Xingwang Zhang

Shandong University

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Shengying Li

Shandong University

Wei Zhang

Nanjing Tech University

Lei Du

Shandong University

Jiawei Guo

Shandong University

Fengwei Li

Shandong University

Li Ma

Shandong University

Fangyuan Cheng

Huazhong University of Science and Technology

Ce Geng

Qingdao Institute of Bioenergy and Bioprocess Technology

Feifei Qi

Chinese Academy of Medical Sciences & Peking Union Medical College

David H. Sherman

University of Michigan–Ann Arbor

Cooperative Institutions

Chinese Academy of Sciences

Shandong University

State Key Laboratory of Microbial Technology

University of Chinese Academy of Sciences

Qingdao Institute of Bioenergy and Bioprocess Technology

Ocean University of China

Qingdao National Laboratory for Marine Science and Technology

Sun Yat-sen University

Zhejiang University

University of Michigan–Ann Arbor

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An enormous Paris polyphylla genome sheds light on genome size evolution and polyphyllin biogenesis

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Jing Li Meiqi Lv Lei Du A Yunga Shijie Hao

Abstract The monocot family Melanthiaceae with varying genome sizes in a range of 230-fold is an ideal model to study the genome size fluctuation in plants. Its family member Paris genus demonstrates an evolutionary trend of bearing huge genomes characterized by an average c-value of 49.22 pg. Here, we report a 70.18 Gb genome assembly out of the 82.55 Gb genome of Paris polyphylla var. yunnanensis (PPY), which represents the biggest sequenced genome to date. We annotate 69.53% repetitive sequences in this genome and 62.50% of which are long-terminal repeat (LTR) transposable elements. Further evolution analysis indicates that the giant genome likely results from the joint effect of common and species-specific expansion of different LTR superfamilies, which might contribute to the environment adaptation after speciation. Moreover, we identify the candidate pathway genes for the biogenesis of polyphyllins, the PPY-specific medicinal saponins, by complementary approaches including genome mining, comprehensive analysis of 31 next-generation RNA-seq data and 55.23 Gb single-molecule circular consensus sequencing (CCS) RNA-seq reads, and correlation of the transcriptome and phytochemical data of five different tissues at four growth stages. This study not only provides significant insights into plant genome size evolution, but also paves the way for the following polyphyllin synthetic biology.

Genome size

10.1101/2020.06.01.126920

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Mixed Micelles with Galactose Ligands for the Oral Delivery of Berberine to Enhance Its Bioavailability and Hypoglycemic Effects

Journal of Biomedical Nanotechnology (2020)

Hao Kang Yao Ying-shui Xingwang Zhang

Diabetes mellitus (DM) has become an epidemic disorder that is an escalating public health risk. Currently, DM treatment is highly challenging due to temporary medical relief rather than a permanent cure. This article reports a ligand-anchored mixed micellar system formed by phospholipids and N -oleoyl- D -galactosamine aiming to enhance the oral bioavailability and hypoglycemic effects of berberine, an antidiabetic agent with poor absorption. Berberine-loaded mixed micelles (BBMMs) were prepared through a solvent diffusion technique. The resulting BB-MMs were characterized by particle size, potential, morphology, entrapment efficiency (EE) and in vitro release. The oral pharmacokinetics and hypoglycemic efficacy of BB-MMs were evaluated in rats and compared with a berberine suspension. As a result, BB-MMs prepared with the preferable formulation had a particle size of approximately 100 nm with an EE of over 85%. BB-MMs exhibited sustained drug release owing to the entrapment in the micelles. After oral administration, BB-MMs ameliorated the pharmacokinetic profile of berberine and significantly enhanced its oral bioavailability (317.17% relative to the suspension). The pharmacological effect (PE) of BB-MMs was approximately 3.44 times greater than that of the suspension. In addition, in situ single-pass intestinal perfusion and cellular testing results illustrated that BB-MMs had good intestinal permeability and cellular uptake. Our findings demonstrate that the oral bioavailability and hypoglycemic effects of berberine could be largely enhanced by encapsulation into mixed micelles with a galactose moiety. Thus, galactosylated micelles may be promising for developing berberine nanomedicines to fight DM.

10.1166/jbn.2020.30041755

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Structural Basis for Selective Oxidation of Phosphorylated Ethylphenols by Cytochrome P450 Monooxygenase CreJ

Applied and Environmental Microbiology (2021)

Sheng Dong Jingfei Chen Xingwang Zhang Fei Guo Li Ma

Selective oxidation of C-H bonds in alkylphenols holds great significance for not only structural derivatization in pharma- and biomanufacturing but also biological degradation of these toxic chemicals in environmental protection. A unique chemomimetic biocatalytic system using enzymes from a p-cresol biodegradation pathway has recently been developed. As the central biocatalyst, the cytochrome P450 monooxygenase CreJ oxidizes diverse p- and m-alkylphenol phosphates with perfect stereoselectivity at different efficiencies. However, the mechanism of regio- and stereoselectivity of this chemomimetic biocatalytic system remained unclear. Here, using p- and m-ethylphenol substrates, we elucidate the CreJ-catalyzed key steps for selective oxidations. The crystal structure of CreJ in complex with m-ethylphenol phosphate was solved and compared with its complex structure with p-ethylphenol phosphate isomer. The results indicate that the conformational changes of substrate-binding residues are slight, while the substrate promiscuity is achieved mainly by the available space in the catalytic cavity. Moreover, the catalytic preferences of regio- and stereoselective hydroxylation for the two ethylphenol substrates is explored by molecular dynamics simulations. The ethyl groups in the complexes display different flexibilities, and the distances of the active oxygen to H pro-S and H pro-R of methylene agree with the experimental stereoselectivity. The regioselectivity can be explained by the distances and bond dissociation energy. These results provide not only the mechanistic insights into CreJ regio- and stereoselectivity but also the structural basis for further P450 enzyme design and engineering.IMPORTANCE The key cytochrome P450 monooxygenase CreJ showed excellent regio- and stereoselectivity in the oxidation of various alkylphenol substrates. C-H bond functionalization of these toxic alkylphenols holds great significance for both biological degradation of these environmental chemicals and production of value-added structural derivatives in pharmaceutical and biochemical industries. Our results, combined with in vitro enzymatic assays, crystal structure determination of enzyme-substrate complex, and molecular dynamics simulations, provide not only significant mechanism elucidation of the regio- and stereoselective catalyzation mediated by CreJ but also the promising directions for future engineering efforts of this enzyme toward more useful products. It also has great extendable potential to couple this multifunctional P450 enzyme with other biocatalysts (e.g., hydroxyl-based glycosylase) to access more alkylphenol-derived high-value chemicals through environment-friendly biocatalysis and biotransformation.

Alkylphenol

10.1128/aem.00018-21

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Cytochrome P450s in algae: Bioactive natural product biosynthesis and light-driven bioproduction

Acta Pharmaceutica Sinica B (2022)

Shanmin Zheng Jiawei Guo Fangyuan Cheng Zhengquan Gao Lei Du

Algae are a large group of photosynthetic organisms responsible for approximately half of the earth's total photosynthesis. In addition to their fundamental ecological roles as oxygen producers and as the food base for almost all aquatic life, algae are also a rich source of bioactive natural products, including several clinical drugs. Cytochrome P450 enzymes (P450s) are a superfamily of biocatalysts that are extensively involved in natural product biosynthesis by mediating various types of reactions. In the post-genome era, a growing number of P450 genes have been discovered from algae, indicating their important roles in algal life-cycle. However, the functional studies of algal P450s remain limited. Benefitting from the recent technical advances in algae cultivation and genetic manipulation, the researches on P450s in algal natural product biosynthesis have been approaching to a new stage. Moreover, some photoautotrophic algae have been developed into "photo-bioreactors" for heterologous P450s to produce high-value added pharmaceuticals and chemicals in a carbon-neutral or carbon-negative manner. Here, we comprehensively review these advances of P450 studies in algae from 2000 to 2021.

Natural product

Bioproduction

Green algae

10.1016/j.apsb.2022.01.013

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Unnatural activities and mechanistic insights of cytochrome P450 PikC gained from site-specific mutagenesis by non-canonical amino acids

Nature Communications (2023)

Yunjun Pan Guobang Li Ruxin Liu Jiawei Guo Yunjie Liu

Cytochrome P450 enzymes play important roles in the biosynthesis of macrolide antibiotics by mediating a vast variety of regio- and stereoselective oxidative modifications, thus improving their chemical diversity, biological activities, and pharmaceutical properties. Tremendous efforts have been made on engineering the reactivity and selectivity of these useful biocatalysts. However, the 20 proteinogenic amino acids cannot always satisfy the requirement of site-directed/random mutagenesis and rational protein design of P450 enzymes. To address this issue, herein, we practice the semi-rational non-canonical amino acid mutagenesis for the pikromycin biosynthetic P450 enzyme PikC, which recognizes its native macrolide substrates with a 12- or 14-membered ring macrolactone linked to a deoxyamino sugar through a unique sugar-anchoring mechanism. Based on a semi-rationally designed substrate binding strategy, non-canonical amino acid mutagenesis at the His238 position enables the unnatural activities of several PikC mutants towards the macrolactone precursors without any sugar appendix. With the aglycone hydroxylating activities, the pikromycin biosynthetic pathway is rewired by the representative mutant PikCH238pAcF carrying a p-acetylphenylalanine residue at the His238 position and a promiscuous glycosyltransferase. Moreover, structural analysis of substrate-free and three different enzyme-substrate complexes of PikCH238pAcF provides significant mechanistic insights into the substrate binding and catalytic selectivity of this paradigm biosynthetic P450 enzyme.

Rational design

Site-directed mutagenesis

Saturated mutagenesis

Aglycone

Protein Engineering

10.1038/s41467-023-37288-0

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Identifying Dominant Spoilage Fungal species and Preservative Treatments for Extending Shelf Life of Whole Lotus Rhizomes at 4°C

LWT (2024)

Chunfang Xu Xingwang Zhang Shengkai Huang Shoulei Yan Jie Li

A preservative for whole lotus rhizome preservation was developed under 4 °C storage in this study. The study included the following steps: Firstly, isolation and identification of spoilage causing fungi of lotus rhizome, and four main spoilage causing fungi were identified, including Penicillium solitum, Geotrichum silvicola, Phytopythium helicoides, and Pseudeurotium zonatum. Secondly, selection of antifungal agent with good inhibitory ability against the above four spoilage causing fungi, finally 0.5 % potassium sorbate was selected considering edible security at the same time. Thirdly, the selection of suitable color fixative according to the indexes of root skin and flesh color differences, and sensory evaluation. The final color fixative composition: EDTA-2Na (8 g/L), ascorbic acid (8 g/L), and D-isoascorbic acid sodium (6 g/L). Finally, the antifungal agent and color fixatives were mixed to make the preservative. Soaked in preservative for 20min, drained and packed into PE bags, vacuumed and stored at 4 °C, the lotus rhizomes could maintain better color, got high sensory score, soluble solids content, and total acid content, and the microbial counts were always lower than the untreated group. The preservative could extend the shelf life of whole lotus rhizome to about 50 d at 4 °C.

10.1016/j.lwt.2024.116263

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Isolation and Absolute Configurations of Diversiform C17, C21 and C25 Terpenoids from the Marine Sponge Cacospongia sp.

Marine Drugs (2018)

Xingwang Zhang Pinglin Li Guo‐Fei Qin Shengying Li Nicole J. de Voogd

Chemical investigation of MeOH extract of a South China Sea sponge Cacospongia sp. yielded 15 terpenoids belonging to three different skeleton-types, including the unusual C17γ-lactone norditerpenoids (1⁻3), the rare C21 pyridine meroterpenoid (7), and the notable C25 manoalide-type sesterterpenoids (4⁻6, 8⁻10). Compounds 1⁻5 were initially obtained as enantiomers, and were further separated to be optically pure compounds (1a, 1b, 2a, 2b, 3a-r, 3b-r, 4a, 4b, 5a and 5b) by chiral HPLC, with a LiAlH₄ reduction aid for 3. Compounds 3a/3b (a pair of inseparable enantiomers), 4a, 5a, 6, and 7 were identified as new compounds, while 1a/1b and 2a/2b were obtained from a natural source and were determined for their absolute configurations for the first time. This is also the first time to encounter enantiomers of the well-known manoalide-type sesterterpenoids from nature. The structures with absolute configurations of the new compounds were unambiguously determined by comprehensive methods including HR-ESI-MS and NMR data analysis, optical rotation comparison, experimental and calculated electronic circular dichroism (ECD), and Mo₂(OAc)₄ induced circular dichroism (ICD) methods. The cytotoxicity of the isolates against selected human tumor cell lines was evaluated, however, the tested compounds showed no activity against selected cell lines.

Absolute Configuration

Sponge

Chirality

10.3390/md17010014

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One‐Pot Biocatalytic Conversion of Chemically Inert Hydrocarbons into Chiral Amino Acids through Internal Cofactor and H2O2 Recycling

Angewandte Chemie International Edition (2024)

Aiwen Wang Yongze Wang Yuanxiang You Zhiqing Huang Xingwang Zhang

Abstract Chemically inert hydrocarbons are the primary feedstocks used in the petrochemical industry and can be converted into more intricate and valuable chemicals. However, two major challenges impede this conversion process: selective activation of C−H bonds in hydrocarbons and systematic functionalization required to synthesize complex structures. To address these issues, we developed a multi‐enzyme cascade conversion system based on internal cofactor and H 2 O 2 recycling to achieve the one‐pot deep conversion from heptane to chiral ( S )‐2‐aminoheptanoic acid under mild conditions. First, a hydrogen‐borrowing‐cycle‐based NADH regeneration method and H 2 O 2 in situ generation and consumption strategy were applied to realize selective C−H bond oxyfunctionalization, converting heptane into 2‐hydroxyheptanoic acid. Integrating subsequent reductive amination driven by the second hydrogen‐borrowing cycle, ( S )‐2‐aminoheptanoic acid was finally accumulated at 4.57 mM with ee p >99 %. Hexane, octane, 2‐methylheptane, and butylbenzene were also successfully converted into the corresponding chiral amino acids with ee p >99 %. Overall, the conversion system employed internal cofactor and H 2 O 2 recycling, with O 2 as the oxidant and ammonium as the amination reagent to fulfill the enzymatic conversion from chemically inert hydrocarbons into chiral amino acids under environmentally friendly conditions, which is a highly challenging transformation in traditional organic synthesis.

Inert

10.1002/anie.202410260

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Citations (1)

Comparative Analysis of Three Pairs of Surrogate Redox Partners for in Vitro Activity Reconstitution of Class I Cytochrome P450 Enzymes

Research Square (Research Square) (2021)

Xiaohui Liu Fengwei Li Tianjian Sun Jiawei Guo Xingwang Zhang

Abstract Cytochrome P450 enzymes (P450s) are highly attractive biocatalysts due to their versatile catalytic activities. A vast majority of P450s require redox partner (RP) proteins to sequentially transfer two electrons for O 2 activation and substrate oxidation. However, little information is available on cognate RPs for P450s, which greatly limits P450 function exploration and practical application. Thus, the stategy of building various hybrid P450 catalytic systems with surrogate RPs has often adopted to engineer P450 biocatalysts for different purposes. In this study, we comprehensively compare three pairs of frequently-used surrogate redox partners Sel Fdx1499/ Sel FdR0978, Adx/AdR and Pdx/PdR and in terms of their electron transfer properties. The three selected bacterial Class I P450s to accept electrons from RPs include PikC, P450sca-2 and CYP-sb21, which are responsible for production of macrolide antibiotics, the cholesterol-lowering drug pravastatin, and a hair-growth-stimulating agent. Both experimental studies and structural analysis show that Sel Fdx1499/ Sel FdR0978 is the most promising RP compared to Adx/AdR and Pdx/PdR. The results provide insights into the domination for P450-redox partner interactions in modulating the catalytic activity of P450s. This study not only produces a more active biocatalyst but also suggests a general chose for a universal reductase which would facilitate engineering of P450 catalyst.

Cytochrome P450 reductase

10.21203/rs.3.rs-1062561/v1

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Three pairs of surrogate redox partners comparison for Class I cytochrome P450 enzyme activity reconstitution

Communications Biology (2022)

Xiaohui Liu Fengwei Li Tianjian Sun Jiawei Guo Xingwang Zhang

Abstract Most P450s require redox partners for the electron transfer during catalysis. However, little information is available on cognate redox partners for P450s, which greatly limits P450 function exploration and practical application. Thus, the stategy of building various hybrid P450 catalytic systems with surrogate redox partner has often adopted to engineer P450 biocatalysts. In this study, we compare three pairs of frequently-used surrogate redox partner Sel Fdx1499/ Sel FdR0978, Adx/AdR and Pdx/PdR and in terms of their electron transfer properties. The three selected bacterial Class I P450s include PikC, P450sca-2 and CYP-sb21, which are responsible for production of high-value-added products. Here we show that Sel Fdx1499/ Sel FdR0978 is the most promising redox partner compared to Adx/AdR and Pdx/PdR. The results provide insights into the domination for P450-redox partner interactions in modulating the catalytic activity of P450s. This study not only produces a more active biocatalyst but also suggests a general chose for a universal reductase which would facilitate engineering of P450 catalyst.

Biocatalysis

10.1038/s42003-022-03764-4

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Citations (23)