But reasons for caution abound. It is easier to pause than to reverse the escalation pitting centrifuges against sanctions. Mistrust remains deep, time is short, and the process remains vulnerable to pressure from domestic and regional detractors. In bringing the sides together, the accord revealed the chasm that separates them.
Success is possible only with political will to isolate the deal — at least for now — from its complex regional context. But a far-reaching resolution of differences will be possible only after a relatively narrow, technical nuclear agreement. Fearing that it would be easier for Iran to reverse its nuclear concessions than for the West to renew its isolation, the group insists on retaining sanctions leverage, even through implementation of the final step of a comprehensive agreement.
It contends that it has been singled out, uniquely among signatories of the Treaty on the Non-Proliferation of Nuclear Weapons NPT , to prove a negative, that its nuclear program does not aim at weaponisation. Tehran insists on preserving a substantial part of its nuclear infrastructure, in view of the enormous cost it has paid for it. While willing to accept heightened verification measures in order to enable the International Atomic Energy Agency IAEA to establish the peaceful nature of its program, it insists that they be temporary and respectful of its national security requirements.
It also demands significant and immediate Western reciprocation of any nuclear concession. Nevertheless, it is still possible to reach a comprehensive agreement on a limited nuclear program — though an uncomfortable one for sceptics like Saudi Arabia and Israel that object on principle to Iran retaining any enrichment capacity. Such a solution would enable them to sell the deal at home and serve as a springboard for developing a different kind of relationship.
This report presents a blueprint for achieving that agreement.
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New roles for bacterial siderophores in metal transport and tolerance. Siderophores are chelators with extremely strong affinity for ferric iron and are best known for their capacity to feed microorganisms with this metal. Despite their preference for iron, they can also chelate numerous other metals with variable affinities. There is also increasing evidence that metals other than iron can activate the prodn.
This article considers this new concept that siderophores play a role in protecting bacteria against metal toxicity and discusses the possible contribution of these chelators to the transport of biol. Advances in the chemical biology of desferrioxamine B. ACS Chem. Desferrioxamine B DFOB was discovered in the late s as a hydroxamic acid metabolite of the soil bacterium Streptomyces pilosus. Many studies have used semisynthetic chem. More recent approaches in chem. The current and potential applications of DFOB continue to inspire a rich body of chem.
Complete genome sequence of the model actinomycete Streptomyces coelicolor A3 2. Nature , , — , DOI: Bentley, S.
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Nature Publishing Group. Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. The 8,, base pair linear chromosome of this organism, contg. The predicted genes include more than 20 clusters coding for known or predicted secondary metabolites.
The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae.
The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering. A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases.
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A review on the nonribosomal peptide synthetase-independent siderophore biosynthesis pathway in bacteria. Topics discussed include genetic studies of NRPS-independent siderophore biosynthesis; sequence anal.
Mixing up the pieces of the desferrioxamine B jigsaw defines the biosynthetic sequence catalyzed by DesD. Seven unsatd. DFOB analogs were produced that were partially resolved by liq. Relative concns. Dimeric compds. Identification of a cluster of genes that directs desferrioxamine biosynthesis in Streptomyces coelicolor M Desferrioxamines are a structurally related family of tris-hydroxamate siderophores that form strong hexadentate complexes with ferric iron.
Desferrioxamine B has been used clin. We have unambiguously identified desferrioxamine E as the major desferrioxamine siderophore produced by Streptomyces coelicolor M and have identified a cluster of four genes desA-D that directs desferrioxamine biosynthesis in this model actinomycete. On the basis of comparative sequence anal.
The desferrioxamine biosynthetic pathway belongs to a new and rapidly emerging family of pathways for siderophore biosynthesis, widely distributed across diverse species of bacteria, which is biochem. A new family of ATP-dependent oligomerization-macrocyclization biocatalysts. Oligomerization and macrocyclization reactions are key steps in the biosynthesis of many bioactive natural products. Important macrocycles include the antibiotic daptomycin, the immunosuppressant FK, the anthelmintic avermectin B1a and the insecticide spinosyn A; important oligomeric macrocycles include the siderophores enterobactin and desferrioxamine E.
Biosynthetic oligomerization and macrocyclization reactions typically involve covalently tethered intermediates and are catalyzed by thioesterase domains of polyketide synthase and nonribosomal peptide synthetase multienzymes. Here we report that the purified recombinant desferrioxamine siderophore synthetase DesD from Streptomyces coelicolor M catalyzes ATP-dependent trimerization-mcrocyclization of a chem. This suggests that DesD is the first biochem.
Biosynthesis of desferrioxamine B in Streptomyces pilosus : Evidence for the involvement of lysine decarboxylase. FEMS Microbiol. Lysine decarboxylase activity E. Appearance of enzyme activity in growing cultures correlated well with productivity of desferrioxamine B. One class of mutants blocked in biosynthesis showed no lysine decarboxylase activity, and feeding of the enzyme product restored biosynthesis. Mutants with increased desferrioxamine B prodn. Both desferrioxamine B biosynthesis and lysine decarboxylase activity were regulated by iron, and for the latter this was found to occur by repression of enzyme synthesis.
Cloning and expression of two genes of Streptomyces pilosus involved in the biosynthesis of the siderophore desferrioxamine B. Gene , 64 , — , DOI: Genes involved in biosynthesis of the siderophore desferrioxamine B have been cloned from S. Mutants in two steps of the pathway can be complemented by a 4. One of these mutants is defective for the first step, lysine decarboxylation.
Expression of lysine decarboxylase by the cloned DNA was found to be regulated by iron. S1 mapping and Northern blotting expts. Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water-soluble zirconium IV chelator. The water soly. The use of a microbiol. The improved water soly. Fluorinated analogues of desferrioxamine B from precursor-directed biosynthesis provide new insight into the capacity of DesBCD.
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The two sets of constitutional isomers and arose from the position of the substrates in the N-acetyl, internal or amine-contg. Other analogs contained two hydroxamic acid groups and three amide bonds. These data are consistent with the following.
This work has provided a potential path to access fluorinated analogs of DFOB and new insight into its biosynthesis. Engineering a cleavable disulfide bond into a natural product siderophore using precursor-directed biosynthesis. Cystamine competed against native 1,5-diaminopentane during assembly. Production of desferrioxamine E and new analogues by directed fermentation and feeding fermentation.
Streptomyces olivaceus TU produces the siderophore desferrioxamine D. Supplementation of the basic prodn. Solution thermodynamics of the ferric complexes of new desferrioxamine siderophores obtained by directed fermentation. Thirteen new desferrioxamine-type siderophores, designated X1-X6, Et1-Et3, Te1-Te3, and P1, were obtained from cultures of Streptomyces olivaceus Tu by supplementing the prodn. The stability consts. The predominant sp. Sulfur containing scaffolds in drugs: Synthesis and application in medicinal chemistry.
Bentham Science Publishers Ltd. The impact of the development of sulfur therapeutics is instrumental to the evolution of the pharmaceutical industry. Sulfur-derived functional groups can be found in a broad range of pharmaceuticals and natural products. For centuries, sulfur continues to maintain its status as the dominating heteroatom integrated into a set of sulfur-contg.