive sugar named dideoxyribose and produce didanosine in a three-step sequence.[2]

References

  1. ^ a b c d e
  2. ^ a b c d e f g

External links

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