scholarly journals Cofactor F420: an expanded view of its distribution, biosynthesis and roles in bacteria and archaea

2021 ◽  
Author(s):  
Rhys Grinter ◽  
Chris Greening
Keyword(s):  
Gene Transfer ◽  
Redox Reactions ◽  
Biosynthetic Pathway ◽  
Antibiotic Biosynthesis ◽  
Heterologous Production ◽  
Biosynthetic Gene ◽  
New Research ◽  
Key Steps ◽  
New Evidence ◽  
Xenobiotic Biodegradation

ABSTRACT Many bacteria and archaea produce the redox cofactor F420. F420 is structurally similar to the cofactors FAD and FMN but is catalytically more similar to NAD and NADP. These properties allow F420 to catalyze challenging redox reactions, including key steps in methanogenesis, antibiotic biosynthesis and xenobiotic biodegradation. In the last 5 years, there has been much progress in understanding its distribution, biosynthesis, role and applications. Whereas F420 was previously thought to be confined to Actinobacteria and Euryarchaeota, new evidence indicates it is synthesized across the bacterial and archaeal domains, as a result of extensive horizontal and vertical biosynthetic gene transfer. F420 was thought to be synthesized through one biosynthetic pathway; however, recent advances have revealed variants of this pathway and have resolved their key biosynthetic steps. In parallel, new F420-dependent biosynthetic and metabolic processes have been discovered. These advances have enabled the heterologous production of F420 and identified enantioselective F420H2-dependent reductases for biocatalysis. New research has also helped resolve how microorganisms use F420 to influence human and environmental health, providing opportunities for tuberculosis treatment and methane mitigation. A total of 50 years since its discovery, multiple paradigms associated with F420 have shifted, and new F420-dependent organisms and processes continue to be discovered.

scholarly journals Widespread Occurrence and Lateral Transfer of the Cyanobactin Biosynthesis Gene Cluster in Cyanobacteria

2008 ◽  
Vol 75 (3) ◽  
pp. 853-857 ◽  
Author(s):  
Niina Leikoski ◽  
David P. Fewer ◽  
Kaarina Sivonen
Keyword(s):  
Gene Transfer ◽  
Horizontal Gene Transfer ◽  
Cyclic Peptides ◽  
Evolutionary History ◽  
Biosynthetic Pathway ◽  
Biosynthetic Gene ◽  
Biosynthesis Gene Cluster ◽  
Widespread Occurrence ◽  
Biosynthesis Gene ◽  
Complex Evolutionary History

ABSTRACT Cyanobactins are small cyclic peptides produced by cyanobacteria. Here we demonstrate the widespread but sporadic occurrence of the cyanobactin biosynthetic pathway. We detected a cyanobactin biosynthetic gene in 48 of the 132 strains included in this study. Our results suggest that cyanobactin biosynthetic genes have a complex evolutionary history in cyanobacteria punctuated by a series of ancient horizontal gene transfer events.

scholarly journals The biosynthetic origin of psychoactive kavalactones in kava

2018 ◽  
Author(s):  
Tomáš Pluskal ◽  
Michael P. Torrens-Spence ◽  
Timothy R. Fallon ◽  
Andrea De Abreu ◽  
Cindy H. Shi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Biosynthetic Pathway ◽  
Chalcone Synthase ◽  
De Novo ◽  
Piper Methysticum ◽  
Heterologous Production ◽  
Traditional Use ◽  
Plant Biochemistry ◽  
Tailoring Enzymes

AbstractFor millennia, humans have used plants for medicinal purposes. However, our limited understanding of plant biochemistry hinders the translation of such ancient wisdom into modern pharmaceuticals1. Kava (Piper methysticum) is a medicinal plant native to the Polynesian islands with anxiolytic and analgesic properties supported by over 3,000 years of traditional use as well as numerous recent clinical trials2–5. The main psychoactive principles of kava, kavalactones, are a unique class of polyketide natural products known to interact with central nervous system through mechanisms distinct from those of the prescription psychiatric drugs benzodiazepines and opioids6,7. Here we reportde novoelucidation of the biosynthetic pathway of kavalactones, consisting of seven specialized metabolic enzymes. Based on phylogenetic and crystallographic analyses, we highlight the emergence of two paralogous styrylpyrone synthases, both of which have neofunctionalized from an ancestral chalcone synthase to catalyze the formation of the kavalactone scaffold. Structurally diverse kavalactones are then biosynthesized by subsequent regio- and stereo-specific tailoring enzymes. We demonstrate the feasibility of engineering heterologous production of kavalactones and their derivatives in bacterial, yeast, and plant hosts, thus opening an avenue towards the development of new psychiatric therapeutics for anxiety disorders, which affect over 260 million people globally8.

Newton's financial misadventures in the South Sea Bubble

2018 ◽  
Vol 73 (1) ◽  
pp. 29-59 ◽  
Author(s):  
Andrew Odlyzko
Keyword(s):  
The South ◽  
Research Directions ◽  
John Maynard Keynes ◽  
Isaac Newton ◽  
Market Rationality ◽  
New Information ◽  
Hard Evidence ◽  
South Sea ◽  
New Research ◽  
New Evidence

A very popular investment anecdote relates how Isaac Newton, after cashing in large early gains, staked his fortune on the success of the South Sea Company of 1720 and lost heavily in the ensuing crash. However, this tale is based on only a few items of hard evidence, some of which are consistently misquoted and misinterpreted. A superficially plausible contrarian argument has also been made that he did not lose much in that period, and John Maynard Keynes even claimed Newton successfully surmounted the South Sea Bubble. This paper presents extensive new evidence that while Newton was a successful investor before this event, the folk tale about his making large gains but then being drawn back into that mania and suffering large losses is almost certainly correct. It probably even understates the extent of his financial miscalculations. Incidental to the clarification of this prominent issue, a controversy between Dale et al . and Shea about an aspect of market rationality during that bubble is settled. Some new information is also presented about Thomas Guy, famous for making a fortune out of the Bubble that paid for the establishment of Guy's Hospital, and other investors. The work reported here suggests new research directions and perspectives on bubbles.

Biosynthesis of the uridine-derived nucleoside antibiotic A-94964: identification and characterization of the biosynthetic gene cluster provide insight into the biosynthetic pathway

2019 ◽  
Vol 17 (3) ◽  
pp. 461-466 ◽  
Author(s):  
Taro Shiraishi ◽  
Makoto Nishiyama ◽  
Tomohisa Kuzuyama
Keyword(s):  
Gene Cluster ◽  
In Silico ◽  
Biosynthetic Pathway ◽  
Gene Deletion ◽  
Biosynthetic Gene Cluster ◽  
Biosynthetic Gene ◽  
Identification And Characterization ◽  
Insight Into

The biosynthetic pathway of the uridine-derived nucleoside antibiotic A-94964 was proposed via in silico analysis coupled with gene deletion experiments.

New evidence from East Timor contributes to our understanding of earliest modern human colonisation east of the Sunda Shelf

Antiquity ◽  
2007 ◽  
Vol 81 (313) ◽  
pp. 523-535 ◽  
Author(s):  
Sue O'Connor
Keyword(s):  
Southeast Asia ◽  
Modern Human ◽  
East Timor ◽  
Sunda Shelf ◽  
Modern Humans ◽  
Research Directions ◽  
Island Southeast Asia ◽  
New Research ◽  
New Evidence ◽  
Southern Route

New dates by which modern humans reached East Timor prompts this very useful update of the colonisation of Island Southeast Asia. The author addresses all the difficult questions: why are the dates for modern humans in Australia earlier than they are in Island Southeast Asia? Which route did they use to get there? If they used the southern route, why or how did they manage to bypass Flores, whereHomo floresiensis, the famous non-sapienshominin known to the world as the ‘hobbit’ was already in residence? New work at the rock shelter of Jerimalai suggests some answers and new research directions.

scholarly journals Cloning and Characterization of the Biosynthetic Gene Cluster for Tomaymycin, an SJG-136 Monomeric Analog

2009 ◽  
Vol 75 (9) ◽  
pp. 2958-2963 ◽  
Author(s):  
Wei Li ◽  
ShenChieh Chou ◽  
Ankush Khullar ◽  
Barbara Gerratana
Keyword(s):  
Cluster Analysis ◽  
Gene Cluster ◽  
Biosynthetic Pathway ◽  
Biosynthetic Gene Cluster ◽  
Gene Replacement ◽  
Biosynthetic Gene

ABSTRACT Tomaymycin produced by Streptomyces achromogenes is a naturally produced pyrrolobenzodiazepine (PBD). The biosynthetic gene cluster for tomaymycin was identified and sequenced. The gene cluster analysis reveals a novel biosynthetic pathway for the anthranilate moiety of PBDs. Gene replacement and chemical complementation studies were used to confirm the proposed biosynthetic pathway.

scholarly journals A revised biosynthetic pathway for the cofactor F420in bacteria

2018 ◽  
Author(s):  
Ghader Bashiri ◽  
James Antoney ◽  
Ehab N. M. Jirgis ◽  
Mihir V. Shah ◽  
Blair Ney ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Heterologous Expression ◽  
Secondary Metabolism ◽  
Biosynthetic Pathway ◽  
Antibiotic Biosynthesis ◽  
Bacterial Persistence ◽  
Redox Transformations ◽  
Terminal Domain ◽  
Primary And Secondary Metabolism ◽  
Drug Activation

AbstractCofactor F420plays critical roles in primary and secondary metabolism in a range of bacteria and archaea as a low-potential hydride transfer agent. It mediates a variety of important redox transformations involved in bacterial persistence, antibiotic biosynthesis, pro-drug activation and methanogenesis. However, the biosynthetic pathway for F420has not been fully eluci-dated: neither the enzyme that generates the putative intermediate 2-phospho-L-lactate, nor the function of the FMN-binding C-terminal domain of the γ-glutamyl ligase (FbiB) in bacteria are known. Here we show that the guanylyltransferases FbiD and CofC accept phosphoenolpyruvate, rather than 2-phospho-L-lactate, as their substrate, leading to the formation of the previously uncharacterized intermediate, dehydro-F420-0. The C-terminal domain of FbiB then utilizes FMNH2 to reduce dehydro-F420-0, which produces mature F420species when combined with the γ-glutamyl ligase activity of the N-terminal domain. This new insight has allowed the heterologous expression F420from a recombinant F420biosynthetic pathway inEscherichia coli.

scholarly journals Understanding Thioamitide Biosynthesis Using Pathway Engineering and Untargeted Metabolomics

2020 ◽  
Author(s):  
Tom H. Eyles ◽  
Natalia M. Vior ◽  
Rodney Lacret ◽  
Andrew W. Truman
Keyword(s):  
Biosynthetic Pathway ◽  
Gene Clusters ◽  
Untargeted Metabolomics ◽  
Pathway Engineering ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Heterologous Host ◽  
Detailed Understanding ◽  
Precursor Peptide ◽  
Modified Peptides

ABSTRACTThiostreptamide S4 is a thioamitide, a family of promising antitumour ribosomally synthesised and post-translationally modified peptides (RiPPs). The thioamitides are one of the most structurally complex RiPP families, yet very few thioamitide biosynthetic steps have been elucidated, even though the gene clusters of multiple thioamitides have been identified. We hypothesised that engineering the thiostreptamide S4 gene cluster in a heterologous host could provide insights into its biosynthesis when coupled with untargeted metabolomics and targeted mutations of the precursor peptide. Modified gene clusters were constructed, and in-depth metabolomics enabled a detailed understanding of the biosynthetic pathway, including the identification of an effector-like protein critical for amino acid dehydration. We use this biosynthetic understanding to bioinformatically identify new widespread families of RiPP biosynthetic gene clusters, paving the way for future RiPP discovery and engineering.

scholarly journals Biosynthetic engineering of the antifungal, anti-MRSA auroramycin

2019 ◽  
Author(s):  
Wan Lin Yeo ◽  
Elena Heng ◽  
Lee Ling Tan ◽  
Yi Wee Lim ◽  
Kuan Chieh Ching ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Genome Editing ◽  
Gene Cluster ◽  
Biosynthetic Pathway ◽  
Biosynthetic Gene Cluster ◽  
Combinatorial Biosynthesis ◽  
Biosynthetic Gene ◽  
Antifungal Activities ◽  
Biosynthetic Engineering

AbstractUsing an established CRISPR-Cas mediated genome editing technique for streptomycetes, we explored the combinatorial biosynthesis potential of the auroramycin biosynthetic gene cluster in Streptomyces roseoporous. Auroramycin is a potent anti-MRSA polyene macrolactam. In addition, it also displays antifungal activities, which is unique among structurally similar polyene macrolactams, such as incednine and silvalactam. In this work, we employed different engineering strategies to target glycosylation and acylation biosynthetic machineries within its recently elucidated biosynthetic pathway. Six auroramycin analogs with variations in C-, N-methylation, hydroxylation and extender units incorporation were produced and characterized. By comparing the bioactivity profiles of these analogs, we determined that unique disaccharide motif of auroramycin is essential for its antimicrobial bioactivity. We further demonstrated that C-methylation of the 3, 5-epi-lemonose unit, which is unique among structurally similar polyene macrolactams, is key to its antifungal activity.

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