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Antibiotics ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 82
Author(s):  
Juan F. Martín ◽  
Paloma Liras

Naringenin and its glycosylated derivative naringin are flavonoids that are synthesized by the phenylpropanoid pathway in plants. We found that naringenin is also formed by the actinobacterium Streptomyces clavuligerus, a well-known microorganism used to industrially produce clavulanic acid. The production of naringenin in S. clavuligerus involves a chalcone synthase that uses p-coumaric as a starter unit and a P450 monoxygenase, encoded by two adjacent genes (ncs-ncyP). The p-coumaric acid starter unit is formed by a tyrosine ammonia lyase encoded by an unlinked, tal, gene. Deletion and complementation studies demonstrate that these three genes are required for biosynthesis of naringenin in S. clavuligerus. Other actinobacteria chalcone synthases use caffeic acid, ferulic acid, sinapic acid or benzoic acid as starter units in the formation of different antibiotics and antitumor agents. The biosynthesis of naringenin is restricted to a few Streptomycess species and the encoding gene cluster is present also in some Saccharotrix and Kitasatospora species. Phylogenetic comparison of S. clavuligerus naringenin chalcone synthase with homologous proteins of other actinobacteria reveal that this protein is closely related to chalcone synthases that use malonyl-CoA as a starter unit for the formation of red-brown pigment. The function of the core enzymes in the pathway, such as the chalcone synthase and the tyrosine ammonia lyase, is conserved in plants and actinobacteria. However, S. clavuligerus use a P450 monooxygenase proposed to complete the cyclization step of the naringenin chalcone, whereas this reaction in plants is performed by a chalcone isomerase. Comparison of the plant and S. clavuligerus chalcone synthases indicates that they have not been transmitted between these organisms by a recent horizontal gene transfer phenomenon. We provide a comprehensive view of the molecular genetics and biochemistry of chalcone synthases and their impact on the development of antibacterial and antitumor compounds. These advances allow new bioactive compounds to be obtained using combinatorial strategies. In addition, processes of heterologous expression and bioconversion for the production of naringenin and naringenin-derived compounds in yeasts are described.


2021 ◽  
Vol 25 ◽  
Author(s):  
Parul Grover ◽  
Deepak K Sharma ◽  
Anuj K. Chhalodia ◽  
Debaraj Mukherjee

: Most of the biologically active microbial natural products and their analogs bear a complex molecular architecture. The semisynthetic modifications and stereospecific diversity-oriented synthesis of these native natural products to generate analogs are difficult and time-consuming. Mutasynthesis is a powerful tool that utilizes the microorganism's genetic and metabolic engineering skills to produce derivatives of complex natural products of microbial origin. Mutasynthesis is based on the cellular uptake of chemically modified intermediates from the culture media and their addition to the secondary metabolism by mutant microorganisms. This review wouldf describe the importance of mutasynthesis in the generation of complex microbial secondary metabolites. We have covered a literature search on mutasynthesis over the last ten years (2011 - 2020) in this review.


2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Lin Zhou ◽  
Yaoyao Shen ◽  
Nannan Chen ◽  
Wanlu Li ◽  
Hou-wen Lin ◽  
...  

Abstract Background Neoantimycins are a group of 15-membered ring depsipeptides isolated from Streptomycetes with a broad-spectrum of anticancer activities. Neoantimycin biosynthesis is directed by the hybrid multimodular megaenzymes of non-ribosomal peptide synthetase and polyketide synthase. We previously discovered a new neoantimycin analogue unantimycin B, which was demonstrated to have selective anticancer activities and was produced from the neoantimycin biosynthetic pathway with a starter unit of 3-hydroxybenzoate, instead of the 3-formamidosalicylate unit that is common for neoantimycins. However, the low fermentation titre and tough isolation procedure have hindered in-depth pharmacological investigation of unantimycin B as an anticancer agent. Results In this work, we genetically constructed two unantimycin B producer strains and inhibited neoantimycins production by removing natO and natJ-L genes essential for 3-formamidosalicylate biosynthesis, therefore facilitating chromatographic separation of unantimycin B from the complex fermentation extract. Based on the ΔnatO mutant, we improved unantimycin B production twofold, reaching approximately 12.8 mg/L, by feeding 3-hydroxybenzoate during fermentation. Furthermore, the production was improved more than sixfold, reaching approximately 40.0 mg/L, in the ΔnatO strain introduced with a chorismatase gene highly expressed under a strong promoter for endogenously over-producing 3-hydroxybenzoate. Conclusion This work provides a case of targeting accumulation and significant production improvement of medicinally interesting natural products via genetic manipulation of precursor biosynthesis in Streptomycetes, the talented producers of pharmaceutical molecules.


2021 ◽  
Vol 7 (20) ◽  
pp. eabg4682
Author(s):  
Ji Hyung Jun ◽  
Nan Lu ◽  
Maite Docampo-Palacios ◽  
Xiaoqiang Wang ◽  
Richard A. Dixon

Proanthocyanidins (PAs) are plant natural products important for agriculture and human health. They are polymers of flavan-3-ol subunits, commonly (−)-epicatechin and/or (+)-catechin, but the source of the in planta extension unit that comprises the bulk of the polymer remains unclear, as does how PA composition is determined in different plant species. Anthocyanidin reductase (ANR) can generate 2,3-cis-epicatechin as a PA starter unit from cyanidin, which itself arises from 2,3-trans-leucocyanidin, but ANR proteins from different species produce mixtures of flavan-3-ols with different stereochemistries in vitro. Genetic and biochemical analyses here show that ANR has dual activity and is involved not only in the production of (−)-epicatechin starter units but also in the formation of 2,3-cis-leucocyanidin to serve as (−)-epicatechin extension units. Differences in the product specificities of ANRs account for the presence/absence of PA polymerization and the compositions of PAs across plant species.


2021 ◽  
Author(s):  
Lin Zhou ◽  
Yaoyao Shen ◽  
Nannan Chen ◽  
Wanlu Li ◽  
Hou-wen Lin ◽  
...  

Abstract BackgroundNeoantimycins are a group of 15-membered ring depsipeptides isolated from streptomycetes with a broad-spectrum of anticancer activities. Their biosynthesis is directed by the hybrid multimodular megaenzymes of non-ribosomal peptide synthetase and polyketide synthase. We have previously discovered a new neoantimycin analogue unantimycin B, which was demonstrated with selective anticancer activities and was produced from neoantimycins biosynthetic pathway with a starter unit of 3-hydroxybenzoate, instead of the 3-formamidosalicylate for neoantimycins. However, the low fermentation yield and tough isolation procedure have been hindering in-depth pharmacology investigation of unantimycin B as anticancer agents.ResultsIn the work, we genetically constructed two unantimycin B producer strains with neoantimycins production destroyed by removing natO and natJ-L genes essential for 3-formamidosalicylate biosynthesis and therefore facilitated chromatographic separation of unantimycin B from the complex fermentation extract. Based on the △natO mutant, we improved unantimycin Bproduction by two times, reaching to approximate 12.8 mg/L, by feeding 3-hydroxybenzoate in fermentation. Further, the production was improved by more than six times, reaching to approximate 40.0 mg/L, in the △natO strain introduced with a chorismatase gene highly expressed under a strong promoter for over-producing 3-hydroxybenzoate endogenously.ConclusionThe work gives a case of targeting accumulation and significant production improvement of medicinally interesting natural products via genetically manipulation of precursor biosynthesis in streptomycetes, the talented producers of pharmaceutical molecules.


2020 ◽  
Vol 117 (47) ◽  
pp. 29669-29676
Author(s):  
Anthony R. Hesser ◽  
Kaitlin Schaefer ◽  
Wonsik Lee ◽  
Suzanne Walker

Carbohydrate polymers exhibit incredible chemical and structural diversity, yet are produced by polymerases without a template to guide length and composition. As the length of carbohydrate polymers is critical for their biological functions, understanding the mechanisms that determine polymer length is an important area of investigation. Most Gram-positive bacteria produce anionic glycopolymers called lipoteichoic acids (LTA) that are synthesized by lipoteichoic acid synthase (LtaS) on a diglucosyl-diacylglycerol (Glc2DAG) starter unit embedded in the extracellular leaflet of the cell membrane. LtaS can use phosphatidylglycerol (PG) as an alternative starter unit, but PG-anchored LTA polymers are significantly longer, and cells that make these abnormally long polymers exhibit major defects in cell growth and division. To determine how LTA polymer length is controlled, we reconstitutedStaphylococcus aureusLtaS in vitro. We show that polymer length is an intrinsic property of LtaS that is directly regulated by the identity and concentration of lipid starter units. Polymerization is processive, and the overall reaction rate is substantially faster for the preferred Glc2DAG starter unit, yet the use of Glc2DAG leads to shorter polymers. We propose a simple mechanism to explain this surprising result: free starter units terminate polymerization by displacing the lipid anchor of the growing polymer from its binding site on the enzyme. Because LtaS is conserved across most Gram-positive bacteria and is important for survival, this reconstituted system should be useful for characterizing inhibitors of this key cell envelope enzyme.


2020 ◽  
Vol 32 (1) ◽  
pp. 33-42
Author(s):  
Lita Yarlina ◽  
Harry Yanto Lumban Batu ◽  
Evy Lindasari ◽  
Arman Mardoko

AbstrakLalu lintas angkutan udara di Bandar Udara Mutiara SIS Al-Jufri, Palu menunjukkan pertumbuhan yang meningkat selama periode 2015-2019. Pengelolaan Ground Support Equipment (GSE) dan Sumber Daya Manusia (SDM) diperlukan untuk memenuhi persyaratan pelayanan ground handling di sisi udara, khususnya apron, untuk mewujudkan keselamatan penerbangan, kinerja ketepatan waktu, kepuasan pelanggan, serta keandalan yang sesuai dengan regulasi. Penelitian ini bertujuan mengetahui kualitas layanan ground handling di Bandar Udasar Mutiara SIS Al-Jufri. Metode yang digunakan adalah metode kualitatif deskriptif dengan mengacu pada kriteria dalam Peraturan Menteri Perhubungan Nomor PM. 91 tahun 2016 tentang Pembatasan Usia Peralatan Penunjang Pelayanan Darat Pesawat Udara (Ground Support Equipment/ GSE) dan Kendaraan Operasional yang Beroperasi di Sisi Udara, serta Surat Keputusan Direktur Jenderal Perhubungan Udara Nomor SKEP/81/X/1998 tentang Pedoman Umum Pengelolaan Ground Support Equipment (GSE). Hasil penelitian menyimpulkan bahwa kegiatan ground handling telah menunjukkan komitmen dalam memenuhi pelayanannya. Walaupun demikian, masih terdapat deviasi berupa kendaraan dengan usia operasi lebih dari 10 tahun yang masih beroperasi di apron, antara lain Aircraft Towing Tractor (ATT), Air Starter Unit (ASU), dan Ground Power Unit (GPU). Oleh karena itu, direkomendasikan untuk melakukan penyesuaian peralatan dengan mengacu pada regulasi yang berlaku.Kata kunci: Bandar Udara Mutiara SIS Al-Jufri, ground handling.Ground Handling Services at Mutiara SIS Al-Jufri Airport Palu: Air transport traffic at Mutiara SIS Al-Jufri Airport, Palu-Indonesia, showed an increase in growth from 2015 until 2019. In an attempt to meet the ground handling service requirements on the air side, especially aprons, it is necessary to properly manage Ground Support Equipment (GSE) and Human Resources to achieve flight safety, punctuality performance, customer satisfaction, and regulatory compliance. This study aimed to determine the quality of ground handling services at Mutiara SIS Al-Jufri Airport. It employeda descriptive qualitative method by referring to the criteria issued in the Regulation of Minister of Transportation PMNo. 91 of 2016 concerning Age Limits for Supporting GSE and Operational Vehicles Operating on the Air Side andthe Decree of the Director-General of Civil Aviation No. SKEP/81/X/1998 on General Guidelines for Management of Ground Support Equipment. The results showed that the ground handling activities hadsuccessfully committedto fulfilling their functions, but a few deviations from the recommended age of vehicles in operation on the aprons were identified. Aircraft Towing Tractor (ATT), Air Starter Unit (ASU), and Ground Power Unit (GPU) had been operated for more than ten years. Therefore, this study recommends that equipment adjustments be made following applicable regulations.Keywords: Mutiara SIS Al-Jufri Airport, ground handling.


2020 ◽  
Author(s):  
Karthik Muthineni ◽  
Akhil Yalagonda ◽  
Praveen Gorla ◽  
Tarun Pulluri

Abstract Agriculture is one of the key enabler for the economic development of India that accounts for one third of nation's income. Due to the problems that agriculture industry is facing, there is a need to introduce automation in agriculture that improves the efficiency. This paper presents the implementation of Automated Motor Starter Unit (AMSU) for smart farming applicable to Indian scenario. In addition, current technologies and attempts in smart farming are reviewed and discussed. More than 90% of Indian farmers have been using motors for their farm fields which are controlled by single phase or three phase power supplies. The AMSU has been designed to turn on/off motor in the farm field using mobile phone having cellular network from any place. The AMSU is selected to increase the operation efficiency by minimizing the manual operation of motors for which farmer need to go to the farm field.


Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1955
Author(s):  
Philipp Schwarzer ◽  
Olga Tsypik ◽  
Chijian Zuo ◽  
Ahmad Alali ◽  
Julia Wunsch-Palasis ◽  
...  

The biological active compound rishirilide B is produced by Streptomyces bottropensis. The cosmid cos4 contains the complete rishirilide B biosynthesis gene cluster. Its heterologous expression in the host Streptomyces albus J1074 led to the production of rishirilide B as a major compound and to small amounts of rishirilide A, rishirilide D and lupinacidin A. In order to gain more insights into the biosynthesis, gene inactivation experiments and gene expression experiments were carried out. This study lays the focus on the functional elucidation of the genes involved in the early biosynthetic pathway. A total of eight genes were deleted and six gene cassettes were generated. Rishirilide production was not strongly affected by mutations in rslO2, rslO6 and rslH. The deletion of rslK4 and rslO3 led to the formation of polyketides with novel structures. These results indicated that RslK4 and RslO3 are involved in the generation or selection of the starter unit for rishirilide biosynthesis. In the rslO10 mutant strain, two novel compounds were detected, which were also produced by a strain containing solely the genes rslK1, rslK2, rslK3, rslK4, and rslA. rslO1 and rslO4 mutants predominately produce galvaquinones. Therefore, the ketoreductase RslO10 is involved in an early step of rishirilide biosynthesis and the oxygenases RslO1 and RslO4 are most probably acting on an anthracene moiety. This study led to the functional elucidation of several genes of the rishirilide pathway, including rslK4, which is involved in selecting the unusual starter unit for polyketide synthesis.


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