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Mechanism of nitrogen fixation


Glycolysis : The term has originated from the Greek word
glycos = glucose
lysis = splitting or breakdown means breakdown of glucose molecule.

 / Feng, Youjun; Napier, Brooke A.; Manandhar, Miglena; Henke, Sarah K.; Weiss, David S.

The nitrogen fixing activity of free-living, non-photosynthetic, aerobic bacteria is strongly dependent on favorablemoisture conditions, oxygen, and an organic food source. Anaerobic representatives (Clostridium) predominate in grassland andwaterlogged soils and soil aggregates where moisture conditions and organic substrates are available but oxygen supply to themicro-environment of the bacteria is severely restricted.

Catalyses:Glucose-6-phosphate (G6P) Fructose-6-phosphate (F6P)

We recently identified a gene (FTN_0818) required for Francisella virulence that seemed likely involved in biotin metabolism. However, the molecular function of this virulence determinant was unclear. Here we show that this protein named BioJ is the enzyme of the biotin biosynthesis pathway that determines the chain length of the biotin valeryl side-chain. Expression of bioJ allows growth of an Escherichia colibioH strain on biotin-free medium, indicating functional equivalence of BioJ to the paradigm pimeloyl-ACP methyl ester carboxyl-esterase, BioH. BioJ was purified to homogeneity, shown to be monomeric and capable of hydrolysis of its physiological substrate methyl pimeloyl-ACP to pimeloyl-ACP, the precursor required to begin formation of the fused heterocyclic rings of biotin. Phylogenetic analyses confirmed that distinct from BioH, BioJ represents a novel subclade of the α/β-hydrolase family. Structure-guided mapping combined with site-directed mutagenesis revealed that the BioJ catalytic triad consists of Ser151, Asp248 and His278, all of which are essential for activity and virulence. The biotin synthesis pathway was reconstituted reaction in vitro and the physiological role of BioJ directly assayed. To the best of our knowledge, these data represent further evidence linking biotin synthesis to bacterial virulence.

N2 - We recently identified a gene (FTN_0818) required for Francisella virulence that seemed likely involved in biotin metabolism. However, the molecular function of this virulence determinant was unclear. Here we show that this protein named BioJ is the enzyme of the biotin biosynthesis pathway that determines the chain length of the biotin valeryl side-chain. Expression of bioJ allows growth of an Escherichia colibioH strain on biotin-free medium, indicating functional equivalence of BioJ to the paradigm pimeloyl-ACP methyl ester carboxyl-esterase, BioH. BioJ was purified to homogeneity, shown to be monomeric and capable of hydrolysis of its physiological substrate methyl pimeloyl-ACP to pimeloyl-ACP, the precursor required to begin formation of the fused heterocyclic rings of biotin. Phylogenetic analyses confirmed that distinct from BioH, BioJ represents a novel subclade of the α/β-hydrolase family. Structure-guided mapping combined with site-directed mutagenesis revealed that the BioJ catalytic triad consists of Ser151, Asp248 and His278, all of which are essential for activity and virulence. The biotin synthesis pathway was reconstituted reaction in vitro and the physiological role of BioJ directly assayed. To the best of our knowledge, these data represent further evidence linking biotin synthesis to bacterial virulence.

Event Code : CDC-FLØØ1-2 Trade Name: CDC Triffid Flax

Might the antibacterial properties of GA contribute to its action in MS? I’m not too familiar with the drug, but is it possible killing gram-negative bacteria shifts the immune response from Th1 to a Th2 and Treg profile, reducing the autoimmune degradation of myelin?

“With the already high dosages of GA employed clinically, it seems likely that critical levels of compound to kill microbes can be reached without compromising safety. For example, this could be relevant in treatment by inhalation of lung infections with P. aeruginosa. e total dosage of 20 mg used routinely in MS therapy would replenish 400 ml of lung uid to the maximum 50 μg/ml concentration used in our studies. e volume of the epithelial lining uid in the lower respira- tory tract, o en a site of P. aeruginosa infection in cystic brosis (CF) patients, has been estimated at 15–70 ml42; therefore, infection in this location would only require a dose of 3.5 mg GA, and hence permit a considerable overload of drug delivered to other sites of infection and compensate for losses to zones outside infection foci.”

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Summary of Basic Genetic Modification

The new chemotypes against traditional targets are particularly interesting – as that article points out, it’s been a long time since any such molecule hit the market. There are other efforts underway (such as the group) to mine chemical space for insights into penetrating gram-negative bacterial membranes and for new chemotypes in general. Screening in the manner is really a no-brainer; there are so many collections that have never been looked at that we would be completely remiss not to go through them. We’re going to need all the help we can get.

* : Selection Marker/Reporter

It’s all ADME. Neglecting distribution and clearance, 30 mg/day in an adult human (~5 L blood volume) by IV dosing would give a Cmax of 6 ug/mL. Distribution effects could lower that number, while clearance could affect it in either direction in the context of a multiple dosing regimen based on the relationship between the dosing interval and the elimination half-life. So it’s really impossible to say without the PK data on the drug, but a Cmax of 6 ug/mL is in the ballpark of the effective blood concentration you mentioned.

Summary of Regulatory Approvals: Country, Year and Type of Approval

One-third of these projects are working on drugs with novel chemotypes and new mechanisms of action, offering high development risk but also high reward.
For example, two small molecules inhibit LpxC, the enzyme that catalyses the synthesis of lipid A, a key component of the outer monolayer of Gram-negative bacteria. Another third are advancing new chemotypes for established mechanisms of action, such as new topoisomerase and gyrase inhibitors. The last third act via established chemotypes and on established mechanisms of action, with the lowest scientific and developmental risk but also offering the lowest potential antimicrobial resistance payout.

Regulatory and Biosafety Information

GA is a random mixture of random peptides of four amino acids ( lysine, glutamate, alanine, and tyrosine) so the basis of antimicrobial activity is uncertain at best. Maybe some specific peptide sequence has the antimicrobial efficacy and could be further tested and refined. As Lynn points out (Hi Lynne!) an in vitro activity of 25-50 ugs/ml is far from spectacular, and depending on PK, could mean large doses are necessary. This is really important since we are talking about peptides in this case, which are notorious for rapid clearance and other challenging ADME properties. There are also a reports of few serious side effects (CV, liver) at the much lower current dosage. So whether this can be effectively repurposed for infection is very much an open question.

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