Tiangang Liu

Stanford University | SU · Department of Chemistry

Granulomatous lobular mastitis (GLM) is a chronic idiopathic granulomatous mastitis of the mammary gland characterized by significant pain and a high propensity for recurrence, the incidence rate has gradually increased, and has become a serious breast disease that should not be ignored. GLM is highly suspected relative to microbial infections, esp...

Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure‐activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potenti...

At the intersection of synthetic biology and materials science, engineered living materials (ELMs) exhibit unprecedented potential. Possessing unique “living” attributes, ELMs represent a significant paradigm shift in material design, showcasing self‐organization, self‐repair, adaptability, and evolvability, surpassing conventional synthetic materi...

Nootkatone is a natural sesquiterpene ketone widely used in food, cosmetics, pharmaceuticals, and agriculture. It is also regarded as one of the most valuable terpenes used commercially. However, plants contain trace amounts of (+)‐nootkatone, and extraction from plants is insufficient to meet market demand. Alpinia oxyphylla is a well‐known medici...

Microbial communication can drive coordinated functions through sensing, analyzing and processing signal information, playing critical roles in biomanufacturing and life evolution. However, it is still a great challenge to develop effective methods to construct a microbial communication system with coordinated behaviors. Here, we report an electron...

Sesquiterpenes have been identified as promising ingredients for aviation fuels due to their high energy density and combustion heat properties. Despite the characterization of numerous sesquiterpene structures, studies testing their performance properties and feasibility as fuels are scarce. In this study, 122 sesquiterpenoid skeleton compounds, o...

Vitamin B5, also called d-pantothenic acid, is an essential vitamin in the human body and is widely used in pharmaceuticals, nutritional supplements, food, and cosmetics. However, few studies have investigated the microbial production of d-pantothenic acid, especially in Saccharomyces cerevisiae. By employing a systematic optimization strategy, we...

Engineered metabolic pathways in microbial cell factories often have no natural organization and have challenging flux imbalances, leading to low biocatalytic efficiency. Modular polyketide synthases (PKSs) are multienzyme complexes that synthesize polyketide products via an assembly line thiotemplate mechanism. Here, we develop a strategy named mi...

Tremulane sesquiterpenoids are key secondary metabolites of the basidiomycete Irpex lacteus, which displays structural diversity and various bioactivities. However, tremulane sesquiterpene synthases have not been reported to date. The tremulane sesquiterpene synthase of I. lacteus was characterized by genome mining, heterologous expression, an in v...

Microbial cell factories reinvigorate current industries by producing complex fine chemicals at low costs. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is the main reducing power to drive the biosynthetic pathways in microorganisms. However, insufficient intrinsic NADPH limits the productivity of microorganisms. Here, we report that...

All known triterpenes are generated by triterpene synthases (TrTSs) from squalene or oxidosqualene¹. This approach is fundamentally different from the biosynthesis of short-chain (C10–C25) terpenes that are formed from polyisoprenyl diphosphates2–4. In this study, two fungal chimeric class I TrTSs, Talaromyces verruculosus talaropentaene synthase (...

Microbial cell factories reinvigorate current industries by producing complex fine chemicals at low costs. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is the main reducing power to drive the biosynthetic pathways in microorganisms. However, the insufficient intrinsic NADPH limits the productivity of microorganisms. Here, we report t...

Metabolomics is an essential discipline in omics technology that promotes research on the biology of microbial systems. Streptomyces albus J1074 is a model organism used in fundamental research and industrial microbiology. Nevertheless, a comprehensive and standardized method for analyzing the metabolome of S. albus J1074 is yet to be developed. Th...

Terpenoids, critical components of human medicine, are the largest family of natural products. Fungi are an important source of terpenoids, but many of the corresponding biosynthetic gene clusters (BGCs) are silent in laboratory conditions. Strategies such as homologous activation and heterologous expression were usually used to active a single clu...

Vitamin E is one of the most widely used vitamins. In the classical commercial synthesis of vitamin E (α-tocopherol), the chemical synthesis of isophytol is the key technical barrier. Here, we established a new process for isophytol synthesis from microbial fermented farnesene. To achieve an efficient pathway for farnesene production, Saccharomyces...

(+)-Nootkatone is a valuable, functional sesquiterpene that is widely used in food, cosmetics, pharmaceutical, agriculture, and other fields. However, only traces of it accumulate in plants, which is insufficient to meet the market demand. Therefore, commercial (+)-nootkatone is currently synthesized from (+)-valencene. Here, we engineered Saccharo...

Testosterone deficiency can lead to depressive symptoms in humans; however, the causes of this deficiency are incompletely understood. Here, we isolated Mycobacterium neoaurum from the fecal samples of testosterone-deficient patients with depression and showed that this strain could degrade testosterone in vitro. Furthermore, gavaging rats with M....

Qingfei Paidu (QFPD) granules have played a critical role during the Coronavirus Disease 2019 (COVID-19) in China. However, worldwide acceptance has been a problem because of the complex ingredients and unique theory of treatment. In this study, high-performance liquid chromatography (HPLC)-Q Exactive Orbitrap-mass spectrometry (MS) and the Orbitra...

Plant-derived natural active products have attracted increasing attention for use in flavors and perfumes. These compounds also have applications in insect pest control because of their environment-friendly properties. Holy basil (Ocimum sanctum), a famous herb used in Ayurveda in India, is a natural source of medical healing agents and insecticida...

Spinosyns are natural broad-spectrum biological insecticides with a double glycosylated polyketide structure that are produced by aerobic fermentation of the actinomycete, Saccharopolyspora spinosa. However, their large-scale overproduction is hindered by poorly understood bottlenecks in optimizing the original strain, and poor adaptability of the...

Significance Chimeric terpene synthases, termed PTTSs, are a unique family of enzymes occurring only in fungi. Characterizing PTTSs is challenging due to the complex reactions they catalyze and the structural complexity of their products. Here, by devising an efficient precursor-providing yeast chassis and incorporating a high-throughput automated...

The spread of COVID-19, the disease caused by SARS-CoV-2, has progressed into a global pandemic. To date, thousands of genetic variants have been identified across strains of SARS-CoV-2 isolated from worldwide patients. However, there is still little direct evidence linking viral variants and clinical features. Based on two tightly linked SNPs, we...

The LianhuaQingwen (LHQW) capsule is a popular traditional Chinese medicine (TCM) for the treatment of viral respiratory diseases. In particular, it has been recently prescribed to treat infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). However, due to its complex composition, little attention has been directed...

Infections with zoonotic viruses, such as flaviviruses, influenza virus, and the SARS-CoV-2 pandemic coronavirus constitute an increasing global risk. Hence, an urgent need exists for the development of broad-spectrum antivirals to prevent such outbreaks. Here, we show that the maduramycin and CP-80,219 aglycone polyether ionophores exhibit effecti...

In article number 2001616, Tiangang Liu and co‐workers develop a cell‐free protein synthesis (CFPS) platform that enables rapid discovery of novel lanthipeptides and guides lanthipeptide overproduction in vivo. This study extends the use of cell‐free systems to address the issue facing lanthipeptide research, while providing the possibility for dev...

Catalytic versatility is an inherent property of many enzymes. In nature, terpene cyclases comprise the foundation of molecular biodiversity as they generate diverse hydrocarbon scaffolds found in thousands of terpenoid natural products. Here, we report that the catalytic activity of the terpene cyclases AaTPS and FgGS can be switched from cyclase...

In article number 2002169, Wu Wei, Yan Li, Tiangang Liu, and co‐workers develop a novel detection technology, nanopore targeted sequencing (NTS), for the accurate and comprehensive detection of SARS‐CoV‐2 and other respiratory viruses. This detection technology is suitable for the identification of suspected COVID‐19 cases and can also monitor muta...

Lanthipeptides have extensive therapeutic and industrial applications. However, because many are bactericidal, traditional in vivo platforms are limited in their capacity to discover and mass produce novel lanthipeptides as bacterial organisms are often critical components in these systems. Herein, the development of a cell‐free protein synthesis (...

The ongoing global novel coronavirus pneumonia COVID‐19 outbreak has engendered numerous cases of infection and death. COVID‐19 diagnosis relies upon nucleic acid detection; however, currently recommended methods exhibit high false‐negative rates and are unable to identify other respiratory virus infections, thereby resulting in patient misdiagnosi...

BACKGROUND: As approximately 19% of global deaths are attributable to infectious diseases, early diagnosis of infection is very important to reduce mortality. Traditional infection detection strategies have limited sensitivity, detection range, and turnaround times; a detection technology that can simultaneously detect bacterial and fungal infectio...

Medium-chain fatty acids (C6–C10) have attracted much attention recently for their unique properties compared to their long-chain counterparts, including low melting points and relatively higher carbon conversion yield. Thioesterase enzymes, which can catalyze the hydrolysis of acyl-ACP (acyl carrier protein) to release free fatty acids (FAs), are...

A very recent outbreak of the novel coronavirus, COVID‐19, in the city of Wuhan, China, in December 2019 and its subsequent spread within and across China have resulted in several deaths and infections. Presently, nucleic acid amplification test is essential for the confirmation of COVID infection. In this report, we summarized the six promising me...

Background The outbreak of COVID-2019 is becoming a global public health emergency. Although its basic clinical features have been reported, the dynamic characteristics of immune system in COVID-2019 patients, especially those critical patients with refractory hypoxemia, are not yet well understood. We aim to describe the dynamic characteristics of...

The ongoing novel coronavirus pneumonia COVID-19 outbreak in Wuhan, China, has engendered numerous cases of infection and death. COVID-19 diagnosis relies upon nucleic acid detection; however, current recommended methods exhibit high false-negative rates, low sensitivity, and cannot identify other respiratory virus infections, thereby resulting pat...

Background 2019-Novel coronavirus (2019-nCoV) outbreaks create challenges for hospital laboratories because thousands of samples must be evaluated each day. Sample types, interpretation methods, and corresponding laboratory standards must be established. The possibility of other infections should be assessed to provide a basis for clinical classifi...

Herein, we report the semisynthetic production of the potent transient receptor potential canonical (TRPC) channel agonist englerin A (EA), using guaia 6,10(14)-diene as the starting ma-terial. Guaia-6,10(14)-diene was systematically engineered in Escherichia coli and Saccharomyces cerevisiae using the CRISPR/Cas9 system and produced with high tite...

Maduramicin is the most efficient and possesses the largest market share of all anti-coccidiosis polyether antibiotics (ionophore); however, its biosynthetic gene cluster (BGC) has yet to been identified, and the associated strains have not been genetically engineered. Herein, we performed whole-genome sequencing of a maduramicin-producing industri...

Herein, we report the semisynthetic production of the potent transient receptor potential canonical (TRPC) channel agonist (−)-englerin A (EA), using guaia-6,10(14)-diene as the starting material. Guaia-6,10(14)-diene was systematically engineered in Escherichia coli and Saccharomyces cerevisiae using the CRISPR/Cas9 system and produced with high t...

The absolute configuration of fusaterpenol (GJ1012E) has been revised by an enantioselective deuteration strategy. A bifunctional enzyme with a terpene synthase and a prenyltransferase domain from Aspergillus brasiliensis was characterised as variediene synthase, and the absolute configuration of its product was elucidated. The uniform absolute con...

Glucose isomerases are important industrial enzymes to produce highfructose corn syrup (HFCS) which is sweetener and widely used in beverages and foods. The gene of glucose isomerase from Streptomyces rubiginosus is overexpressed under the control of strong promoter (rRNA promoter) which integrated on the chromosome as marker‐free form, so the high...

Lycopene is widely used in foods, cosmetics, nutritional supplements, and pharmaceuticals. Microbial production of lycopene has been intensively studied. However, there are few systematic engineering studies in Saccharomyces cerevisiae aimed at high-yield lycopene production. In the current study, employing a systematic optimization strategy, we sc...

Enzymatic reactions in living cells are highly dynamic but simultaneously tightly regulated. Enzyme engineers seek to construct multienzyme complexes to prevent intermediate diffusion, to improve product yield, and to control the flux of metabolites. Here we choose a pair of short peptide tags (RIAD and RIDD) to create scaffold-free enzyme assembli...

Lanthipeptides have extensive therapeutic and industrial applications; however, since many are bactericidal, traditional in vivo platforms are limited in their capacity to discover and mass produce novel lanthipeptides as bacterial organisms are often critical components in these systems. We developed a cell-free protein synthesis (CFPS) platform t...

Sesquiterpene synthases in Trichoderma viride have been seldom studied, despite the efficiency of filamentous fungi for terpenoid production. Using the farnesyl diphosphate-overexpressing Saccharomyces cerevisiae platform to produce diverse terpenoids, we herein identified an unknown sesquiterpene synthase from T. viride by genome mining and determ...

Multienzyme complexes, or metabolons, are assemblies or clusters of sequential enzymes that naturally exist in metabolic pathways. These nanomachineries catalyze the conversion of metabolites more effectively than the freely floating enzymes by minimizing the diffusion of intermediates in vivo. Bioengineers have devised synthetic versions of multie...

Xylose/glucose isomerases are important industrial enzymes that are most widely used in food industries; however, their previously reported expression levels do not meet the requirements for industrial application. Here, an antibiotic resistance marker (ARM)-free system driven by ribosomal RNA (rRNA) promoters is developed to obtain high-level xylo...

In pharmaceutical industry, isepamicin is mainly manufactured from gentamicin B, which is produced by Micromonospora echinospora as a minor component of the gentamicin complex. Improvement of gentamicin B production through metabolic engineering is therefore important to satisfy the increasing demand for isepamicin. We hypothesized that gentamicin...

Sesquiterpenes represent a class of important terpenoids with high structural diversity and a wide range of applications. The cyclized core skeletons are generated by sesquiterpene cyclases, and the structural diversity is further increased by a series of modification steps. Cytochromes P450 (P450s) are a class of monooxygenases and one of the main...

Saccharomyces cerevisiae is an efficient host for natural-compound production and preferentially employed in academic studies and bioindustries. However, S. cerevisiae exhibits limited production capacity for lipophilic natural products, especially compounds that accumulate intracellularly, such as polyketides and carotenoids, with some engineered...

The potential of the polyether salinomycin as an inhibitory agent against cancer stem cells has attracted interest in this family of compounds. In this study, we found that the aglycone polyether nanchangmycin and its homologues show promising activities against breast cancer stem cells as well as 38 other different types of cancer cells in in vitr...

Based on a terpenoid overproduction platform in yeast for genome mining, a chimeric diterpene synthase from the endophytic fungus Colletotrichum gloeosporioides ES026 was characterized as (5R,12R,14S)‐dolasta‐1(15),8‐diene synthase. The absolute configuration was independently verified by use of enantioselectively deuterated terpene precursors whic...

This study constructed cell‐free glycolytic enzyme systems and compared them to their in vivo functions in Escherichia coli. Under in vitro conditions, flux regulation followed enzyme concentrations and kinetics. In E. coli, only one of the isozymes of phosphofructokinase (PfkA) and fructose‐bisphosphate aldolase (FbaA) facilitate Embden‐Meyerhof‐P...

Cell-free protein synthesis (CFPS) is a valuable tool for basic and applied research. The Escherichia coli cell lysate-based system is the most widely used for in vitro transcription and translation (TX-TL). To optimize this system and increase target protein production, the present study investigated the contribution of most of the macromolecular...

Spinosad is a potent insecticide that exhibits an excellent environmental and mammalian profile. However, spinosad production in the original producer, Saccharopolyspora spinosa, is insufficient for the huge global demand. Great efforts have been exerted to improve the production of spinosad. Strategies for spinosad overproduction in actinomycetes...

There is considerable interest in mining organisms for new natural products (NPs) and in improving methods to overproduce valuable NPs. Because of the rapid development of tools and strategies for metabolic engineering and the markedly increased knowledge of the biosynthetic pathways and genetics of NP-producing organisms, genome mining and overpro...

The potential power of sesquiterpene synthase FgJ03939 from Fusarium graminearum was fully exploited in a farnesyl diphosphate-overexpressing Saccharomyces cerevisiae chassis to produce the novel sesquiterpenes fusariumdiene (1), epi-fusagramineol (2), and fusagramineol (3) with 5/7 bicyclic and 5/6/3 tricyclic ring systems, respectively, as well a...

ɛ‐poly‐L‐lysine (ɛ‐PL) is a novel commercial food preservative, and glucose and glycerol are two carbon sources commonly used in ɛ‐PL fermentation. Using MALDI‐TOF and NMR, we determined that when grown in glycerol‐based medium, but not glucose‐based medium, Streptomyces albulus J1‐005 produces a derivative of ɛ‐PL in which the terminal carboxyl gr...

Terpenoids represent a highly diverse group of natural products with wide applications. Engineering approaches have been used to increase titers of many value-added terpenoids, such as farnesene, taxadiene, lycopene, and astaxanthin. In this chapter, we review the in vitro reconstitution-based targeted engineering of terpenoids, as well as approach...

Terpenoids comprise the largest family of natural products and have widespread applications. The overproduction of value-added terpenoids and the efficient mining of new terpenoids represent major challenges in the fields of metabolic engineering and natural product discovery. For terpenoid overproduction in microbial systems, in vitro reconstituti...

Terpenoids represent the largest family of natural products. Their structural diversity is largely due to variable skeletons generated by terpene synthases. However, terpene skeletons found in nature are much more than those generated from known terpene synthases. Most promiscuous terpene synthases (i.e. those that can generate more than one produc...

Proinsulin (Pins) is the precursor of insulin. The expression of proinsulin in Escherichia coli forms inclusion body, so that the recombinant protein should be processed with multiple steps to form active insulin. With the development in biotechnology, cell-free protein synthesis (CFPS) system is becoming a valuable tool in protein expression by de...

With the advent of the genomics era, heterologous gene expression has been used extensively as a mean of accessing natural products (NPs) from environmental DNA samples. However, the heterologous production of NPs often has very low efficiency or is unable to produce targeted NPs. Moreover, due to the complicated transcriptional and metabolic regul...

Approximately 76,000 discovered makes terpenoids the largest family of natural products in nature with widespread applications. The wide-spectrum of structural diversity of the terpenoids were largely due to the variable skeletons generated by terpene synthases. The number of terpene skeletons found in nature, however, were so much more than those...