Studies on the chemical nature of the microbial biosynthesis of vitamin B12[1.141 have revealed that the organization of the individual reactions in the aerobe Pseudomonas denitriJicans and the anaerobe Propionibacterium shermanii differs significantly, and that these differences could be evolutionary in their origins. The work of Blanche, Crouzet et al.lla-cl has provided deep insight into the molecular nature of vitamin B, , synthesis. Their construction and efficient application of recombinant strains of P. denitrificans led to the discovery and isolation of new and spectacular vitamin B,, precursors with the responsible cloned enzymes.It was shown that the tetrapyrrolic vitamin B,, ligand hydrogenobyrinic acid 7I2] is synthesized without cobalt via the precorrins 2(1) and 3(2)r2a, l 4 I as well as the newly discovered ring-contracted precorrins 4(3)[31, 6~( 4 ) , [~] 6y(5),I5' and 8~( 6 ) [~J (Scheme 1). After two obligatory amidations leading to 7-a,c-diamide,['I cobalt is inserted by the cobaltchelatase responsible for vitamin B,, formation."' In the case of P. shermanii neither 7 nor 7-apdiamide are precursors of vitamin B,, . [ 2 9 9 a 1 Instead cobyrinic acid @), the cobaltcontaining analogue of 7, and 8-a,c-diamide appear in the biosynthetic pathway.['". O1 Enzyme preparations from P. shermanii are able to transform in vitro not only the oxidized and aromatized precorrins 2(1 a) and 3(2a)r2".'41 (known as factors I1 and 111, respectively) into 8, but also the cobalt complexes of 1 a and 2a.[91 In contrast, the enzyme systems from P. denitrificans that produce 7 are able to

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This paper reports on the drug release mechanisms of silicone structures with embedded steroids applied in pacing leads. Different derivatives of the steroid dexamethasone, which is associated with the reduction of acute stimulation thresholds, were evaluated together with different matrix based release control mechanisms with the target to potentially match optimal drug release rates during the first month after implantation. By incorporating dexamethasone-21-dihydrogen phosphate in silicone matrices in combination with release rate adaption layers, almost continuous release rates were obtained under physiological test settings.

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