Journal
COMMUNICATIONS BIOLOGY
Volume 3, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-020-01184-w
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Funding
- National Key Research and Development Program Grant [2017YFA0504104]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
- National Natural Science Foundation of China [31500638, 31470204, 21903089]
- Guangdong Provincial Key Laboratory of Biocomputing [2016B030301007]
- Youth Innovation Promotion Association of the Chinese Academy of Sciences [2018390]
- Qingdao National Laboratory for Marine Science and Technology [QNLM2016ORP0304]
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Amine compounds biosynthesis using omega -transaminases has received considerable attention in the pharmaceutical industry. However, the application of omega -transaminases was hampered by the fundamental challenge of severe by-product inhibition. Here, we report that omega -transaminase CrmG from Actinoalloteichus cyanogriseus WH1-2216-6 is insensitive to inhibition from by-product alpha -ketoglutarate or pyruvate. Combined with structural and QM/MM studies, we establish the detailed catalytic mechanism for CrmG. Our structural and biochemical studies reveal that the roof of the active site in PMP-bound CrmG is flexible, which will facilitate the PMP or by-product to dissociate from PMP-bound CrmG. Our results also show that amino acceptor caerulomycin M (CRM M), but not alpha -ketoglutarate or pyruvate, can form strong interactions with the roof of the active site in PMP-bound CrmG. Based on our results, we propose that the flexible roof of the active site in PMP-bound CrmG may facilitate CrmG to overcome inhibition from the by-product. Xu, Tang et al. show that omega -transaminase CrmG is insensitive to the inhibition from by-products alpha -ketoglutarate or pyruvate. They find that these by-products cannot interact strongly with the flexible roof of the active site in CrmG. This study provides insights into the rational design of transaminase to eliminate by-product inhibition.
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