Genome Mining and Assembly-Line Biosynthesis of the UCS1025A Pyrrolizidinone Family of Fungal Alkaloids

被引：48

作者：

Li, Li ^{[1
,2
,3
]}

Tang, Man-Cheng ^{[3
]}

Tang, Shoubin ^{[5
]}

Gao, Shushan ^{[3
]}

Soliman, Sameh ^{[3
,7
]}

Hang, Leibniz ^{[4
]}

Xu, Wei ^{[3
]}

Ye, Tao ^{[5
]}

Watanabe, Kenji ^{[6
]}

Tang, Yi ^{[3
,4
]}

机构：

[1] Fujian Normal Univ, Engn Res Ctr Ind Microbiol, Minist Educ, Fuzhou 350117, Fujian, Peoples R China

[2] Fujian Normal Univ, Coll Life Sci, Fuzhou 350117, Fujian, Peoples R China

[3] Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[5] Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, State Key Lab Chem Oncogen, Shenzhen 518055, Peoples R China

[6] Univ Shizuoka, Dept Pharmaceut Sci, Shizuoka 4228526, Japan

[7] Univ Sharjah, Dept Med Chem, Coll Pharm, Sharjah 27272, U Arab Emirates

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2018年 / 140卷 / 06期

关键词：

MYCELIOPHTHORA-THERMOPHILA; ANTIBIOTIC CJ-16,264; ENGINEERED YEAST; NATURAL-PRODUCTS; PATHWAY; ACID; DISCOVERY; ANALOGS;

D O I：

10.1021/jacs.8b00056

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

UCS1025A is a fungal polyketide/alkaloid that displays strong inhibition of telomerase. The structures of UCS1025A and related natural products are featured by a tricyclic furopyrrolizidine connected to a trans-decalin fragment. We mined the genome of a thermophilic fungus and activated the ucs gene cluster to produce UCS1025A at a high titer. Genetic and biochemical analysis revealed a PKS-NRPS assembly line that activates 2S,3S-methylproline derived from L-isoleucine, followed by Knoevenagel condensation to construct the pyrrolizidine moiety. Oxidation of the 3S methyl group to a carboxylate leads to an oxa-Michael cyclization and furnishes the furopyrrolizidine. Our work reveals a new strategy used by nature to construct heterocyclic alkaloid-like ring systems using assembly line logic.

引用

页码：2067 / 2071

页数：5

共 31 条

[1] UCS1025A and B, new antitumor antibiotics from the fungus Acremonium species [J].

Agatsuma, T ;

Akama, T ;

Nara, S ;

Matsumiya, S ;

Nakai, R ;

Ogawa, H ;

Otaki, S ;

Ikeda, S ;

Saitoh, Y ;

Kanda, Y .

ORGANIC LETTERS, 2002, 4 (25) :4387-4390

[2] Molecular Diversity Sculpted by Fungal PKS-NRPS Hybrids [J].

Boettger, Daniela ;

Hertweck, Christian .

CHEMBIOCHEM, 2013, 14 (01) :28-42

[3] Quinolactacins revisited: from lactams to imide and beyond [J].

Clark, B ;

Capon, RJ ;

Lacey, E ;

Tennant, S ;

Gill, JH .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2006, 4 (08) :1512-1519

[4] Efficient synthesis and resolution of pyrrolizidines [J].

de Figueiredo, Renata Marcia ;

Froehlich, Roland ;

Christmann, Mathias .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2007, 46 (16) :2883-2886

[5] Characterization of a Unique Pathway for 4-Cresol Catabolism Initiated by Phosphorylation in Corynebacterium glutamicum [J].

Du, Lei ;

Ma, Li ;

Qi, Feifei ;

Zheng, Xianliang ;

Jiang, Chengying ;

Li, Ailei ;

Wan, Xiaobo ;

Liu, Shuang-Jiang ;

Li, Shengying .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (12) :6583-6594

[6]

Hartmann T, 2000, TOP CURR CHEM, V209, P207

[7] SYNTHESIS OF HOMOCHIRAL 3-SUBSTITUTED GLUTAMIC ACIDS AND PROLINES FROM PYROGLUTAMIC ACID [J].

HERDEIS, C ;

HUBMANN, HP ;

LOTTER, H .

TETRAHEDRON-ASYMMETRY, 1994, 5 (03) :351-354

[8] Comparative Diels-Alder reactivities within a family of valence bond isomers:: A biomimetic total synthesis of (±)-UCS1025A [J].

Hoye, TR ;

Dvornikovs, V .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (08) :2550-2551

[9] EcdGHK Are Three Tailoring Iron Oxygenases for Amino Acid Building Blocks of the Echinocandin Scaffold [J].

Jiang, Wei ;

Cacho, Ralph A. ;

Chiou, Grace ;

Garg, Neil K. ;

Tang, Yi ;

Walsh, Christopher T. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135 (11) :4457-4466

[10] Total synthesis of UCS1025A [J].

Lambert, TH ;

Danishefsky, SJ .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (02) :426-427

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