Caerulomycin and collismycin antibiotics share a trans-acting flavoprotein-dependent assembly line for 2,2’-bipyridine formation

AbstractLinear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids through assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges our understanding in NRPS and PKS-programmed, diverse biosynthetic processes using amino acid and carboxylate building blocks. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an assembly line that involves unusual NRPS activity to engage a trans-acting flavoprotein in C-C bond formation and heterocyclization during 2,2’-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2’-bipyridine intermediates through differential treatment of the sulfhydryl group arising from l-cysteine incorporation. Subsequent l-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2’-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.

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Caerulomycin and Collismycin Antibiotics Share a trans Flavin-Dependent Assembly Line for 2,2’-Bipyridine Formation and Sulfur Fate Differentiation

10.1101/2020.12.07.415471 ◽

2020 ◽

Author(s):

Bo Pang ◽

Rijing Liao ◽

Zhijun Tang ◽

Shengjie Guo ◽

Zhuhua Wu ◽

...

Keyword(s):

Amino Acid ◽

Assembly Line ◽

Bond Formation ◽

Sulfhydryl Group ◽

Polyketide Synthases ◽

Differential Treatment ◽

Nonribosomal Peptides ◽

Peptide Synthetases ◽

In Trans ◽

Hybrid Antibiotics

ABSTRACTLinear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids though assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges the understanding in the diverse polymerization processes of amino acid and carboxylate monomers programmed by various NRPSs and PKSs in nature. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an unusual assembly line that involves NRPS activity to recruit a flavoprotein acting in trans and catalyze C-C bond formation and heterocyclization during 2,2’-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2’-bipyridine intermediates through differential treatment of the sulfhydryl group arising from L-cysteine incorporation. Subsequent L-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2’-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.

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Engineering the acyltransferase substrate specificity of assembly line polyketide synthases

Journal of The Royal Society Interface ◽

10.1098/rsif.2013.0297 ◽

2013 ◽

Vol 10 (85) ◽

pp. 20130297 ◽

Cited By ~ 71

Author(s):

Briana J. Dunn ◽

Chaitan Khosla

Keyword(s):

Natural Products ◽

Substrate Specificity ◽

Assembly Line ◽

Current Knowledge ◽

Structural Diversity ◽

Structural Data ◽

Building Blocks ◽

Polyketide Synthases ◽

Biologically Active ◽

Recent Developments

Polyketide natural products act as a broad range of therapeutics, including antibiotics, immunosuppressants and anti-cancer agents. This therapeutic diversity stems from the structural diversity of these small molecules, many of which are produced in an assembly line manner by modular polyketide synthases. The acyltransferase (AT) domains of these megasynthases are responsible for selection and incorporation of simple monomeric building blocks, and are thus responsible for a large amount of the resulting polyketide structural diversity. The substrate specificity of these domains is often targeted for engineering in the generation of novel, therapeutically active natural products. This review outlines recent developments that can be used in the successful engineering of these domains, including AT sequence and structural data, mechanistic insights and the production of a diverse pool of extender units. It also provides an overview of previous AT domain engineering attempts, and concludes with proposed engineering approaches that take advantage of current knowledge. These approaches may lead to successful production of biologically active ‘unnatural’ natural products.

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Formation of Carbon-Oxygen Bond Mediated by Hypervalent Iodine Reagents Under Metal-free Conditions

Mini-Reviews in Organic Chemistry ◽

10.2174/1570193x17999200807140943 ◽

2020 ◽

Vol 17 ◽

Author(s):

Ayesha Jalil ◽

Yaxin O Yang ◽

Zhendong Chen ◽

Rongxuan Jia ◽

Tianhao Bi ◽

...

Keyword(s):

Natural Products ◽

Bond Formation ◽

Building Blocks ◽

Review Article ◽

Hypervalent Iodine ◽

Metal Free ◽

Bioactive Natural Products ◽

The Past ◽

Oxygen Bond ◽

Privileged Scaffolds

: Hypervalent iodine reagents are a class of non-metallic oxidants have been widely used in the construction of several sorts of bond formations. This surging interest in hypervalent iodine reagents is essentially due to their very useful oxidizing properties, combined with their benign environmental character and commercial availability from the past few decades ago. Furthermore, these hypervalent iodine reagents have been used in the construction of many significant building blocks and privileged scaffolds of bioactive natural products. The purpose of writing this review article is to explore all the transformations in which carbon-oxygen bond formation occurred by using hypervalent iodine reagents under metal-free conditions

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PoGB-Pred: Prediction of Antifreeze Proteins Sequences using Amino Acid Composition with Feature Selection followed by a Sequential based Ensemble Approach

Current Bioinformatics ◽

10.2174/1574893615999200707141926 ◽

2020 ◽

Vol 15 ◽

Author(s):

Affan Alim ◽

Abdul Rafay ◽

Imran Naseem

Keyword(s):

Amino Acid ◽

Dimension Reduction ◽

Protein Identification ◽

Cold Water ◽

Genomic Sequence ◽

Sequence Data ◽

Antifreeze Proteins ◽

Building Blocks ◽

Gradient Boosting ◽

Proposed Model

Background: Proteins contribute significantly in every task of cellular life. Their functions encompass the building and repairing of tissues in human bodies and other organisms. Hence they are the building blocks of bones, muscles, cartilage, skin, and blood. Similarly, antifreeze proteins are of prime significance for organisms that live in very cold areas. With the help of these proteins, the cold water organisms can survive below zero temperature and resist the water crystallization process which may cause the rupture in the internal cells and tissues. AFP’s have attracted attention and interest in food industries and cryopreservation. Objective: With the increase in the availability of genomic sequence data of protein, an automated and sophisticated tool for AFP recognition and identification is in dire need. The sequence and structures of AFP are highly distinct, therefore, most of the proposed methods fail to show promising results on different structures. A consolidated method is proposed to produce the competitive performance on highly distinct AFP structure. Methods: In this study, we propose to use machine learning-based algorithms Principal Component Analysis (PCA) followed by Gradient Boosting (GB) for antifreeze protein identification. To analyze the performance and validation of the proposed model, various combinations of two segments composition of amino acid and dipeptide are used. PCA, in particular, is proposed to dimension reduction and high variance retaining of data which is followed by an ensemble method named gradient boosting for modelling and classification. Results: The proposed method obtained the superfluous performance on PDB, Pfam and Uniprot dataset as compared with the RAFP-Pred method. In experiment-3, by utilizing only 150 PCA components a high accuracy of 89.63 was achieved which is superior to the 87.41 utilizing 300 significant features reported for the RAFP-Pred method. Experiment-2 is conducted using two different dataset such that non-AFP from the PISCES server and AFPs from Protein data bank. In this experiment-2, our proposed method attained high sensitivity of 79.16 which is 12.50 better than state-of-the-art the RAFP-pred method. Conclusion: AFPs have a common function with distinct structure. Therefore, the development of a single model for different sequences often fails to AFPs. A robust results have been shown by our proposed model on the diversity of training and testing dataset. The results of the proposed model outperformed compared to the previous AFPs prediction method such as RAFP-Pred. Our model consists of PCA for dimension reduction followed by gradient boosting for classification. Due to simplicity, scalability properties and high performance result our model can be easily extended for analyzing the proteomic and genomic dataset.

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Axially Chiral Bis(α-amino Acid)s and Their Deamino Analogues. Synthesis and Configurational Assignment

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19980211 ◽

1998 ◽

Vol 63 (2) ◽

pp. 211-221 ◽

Cited By ~ 5

Author(s):

Miloš Tichý ◽

Luděk Ridvan ◽

Miloš Buděšínský ◽

Jiří Závada ◽

Jaroslav Podlaha ◽

...

Keyword(s):

Amino Acid ◽

Nmr Spectra ◽

Building Blocks ◽

X Ray Diffraction ◽

Amino Groups ◽

X Ray ◽

Configurational Assignment ◽

Symmetry Properties ◽

Axially Chiral ◽

Polymeric Structures

The axially chiral bis(α-amino acid)s cis-2 and trans-2 as possible building blocks for polymeric structures of novel type of helicity were prepared. Their configuration has been determined by NMR spectroscopy and, in the case of the trans-isomer, confirmed by single-crystal X-ray diffraction. Analogous pair of stereoisomeric diacids cis-3 and trans-3, devoid of the amino groups, was also prepared and their configuration assigned. The observed differences in the NMR spectra of cis- and trans-isomers of 2 and 3 are discussed from the viewpoint of their different symmetry properties.

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Self-assembly of cyclic homo- and hetero-β-peptides with cis- furanoid sugar amino acid and β-hGly as building blocks

Chemical Communications ◽

10.1039/b610858j ◽

2006 ◽

pp. 4847-4849 ◽

Cited By ~ 34

Author(s):

Bulusu Jagannadh ◽

Marepally Srinivasa Reddy ◽

Chennamaneni Lohitha Rao ◽

Anabathula Prabhakar ◽

Bharatam Jagadeesh ◽

...

Keyword(s):

Amino Acid ◽

Self Assembly ◽

Building Blocks

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Oxidative Peptide Bond Formation of Glycine-Amino Acid using 2-(Aminomethyl)malononitrile as a Glycine Unit

Chemical Communications ◽

10.1039/d1cc00130b ◽

2021 ◽

Author(s):

Xiaoling Wang ◽

Jing Li ◽

Yujiro Hayashi

Keyword(s):

Aqueous Solution ◽

Amino Acid ◽

Bond Formation ◽

Peptide Bond ◽

Peptide Bond Formation ◽

Amide Linkage

Amide linkage of glycine-amino acid was synthesized by coupling of substituted 2-(aminomethyl)malononitrile as a C-terminal glycine unit and N-terminal amine using CsOAc and O2 in aqueous solution. This is a...

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