The Liu Hongwei team of the Institute of Microbiology clarified the anti-Alzheimer's Hericium erinaceus diterpene biosynthesis network, and constructed "non-natural" active diterpene engineering bacteria

The guanane-type diterpene compounds have a unique 5-6-7 tricyclic skeleton.
Such substances have a wide range of biological activities, including antiviral, anti-inflammatory, and tumor cytotoxic activities.
Among them, the most interesting is The neurotrophic effect of these substances
.

Ornithane diterpenes are only found in a few genera of large fungi in nature, including Hericium Hericium, Cyathus Cyathus, Sarcodon and so on
.

The erinacine A found in Hericium erinaceus has been shown to inhibit ROS-mediated neuroinflammation, activate signal pathways for nerve survival, promote the synthesis of nerve growth factor and the growth of nerve cell synapses
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The guanane-type diterpene is expected to be developed as a new type of medicine for the treatment of neurodegenerative diseases
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However, the acquisition of guanane diterpene hinders the in-depth evaluation of druggability for this type of molecule, and the development of synthetic biology provides the possibility for its large-scale preparation
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The research team of Hongwei Liu from the Institute of Microbiology, Chinese Academy of Sciences has long been committed to the discovery, active mechanism and biosynthesis of the active ornithane diterpene.
The relevant research results have been published in Angew.
Chem.
Int.
Ed.
, J.
Biol.
Chem.
, Eur.
J .
Med.
Chem.
, J.
Antibio.
, Food Chem and other publications
.

On the basis of revealing the function of the guanane diterpene biosynthesis gene cluster and the guanane diterpene cyclase EriG, this paper realized the reconstruction of the guanane diterpene biosynthetic pathway in Saccharomyces cerevisiae, and completed 22 different structures.
Construction of guanane diterpene-producing strains with a yield of up to 112.
1 mg/L; using the comparative analysis of homologous gene clusters as a clue, the functions of three extra-cluster related genes (eriM, eriO and eriP) were discovered and clarified; It is revealed that the formation of allyl aldehyde is catalyzed by the FAD-dependent oxidase EriM.
The formation of allyl aldehyde triggers the tandem Michael addition-elimination reaction to form the molecule erinacine A with significant neurotrophic activity
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Reductase EriB then applied to the spontaneous reaction to form an intermediate reduction product erinacine B C erinacine
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At the same time, based on the heterogeneity of the substrates of glycosyltransferase EriJ, dehydrogenase EriH and FAD-dependent oxidase EriM, strains that produce new structural "non-natural" analogs were designed and constructed
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The new structural substances also exhibit neurotrophic activity on PC12 cells.
The discovery of these new structural substances will also provide a material basis for structure-activity relationship analysis and provide a leading molecule for the development of new drugs
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The above research results were published in Acta Pharmaceutica Sinica B, a TOP journal in Pharmacy District I in September 2021.
Ma Ke (now a postdoctoral fellow at Peking University), a doctoral student at the State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, is the first author of the paper , Researcher Liu Hongwei is the corresponding author of the paper
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The research was supported by the National Natural Science Foundation of China and the key research and development projects of the Ministry of Science and Technology
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Article information: Acta Pharmaceutica Sinica B 2021;11(9):2945e2956 Original link: https://doi.
org/10.
1016/j.
apsb.
2021.
04.
014