AbstractEnzymatic platforms for producing malonyl‐CoA‐based extender units required for polyketide biosynthesis are often based on malonyl‐CoA ligases such as MatB from Rhizobium trifolii and Rhodopseudomonas palustris. However, despite broad interest in the fluorination of polyketides and prior success with engineering MatB homologs, the suitability of MatB for accessing the tertiary substituted fluoromethylmalonyl‐CoA needed to produce flurithromycin and solithromycin has not yet been reported. Herein, we report the structure‐guided engineering of a MatB homolog to optimize the production of fluoromethylmalonyl‐CoA, resulting in a variant with increased conversion and providing a platform to produce a suitable building block mixture for fluorinated macrolide production. Additionally, the mutant demonstrated broad utility for various substituted malonyl‐CoAs. The MatB mutant sets the stage to access fluorinated macrolides by coupling it with altered PKS machinery to install fluorinated malonyl‐CoA into macrolide scaffolds.

28 Jun 2008·Clinical and Experimental ImmunologyQ3 · MEDICINE

Combination chemo-immunotherapy: kinetics of in vivo and in vitro generation of natural killer cells and lymphokine-activated killer cells in the rat

Q3 · MEDICINE

Article

Author: THOMSON, A W ; SEWELL, A F ; STEWART, L S

SUMMARYRats received a single high dose of cyclophosphamide (Cy) (150 mg/kg). followed 48 h later (on day 0) by immunization with a T cell-dependent soluble antigen, ovalbumin in Freund's complete adjuvant (FCA). The effect of this treatment on lymphoid cell subpopulalions in the spleen, natural killer (NK) cell and interieukin-2 (IL-2) induced lymphokine-activated killer (LAK) cell activity was examined. Cy (with and without ovalbumin) caused a large relative increase (by day 14) in splenic OX 8+, OX 19-cells with NK morphology. A marked relative increase in fresh NK cell activity was noted after Cy+ovalbumin, but not consistently after Cy alone. Elevated NK activity was Cy dose- and time-dependent, was evident within 7 days post Cy/ovalbumin and persisted for at least 28 days. Pooled splente mononuclear cells (MNC), obtained 14 days after Cy/ovulbumin, lost all cytolytic activity against YAC-I cells when cultured in the absence of human recombinant IL-2 (rIL-2). In contrast, similarly maintained cells from normal rats displayed NK activity higher than normal‘fresh’levels. Upon culture in medium containing 500 U/ml rIL-2, however,‘augmented’NK. activity was equivalent, on a per-cell basis, in both normal and Cy/ovaibumin-pretreuted groups. LAK activity generated in vitro (i.e. against NK.-resistant target cells) was significantly lower in the latter group, and the overall yield of cells was reduced. By day 21 after Cy/ovaibumin, augmented NK activity was significantly greater lhan controls, on a per-cell and total culture yield basis. Moreover, LAK activity was now similar between groups. It is concluded that the chemotherapy/immunization protocol which we have used can greatly enhance NK activity in vitro and that these cells are responsive to induction of LAK activity by IL-2 in ritro.

28 Jun 2008·Clinical and Experimental ImmunologyQ3 · MEDICINE

Macrophage depletion decreases IgG anti-DNA in cultures from (NZB · NZW)F1 spleen cells by eliminating the main source of IL-6

Q3 · MEDICINE

Article

Author: FERNÁNDEZ, C ; MÖLLER, G ; ALARCÓN-RIQUELME, M E

SUMMARYWe have studied ihe rote of macrophages in the produclion of IgG anli-DNA autoanlibodies by (NZB × NZW)F1 tnice(B/W). One of the main features of the syslemic lupus cryibematosus(SLE)-like disease that aftects these mice, h ihe presence of circuialing IgG autoantibodies and immune complexes, which lead lo renal failure and death by the age of 8–9 months. IgG autoantibodies are produced without in vitro siimulallon by lolal spleen eells from these miee when they reach tbe age of 6 monlhs. We have demonstrated ihat IL-6 increases ihe production of IgG autoantibodies in cultures of splenic purified B cells from the old B/W miee. The aim of this study was to show the involvement of macrophages in the production of IL-6 and consequently in the produclion of IgG anti-DNA antibodies in ritro. We show thai elimination of the macrophages by different treatments led to reduction of the content of IL-6 in ihe supernalants as well as of IgG anti-DNA autoantibodies. Addition of fresh, splenic or peritoneal macrophages restored the produclion of autoantibodies in macrophage-depleted cultures from old B/W miee. There were no ditferences in the capacity of IL-6 produelion between macrophages from old or young B/W miee. but an imporiani difference was observed between peritoneal and splenic maerophages, where the former produced mueh higher levels ol IL-6, and eonsequently were more potent inducers of IgG autoantibodies. The present results reinforee Ihe role of macrophages and lL-6 in Ihe production of IgG anti-DNA autoantibodies in B/W mice. The implieations of these results in the pathogenesis of the disease are discussed.

100 Deals associated with Flurithromycin Ethyl Succinate

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KEGG	Wiki	ATC	Drug Bank
-	Flurithromycin Ethyl Succinate	J01FA14	DB13338

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Indication	Country/Location	Organization	Date
Mouth Diseases	IT	-	22 Apr 1998
Respiratory Tract Infections	IT	-	19 Apr 1998
Bacterial Infections	-	-	-

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