AMAbiotics SAS

Paris, France

AMAbiotics SAS

Paris, France
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Liu M.F.,French National Institute for Agricultural Research | Liu M.F.,Jilin University | Cescau S.,Institute Pasteur Paris | Mechold U.,Institute Pasteur Paris | And 6 more authors.
Microbiology | Year: 2012

In Escherichia coli, only one essential oligoribonuclease (Orn) can degrade oligoribonucleotides of five residues and shorter in length (nanoRNA). In Bacillus subtilis, NrnA and NrnB, which do not show any sequence similarity to Orn, have been identified as functional analogues of Orn. Sequence comparisons did not identify orn, nrnA or nrnB homologues in the genomes of the Chlamydia/Cyanobacteria and Alphaproteobacteria family members. Screening a genomic library from Bartonella birtlesii, a member of the Alphaproteobacteria, for genes that can complement a conditional orn mutant in E. coli, we identified BA0969 (NrnC) as a functional analogue of Orn. NrnC is highly conserved (more than 80% identity) in the Bartonella genomes sequenced to date. Biochemical characterization showed that this protein exhibits oligo RNA degradation activity (nanoRNase activity). Like Orn from E. coli, NrnC is inhibited by micromolar amounts of 39- phosphoadenosine 59-phosphate in vitro. NrnC homologues are widely present in genomes of Alphaproteobacteria. Knock down of nrnC decreases the growth ability of Bartonella henselae, demonstrating the importance of nanoRNase activity in this bacterium. © 2012 SGM.

Danchin A.,Institute of Cardiometabolism and Nutrition | Braham S.,AMAbiotics SAS
Microbial Biotechnology | Year: 2017

Microbial communities thrive in a number of environments. Exploration of their microbiomes – their global genome – may reveal metabolic features that contribute to the development and welfare of their hosts, or chemical cleansing of environments. Yet we often lack final demonstration of their causal role in features of interest. The reason is that we do not have proper baselines that we could use to monitor how microbiota cope with key metabolites in the hosting environment. Here, focusing on animal gut microbiota, we describe the fate of cobalamins – metabolites of the B12 coenzyme family – that are essential for animals but synthesized only by prokaryotes. Microbiota produce the vitamin used in a variety of animals (and in algae). Coprophagy plays a role in its management. For coprophobic man, preliminary observations suggest that the gut microbial production of vitamin B12 plays only a limited role. By contrast, the vitamin is key for structuring microbiota. This implies that it is freely available in the environment. This can only result from lysis of the microbes that make it. A consequence for biotechnology applications is that, if valuable for their host, B12-producing microbes should be sensitive to bacteriophages and colicins, or make spores. © 2017 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

Danchin A.,AMAbiotics SAS | Sekowska A.,AMAbiotics SAS
Environmental Microbiology | Year: 2014

Intermediary metabolism molecules are orchestrated into logical pathways stemming from history (L-amino acids, d-sugars) and dynamic constraints (hydrolysis of pyrophosphate or amide groups is the driving force of anabolism). Beside essential metabolites, numerous variants derive from programmed or accidental changes. Broken down, variants enter standard pathways, producing further variants. Macromolecule modification alters enzyme reactions specificity. Metabolism conform thermodynamic laws, precluding strict accuracy. Hence, for each regular pathway, a wealth of variants inputs and produces metabolites that are similar to but not the exact replicas of core metabolites. As corollary, a shadow, paralogous metabolism, is associated to standard metabolism. We focus on a logic of paralogous metabolism based on diversion of the core metabolic mimics into pathways where they are modified to minimize their input in the core pathways where they create havoc. We propose that a significant proportion of paralogues of well-characterized enzymes have evolved as the natural way to cope with paralogous metabolites. A second type of denouement uses a process where protecting/deprotecting unwanted metabolites - conceptually similar to the procedure used in the laboratory of an organic chemist - is used to enter a completely new catabolic pathway. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

Danchin A.,AMAbiotics SAS | Danchin A.,University of Hong Kong
FEBS Letters | Year: 2012

Using comparative genomics and functional analysis, this work summarises how the cell's genome is organised, with emphasis on the importance of the cell's chassis. Some discrete but important engineering constraints are reviewed, beginning with the need for scaffolds, as well as the question posed by the difficult task of putting a very long random thread (DNA) into a limited volume. Subsequently, to illustrate overlooked essential functions, we show the importance of safety valves, as well as the need to cope with leftovers. The third section discusses how transplantation experiments point out a remarkable feature of the cell factory: the program replicates (makes identical copies of itself), whereas the cell reproduces (makes similar copies of itself), placing in the limelight the role of informational maintenance. A final section identifies the need to put together a globally linear behaviour of the cell with intrisically non-linear genetic constructs. The discussion ends with the central question of evolvability of artificial constructs and to suggest that combining in vivo Synthetic Biology with biochemical reactors might be an efficient way forward. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Porcar M.,University of Valencia | Danchin A.,AMAbiotics SAS | de Lorenzo V.,CSIC - National Center for Biotechnology
BioEssays | Year: 2015

The emphasis of systems and synthetic biology on quantitative understanding of biological objects and their eventual re-design has raised the question of whether description and construction standards that are commonplace in electric and mechanical engineering are applicable to live systems. The tuning of genetic devices to deliver a given activity is generally context-dependent, thereby undermining the re-usability of parts, and predictability of function, necessary for manufacturing new biological objects. Tolerance (acceptable limits within the unavoidable divergence of a nominal value) and allowance (deviation introduced on purpose for the sake of flexibility and hence modularity, i.e. fitting together with a variety of other components) are key aspects of standardization that need to be brought to biological design. These should endow functional building blocks with a pre-specified level of confidence for bespoke biosystems engineering. However, in the absence of more fundamental knowledge, fine-tuning necessarily relies on evolutionary/combinatorial gravitation toward a fixed objective. © 2015 WILEY Periodicals, Inc.

Chan C.-M.,University of Hong Kong | Danchin A.,AMAbiotics SAS | Marliere P.,Genoscope Center National Of Sequencage | Sekowska A.,AMAbiotics SAS
Environmental Microbiology | Year: 2014

Metabolism is prone to produce analogs of essential building blocks in the cell (here named paralogous metabolism). The variants result from lack of absolute accuracy in enzyme-templated reactions as well as from molecular aging. If variants were left to accumulate, the earth would be covered by chemical waste. The way bacteria cope with this situation is essentially unexplored. To gain a comprehensive understanding of Bacillus subtilis sulphur paralogous metabolism, we used expression profiling with DNA arrays to investigate the changes in gene expression in the presence of S-methyl-cysteine (SMeC) and its close analog, methionine, as sole sulphur source. Altogether, more than 200 genes whose relative strength of induction was significantly different depending on the sulphur source used were identified. This allowed us to pinpoint operon ytmItcyJKLMNytmO_ytnIJ_rbfK_ytnLM as controlling the pathway cycling SMeC directly to cysteine, without requiring sulphur oxygenation. Combining genetic and physiological experiments, we deciphered the corresponding pathway that begins with protection of the metabolite by acetylation. Oxygenation of the methyl group then follows, and after deprotection (deacetylation), N-formyl cysteine is produced. This molecule is deformylated by the second deformylase present in B.subtilisDefB, yielding cysteine. This pathway appears to be present in plant-associated microbes. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

Engelen S.,AMAbiotics SAS | Engelen S.,French Atomic Energy Commission | Vallenet D.,French Atomic Energy Commission | Medigue C.,French Atomic Energy Commission | And 2 more authors.
BMC Genomics | Year: 2012

Background: Bacterial genomes displaying a strong bias between the leading and the lagging strand of DNA replication encode two DNA polymerases III, DnaE and PolC, rather than a single one. Replication is a highly unsymmetrical process, and the presence of two polymerases is therefore not unexpected. Using comparative genomics, we explored whether other processes have evolved in parallel with each polymerase.Results: Extending previous in silico heuristics for the analysis of gene co-evolution, we analyzed the function of genes clustering with dnaE and polC. Clusters were highly informative. DnaE co-evolves with the ribosome, the transcription machinery, the core of intermediary metabolism enzymes. It is also connected to the energy-saving enzyme necessary for RNA degradation, polynucleotide phosphorylase. Most of the proteins of this co-evolving set belong to the persistent set in bacterial proteomes, that is fairly ubiquitously distributed. In contrast, PolC co-evolves with RNA degradation enzymes that are present only in the A+T-rich Firmicutes clade, suggesting at least two origins for the degradosome.Conclusion: DNA replication involves two machineries, DnaE and PolC. DnaE co-evolves with the core functions of bacterial life. In contrast PolC co-evolves with a set of RNA degradation enzymes that does not derive from the degradosome identified in gamma-Proteobacteria. This suggests that at least two independent RNA degradation pathways existed in the progenote community at the end of the RNA genome world. © 2012 Engelen et al; licensee BioMed Central Ltd.

Toledano E.,Institute Pasteur Paris | Ogryzko V.,Institute Gustave Roussy | Danchin A.,AMAbiotics SAS | Ladant D.,Institute Pasteur Paris | Mechold U.,Institute Pasteur Paris
Biochemical Journal | Year: 2012

pAp (3′-5′ phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the K m and the V max of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl) ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity. © The Authors Journal compilation © 2012 Biochemical Society.

Acevedo-Rocha C.G.,Max-Planck-Institut für Kohlenforschung | Acevedo-Rocha C.G.,University of Marburg | Fang G.,Yale University | Schmidt M.,International Dialogue and Conflict Management | And 4 more authors.
Trends in Genetics | Year: 2013

A central undertaking in synthetic biology (SB) is the quest for the 'minimal genome'. However, 'minimal sets' of essential genes are strongly context-dependent and, in all prokaryotic genomes sequenced to date, not a single protein-coding gene is entirely conserved. Furthermore, a lack of consensus in the field as to what attributes make a gene truly essential adds another aspect of variation. Thus, a universal minimal genome remains elusive. Here, as an alternative to defining a minimal genome, we propose that the concept of gene persistence can be used to classify genes needed for robust long-term survival. Persistent genes, although not ubiquitous, are conserved in a majority of genomes, tend to be expressed at high levels, and are frequently located on the leading DNA strand. These criteria impose constraints on genome organization, and these are important considerations for engineering cells and for creating cellular life-like forms in SB. © 2012 Elsevier Ltd.

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: KBBE-2007-3-2-07;KBBE-2007-3-2-08 | Award Amount: 7.53M | Year: 2009

The exponential increase in microbial genome and metagenome sequencing throughput has widened the gap between sequence and functional understanding. A clear picture of metabolic processes across the spectrum of bacterial species is essential to enable the exploitation of microbial genomics for the purposes of environmental biotechnology. The Microme project endeavors to extend the scope of microbial genome annotation from functional assignment at the gene level to the systematic generation of pathway assemblies and genome-scale metabolic models. A few key ideas and design principles will enable the Microme reconstruction pipeline to achieve this ambitious goal.A clear definition of a metabolic pathway as a collection of reaction sets, each of which convert the same defined inputs into the same outputs, will allow species-specific pathway variants to be identified, assembled into networks, compared across species, and used for downstream computations. A unique pathways projection, curation and assembly cycle, feeding directly into the flow of newly sequenced genomes, will allow a qualitative increase in the speed and reliability of the pathway generation process. Pathways and models produced the pipeline will be accessible to the scientific community as an integrated resource via the Microme portal. Finally, taking advantage of the availability of pathway assemblies from a large sample of genomes, methods for comparative and phylogenetic analyses and novel metabolic engineering strategies for environmental biotechnology goals will be developed, applied to proof-of-concept studies, and integrated to the resource as an analytical tool layer. Microme will be supported by a robust bioinformatics infrastructure, developed by integrating a set of established European databases and tools, integrated with reference protein annotation, metabolites and reactions databases, and interfaced with the annotation pipelines of the two main European sequencing centers.

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