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Tropinane alkaloids (TAs) are a class of alkaloids with the basic skeleton of tropinane composed of pyrrolecyclic and piperidine cyclopyridine, and its representative members hyoscyamine and cocaine are important natural drugs
with a long history of medicinal use and are still widely used in clinical practice.
In 1860, cocaine was isolated and purified from coca leaves, and then used as an anesthetic for ophthalmic surgery, which was the first local anesthetic discovered and used in history, and the current clinical use of caine-like local anesthetics are all modified from cocaine
.
In addition, cocaine was once one of
the recipes for famous beverages.
However, due to the addictive nature, since 1914 the use of cocaine and coca leaf
has been prohibited except for medical treatment.
In 2018, cocaine was approved by the FDA as a local anesthetic
for oral and nasal surgery due to its irreplaceable benefits.
The State Key Laboratory of Phytochemistry and Sustainable Utilization of Western Plant Resources at the Kunming Institute of Botany, Chinese Academy of Sciences, led by researcher Huang Shengxiong, has long focused on the biosynthesis of tropine alkaloids and made a series of important breakthroughs
.
In 2019, Huang Shengxiong's task force identified polyketosynthase PYKS from nightshade plants involved in the construction of hyoscyolamine tropine skeleton, and analyzed its catalytic mechanism through protein crystal structure and site-directed mutation experiments (Nat Commun, 2019, 10).
, 4036), which was the first to experimentally demonstrate that Robinson's classical tropenone chemical total synthesis is biomimetic; In 2020, the group elucidated a key enzyme gene responsible for the hyoscyamine esterification step (New Phytol, 2020, 225, 1906); In 2021, this group resolved the catalytic mechanism of the oxidoreductase HDH, which catalyzes the formation of hyoscyola aldehyde to hyoscyolamine, and achieved a complete analysis of the biosynthetic pathway of hyoscyamine (ACS Catal, 2021 , 11, 2912）； He was invited to write a review of the biosynthesis of tropine alkaloids in the past 100 years (Nat Prod Rep, 2021, 38, 1634).
This year, the group identified polyketone synthase PKS1/2 involved in cocainetropane backbone construction from coca plants and revealed the unique phenomenon of independent evolution but functional convergence of coca and nightshade polyketone synthases (Nat Commun, 2022, 13, 4994).
）
。
Recently, the group comprehensively used transcriptome analysis, molecular biology and organic chemical synthesis to solve the century problem of the construction of the long-standing cocainetropine skeleton, and realized the de novo construction
of the cocaine synthesis path in tobacco.
This study identified the oxidase CYP81AN15 and methyltransferase MT4, which are responsible for the construction of the cocainetropine backbone, and clarified the formation process of the cocainetropine backbone (Figure A): S-MPOA The unstable intermediate bud ketone is formed by oxidase CYP81AN15 oxidative cyclization, followed by methyltransferase MT4 catalyzed methylation to produce (+)-methyl bud ketone, thereby correcting long-standing but incorrect incorrectness Conjecture
that MPOA is methylated and then oxidized.
Interestingly, the oxidase CYP81AN15 in the cocaine biosynthesis pathway is responsible for catalyzing the production of the intermediate product germinone, and Robinson's one-pot synthesis of tropenone is also carried out through bud ketone as an intermediate, which once again clarifies the beauty of biomimetic synthesis of classical tropenone chemical total synthesis (Figure).
A and B).
On this basis, the researchers further characterized the substrate chirality selectivity of oxidase CYP81AN15 and methyltransferase MT4 using in vitro enzymatic assays, addressing how to change from racemic MPOA in the cocaine biosynthesis pathway Doubts about generating chiral tropine backbones (Figure A).
Finally, the researchers utilized the oxidase CYP81AN15 and methyltransferase MT4, as well as four identified functional enzymes (PMT1, PKS1, MecgoR, and CS).
The formation of minimalist biosynthetic pathways in tobacco enables de novo synthesis of cocaine, which marks the elucidation of a near-complete cocaine biosynthetic pathway (Figure C).
The above research is titled Discovery and Engineering of the Cocaine Biosynthetic Pathway and will be published in the Journal of the American Chemical Society Published as Front Cover.
Postdoctoral fellow Wang Yongjiang, Associate Professor Huang Jianping and Dr.
Tian Tian of Huang Shengxiong's special group are the co-first authors of this paper, Professor Huang Shengxiong is the corresponding author, Professor Syngenta Gu Yucheng and Professor Chen Jianghua of Xishuangbanna Tropical Botanical Garden of the Chinese Academy of Sciences provided strong support
for this research.
The above research work has been supported
by the National Key Research and Development Program of Synthetic Biology, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, the National Natural Science Foundation of China, the Center for Excellence in Molecular Plant Science, and the Department of Science and Technology of Yunnan Province.
Article link
A: Cocaine tropane skeleton synthesis pathway; B: Classical tropinone chemical total synthesis; C: Cocaine synthesis pathways constructed de novo in tobacco
