Professional Education

  • Bachelor of Science, Nankai University (2007)
  • Doctor of Philosophy, University of California Los Angeles (2012)
  • Bachelor of Engineering, Tianjin University (2007)

Stanford Advisors


Journal Articles

  • Discovery and Characterization of a Group of Fungal Polycyclic Polyketide Prenyltransferases JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Chooi, Y., Wang, P., Fang, J., Li, Y., Wu, K., Wang, P., Tang, Y. 2012; 134 (22): 9428-9437


    The prenyltransferase (PTase) gene vrtC was proposed to be involved in viridicatumtoxin (1) biosynthesis in Penicillium aethiopicum. Targeted gene deletion and reconstitution of recombinant VrtC activity in vitro established that VrtC is a geranyl transferase that catalyzes a regiospecific Friedel-Crafts alkylation of the naphthacenedione carboxamide intermediate 2 at carbon 6 with geranyl diphosphate. VrtC can function in the absence of divalent ions and can utilize similar naphthacenedione substrates, such as the acetyl-primed TAN-1612 (4). Genome mining using the VrtC protein sequence leads to the identification of a homologous group of PTase genes in the genomes of human and animal-associated fungi. Three enzymes encoded by this new subgroup of PTase genes from Neosartorya fischeri, Microsporum canis, and Trichophyton tonsurans were shown to be able to catalyze transfer of dimethylallyl to several tetracyclic naphthacenedione substrates in vitro. In total, seven C(5)- or C(10)-prenylated naphthacenedione compounds were generated. The regioselectivity of these new polycyclic PTases (pcPTases) was confirmed by characterization of product 9 obtained from biotransformation of 4 in Escherichia coli expressing the N. fischeri pcPTase gene. The discovery of this new subgroup of PTases extends our enzymatic tools for modifying polycyclic compounds and enables genome mining of new prenylated polyketides.

    View details for DOI 10.1021/ja3028636

    View details for Web of Science ID 000304837800068

    View details for PubMedID 22590971

  • Comparative Characterization of Fungal Anthracenone and Naphthacenedione Biosynthetic Pathways Reveals an alpha-Hydroxylation-Dependent Claisen-like Cyclization Catalyzed by a Dimanganese Thioesterase JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Li, Y., Chooi, Y., Sheng, Y., Valentine, J. S., Tang, Y. 2011; 133 (39): 15773-15785


    The linear tetracyclic TAN-1612 (1) and BMS-192548 (2) were isolated from different filamentous fungal strains and have been examined as potential neuropeptide Y and neurokinin-1 receptor antagonists, respectively. Although the biosynthesis of fungal aromatic polyketides has attracted much interest in recent years, the biosynthetic mechanism for such naphthacenedione-containing products has not been established. Using a targeted genome mining approach, we first located the ada gene cluster responsible for the biosynthesis of 1 in Aspergillus niger ATCC 1015. The connection between 1 and the ada pathway was verified through overexpression of the Zn(2)Cys(6)-type pathway-specific transcriptional regulator AdaR and subsequent gene expression analysis. The enzymes encoded in the ada gene cluster share high sequence similarities to the known apt pathway linked to the biosynthesis of anthraquinone asperthecin 3. Subsequent comparative investigation of these two highly homologous gene clusters by heterologous pathway reconstitution in Saccharomyces cerevisiae revealed a novel ?-hydroxylation-dependent Claisen cyclization cascade, which involves a flavin-dependent monooxygenase that hydroxylates the ?-carbon of an acyl carrier protein-bound polyketide and a bifunctional metallo-?-lactamase-type thioesterase (M?L-TE). The bifunctional M?L-TE catalyzes the fourth ring cyclization to afford the naphthacenedione scaffold upon ?-hydroxylation, whereas it performs hydrolytic release of an anthracenone product in the absence of ?-hydroxylation. Through in vitro biochemical characterizations and metal analyses, we verified that the apt M?L-TE is a dimanganese enzyme and requires both Mn(2+) cations for the observed activities. The M?L-TE is the first example of a thioesterase in polyketide biosynthesis that catalyzes the Claisen-like condensation without an ?/? hydrolase fold and forms no covalent bond with the substrate. These mechanistic features should be general to the biosynthesis of tetracyclic naphthacenedione compounds in fungi.

    View details for DOI 10.1021/ja206906d

    View details for Web of Science ID 000295911500082

    View details for PubMedID 21866960

  • Classification, prediction, and verification of the regioselectivity of fungal polyketide synthase product template domains. journal of biological chemistry Li, Y., Image, I. I., Xu, W., Image, I., Tang, Y., Image, I. 2010; 285 (30): 22764-22773


    The fungal iterative nonreducing polyketide synthases (NRPKSs) synthesize aromatic polyketides, many of which have important biological activities. The product template domains (PT) embedded in the multidomain NRPKSs mediate the regioselective cyclization of the highly reactive polyketide backbones and dictate the final structures of the products. Understanding the sequence-activity relationships of different PT domains is therefore an important step toward the prediction of polyketide structures from NRPKS sequences and can enable the genome mining of hundreds of cryptic NRPKSs uncovered via genome sequencing. In this work, we first performed phylogenetic analysis of PT domains from NRPKSs of known functions and showed that the PT domains can be classified into five groups, with each group corresponding to a unique product size or cyclization regioselectivity. Group V contains the formerly unverified PT domains that were identified as C6-C11 aldol cyclases. The regioselectivity of PTs from this group were verified by product-based assays using the PT domain excised from the asperthecin AptA NRPKS. When combined with dissociated PKS4 minimal PKS, or replaced the endogenous PKS4 C2-C7 PT domain in a hybrid NRPKS, AptA-PT directed the C6-C11 cyclization of the nonaketide backbone to yield a tetracyclic pyranoanthraquinone 4. Extensive NMR analysis verified that the backbone of 4 was indeed cyclized with the expected regioselectivity. The PT phylogenetic analysis was then expanded to include approximately 100 PT sequences from unverified NRPKSs. Using the assays developed for AptA-PT, the regioselectivities of additional PT domains were investigated and matched to those predicted by the phylogenetic classifications.

    View details for DOI 10.1074/jbc.M110.128504

    View details for PubMedID 20479000

  • Cyclization of aromatic polyketides from bacteria and fungi NATURAL PRODUCT REPORTS Zhou, H., Li, Y., Tang, Y. 2010; 27 (6): 839-868

    View details for DOI 10.1039/b911518h

    View details for Web of Science ID 000278100100002

    View details for PubMedID 20358042

  • Engineered biosynthesis of bacterial aromatic polyketides in Escherichia coli PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhang, W., Li, Y., Tang, Y. 2008; 105 (52): 20683-20688


    Bacterial aromatic polyketides are important therapeutic compounds including front line antibiotics and anticancer drugs. It is one of the last remaining major classes of natural products of which the biosynthesis has not been reconstituted in the genetically superior host Escherichia coli. Here, we demonstrate the engineered biosynthesis of bacterial aromatic polyketides in E. coli by using a dissected and reassembled fungal polyketide synthase (PKS). The minimal PKS of the megasynthase PKS4 from Gibberella fujikuroi was extracted by using two approaches. The first approach yielded a stand-alone Ketosynthase (KS)_malonyl-CoA:ACP transferase (MAT) didomain and an acyl-carrier protein (ACP) domain, whereas the second approach yielded a compact PKS (PKS_WJ) that consists of KS, MAT, and ACP on a single polypeptide. Both minimal PKSs produced nonfungal polyketides cyclized via different regioselectivity, whereas the fungal-specific C2-C7 cyclization mode was not observed. The kinetic properties of the two minimal PKSs were characterized to confirm both PKSs can synthesize polyketides with similar efficiency as the parent PKS4 megasynthase. Both minimal PKSs interacted effectively with exogenous polyketide cyclases as demonstrated by the synthesis of predominantly PK8 3 or NonaSEK4 6 in the presence of a C9-C14 or a C7-C12 cyclase, respectively. When PKS_WJ and downstream tailoring enzymes were expressed in E. coli, the expected nonaketide anthraquinone SEK26 was recovered in good titer. High-cell density fermentation was performed to demonstrate the scale-up potential of the in vivo platform for the biosynthesis of bacterial polyketides. Using engineered fungal PKSs can therefore be a general approach toward the heterologous biosynthesis of bacterial aromatic polyketides in E. coli.

    View details for DOI 10.1073/pnas.0809084105

    View details for Web of Science ID 000262092800023

    View details for PubMedID 19075227

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