8QHE

Crystal structure IR-09

Summary for 8QHE

• Entry DOI: 10.2210/pdb8qhe/pdb
• Descriptor: 6-phosphogluconate dehydrogenase NADP-binding domain-containing protein, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ~{N}-methylcyclohexanamine, ... (5 entities in total)
• Functional Keywords: reductase, biosynthetic protein
• Biological source: Aspergillus lentulus
• Total number of polymer chains: 1
• Total formula weight: 33068.60

Authors

Levy, C.W. (deposition date: 2023-09-07, release date: 2023-10-11, Last modification date: 2023-10-25)

Primary citation

Casamajo, A.R.,Yu, Y.,Schnepel, C.,Morrill, C.,Barker, R.,Levy, C.W.,Finnigan, J.,Spelling, V.,Westerlund, K.,Petchey, M.,Sheppard, R.J.,Lewis, R.J.,Falcioni, F.,Hayes, M.A.,Turner, N.J.
Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters.
J.Am.Chem.Soc., 145:22041-22046, 2023

PubMed Abstract: Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling the construction of structure-activity-property-toxicology relationships. Complex chiral molecules containing multiple stereocenters are an important component in compound library expansion but can be difficult to access by traditional organic synthesis. Herein, we report a biocatalytic process to access a specific diastereomer of a chiral amine building block used in drug discovery. A reductive aminase (RedAm) was engineered following a structure-guided mutagenesis strategy to produce the desired isomer. The engineered RedAm (IR-09 W204R) was able to generate the (,,)-isomer in 45% conversion and 95% ee from the racemic ketone . Subsequent palladium-catalyzed deallylation of yielded the target primary amine in a 73% yield. This engineered biocatalyst was used at preparative scale and represents a potential starting point for further engineering and process development.

PubMed: 37782882
DOI: 10.1021/jacs.3c07010

Experimental method

X-RAY DIFFRACTION (1.6 Å)