A tryptophan 6-halogenase and an amidotransferase are involved in thienodolin biosynthesis
The biosynthetic gene cluster for the plant growth-regulating compound thienodolin was identified in and cloned from the producer organism Streptomyces albogriseolus MJ286-76F7. Sequence analysis of a 27 kb DNA region revealed the presence of 21 ORFs, 14 of which are involved in thienodolin biosynthesis. Three insertional inactivation mutants were generated in the sequenced region to analyze their involvement in thienodolin biosynthesis and to functionally characterize specific genes. The gene inactivation experiments together with enzyme assays with enzymes obtained by heterologous expression and feeding studies showed that the first step in thienodolin biosynthesis is catalyzed by a tryptophan 6-halogenase and that the last step is the formation of a carboxylic amide group catalyzed by an amidotransferase. The results led to a hypothetical model for thienodolin biosynthesis. The skeleton lives: Thienodolin shows concentration-dependent growth-regulating activity towards rice seedlings. This secondary metabolite has a thienoindole skeleton chlorinated in the 6-position of the indole ring. Here we present insights into the biosynthesis of the alkaloid, including the complete gene cluster and elucidation of two biosynthetic steps.
Structure-activity relationship study of novel necroptosis inhibitors
Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling necrosis. It can be induced in a FADD-deficient variant of human Jurkat T cells treated with TNF-α. 5-(1H-Indol-3-ylmethyl)-2-thiohydantoins and 5-(1H-indol-3-ylmethyl)hydantoins were found to be potent necroptosis inhibitors (called necrostatins). A SAR study revealed that several positions of the indole were intolerant of substitution, while small substituents at the 7-position resulted in increased inhibitory activity. The hydantoin ring was also quite sensitive to structural modifications. A representative member of this compound class demonstrated moderate pharmacokinetic characteristics and readily entered the central nervous system upon intravenous administration.
Teng, Xin,Degterev, Alexei,Jagtap, Prakash,Xing, Xuechao,Choi, Sungwoon,Denu, Regine,Yuan, Junying,Cuny, Gregory D.
p. 5039 - 5044
(2007/10/03)
Synthesis of tryptophans
The preparation of racemic and optically pure tryptophans is described. The D-enantiomers of the 6-substituted compounds possess a potent sweetening capability. Novel intermediates are also disclosed.
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(2008/06/13)
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