Applying Biocatalysis: A Technical Forum - Pharmaceutical Technology

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Applying Biocatalysis: A Technical Forum
Scientists from DSM and Kaneka discuss various techniques in this roundtable moderated by Patricia Van Arnum.


Pharmaceutical Technology


Chiral amines

Chiral amines are the remaining frontier of chiral synthesis. About 70% of central-nervous-system drugs possess amine moieties because neuronal receptors are usually triggered by amines. To date, however, no single technology stands out as being the best to make chiral amines at commercial scale. Catalytic hydrogenation has not been successful so far because of its high-pressure requirements, and optical resolution has not been universally applicable. Enzymatic synthesis using a transaminase is certainly a promising concept, although a long-standing issue has been its poor conversion rate. The transamination reaction is reversible, which makes it quite difficult to isolate the desired amines from the complex reaction mixture, including the three other chemical species: the substrate ketone, the amino donor, and the resultant ketone.


Figure 5: Multienzyme harmonic systems of transaminase. (FIGURE COURTESY OF KANEKA)
Kaneka has developed a practical transaminase system by creating a transaminase-containing E. coli transfectant and introducing a special module that efficiently drives the system (see Figure 5). The system produces chiral amines in high yield and high enantiopurity from the corresponding ketones. The key is the special module, which shifts the equilibrium to the desired amines (8–10). This whole system accommodates a variety of ketone substrates, including aliphatic, aromatic, and cyclic ketones, and produces both the R and S isomers through the selection of robust transaminase libraries.

Conclusion

By implementing a systems-biotechnology approach, Kaneka has introduced industrialized processes to manufacture nonnatural L-amino acids using reductive amination or deracemization technology. Depending on the availability of the substrates, the best arrangements can be selected. These harmonic systems are effective in surpassing other methodologies, particularly in the case of L-t-leucine. In addition, the company's chiral-amine transaminase systems produces a wide range of amines, aromatic, aliphatic, and cyclic compounds for projects in development and at commercial scale. The industrialization of these compounds is supported by large-scale capabilities in genetically modified organisms, synthetic technology, and process-engineering technology, including amino-acid–peptide purification systems.

Section references

1. H. Nanba et al., "Bioreactor Systems for the Production of Optically Active Amino Acids and Alcohols," Org. Process Res. Dev. 11 (3), 503–508 (2007).

2. J. Hasegawa et al., Large-Scale Asymmetric Catalysis (Wiley-VCH, Weinheim, Germany, in press in 2009).

3. The Commendation for Science and Technology in the Development Category awarded by Japan's Minister of Education, Culture, Sports, Science and Technology, Tokyo, May 2008.

4. The Japan Chemical Industry Association Technology Award Grand Prize, Tokyo, June 2008.

5. H. Nanba et al., "Purification and Characterization of an Alpha-Haloketone-Resistant Formate Dehydrogenase from Thiobacillus sp. strain KNK65MA and Cloning of the Gene," Biosci. Biotechnol. Biochem. 67 (10), 2145–2153 (2003).

6. H. Kanamaru et al., "D-Amino Acid Oxidase and Method for Production of L-Amino Acid, 2-Oxo Acid or Cylic Imine," EP 1918375, May 2008.

7. T. Ohishi et al., "Integrated Solutions of Unnatural α-Amino Acids" in Asymmetric Synthesis and Application of α-Amino Acids, V.A. Soloshonok and K. Izawa, Eds. (Oxford University Press, Oxford, UK, 2009), p. 337.

8. A. Iwasaki et al., "Microbial Synthesis of Chiral Amines by (R)-Specific Transamination with Arthrobacter sp KNK168," Appl. Microbiol. Biotechnol. 69 (5), 499–505 (2006).

9. A. Iwasaki et al., "Microbial Synthesis of (R)- and (S)-3,4-Dimethoxyamphetamines through Stereoslective Transamination, Biotechnol. Lett. 25 (21), 1843–1846 (2003).

10. S. Kawano et al., "Method for Production of Optically Active Amine Compound, Recombinant Vector and Transformant Carrying the Vector," EP 2022852 , Feb. 2009.


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