Bioretrosynthesis is a technique for synthesizing

organic chemical In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The st ...

s from inexpensive precursors and evolved

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s.
The technique builds on the retro-evolution hypothesis proposed in 1945 by geneticist

Norman Horowitz Norman Harold Horowitz (March 19, 1915 – June 1, 2005) was a geneticist at Caltech who achieved national fame as the scientist who devised experiments to determine whether life might exist on Mars. His experiments were carried out by the Vikin ...

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. For each precursor, the enzyme is evolved using induced mutations and

natural selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Charle ...

to produce a more productive version. The evolutionary process can be repeated over multiple generations until acceptable productivity is achieved. The process does not require high temperature, high pressure, the use of exotic

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

s or other elements that can increase costs. 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.

Didanosine

In 2014 the technique was used to produce the

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

drug didanosine: 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. The

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

that creates the enzyme was then "copied", adding random

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

s to each copy using

ribokinase In enzymology, a ribokinase () is an enzyme that catalyzes the chemical reaction :ATP + -ribose ⇌ ADP + -ribose 5-phosphate Thus, the two substrates of this enzyme are ATP and -ribose, whereas its two products are ADP and -ribose 5-phosph ...

engineering. The mutant genes were inserted into ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

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

References

External links

* {{chemical synthesis Chemical synthesis Genetic engineering Organic chemistry