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Articles by Wei Ding
Total Records ( 2 ) for Wei Ding
  Qing Zhang , Ada Solidar , Nicholas J. Murgolo , Wynand Alkema , Wei Ding , Peter M. Groenen , Jonathan R. Greene , Eric L. Gustafson , Jan Klomp , Ellie D. Norris , Ping Qiu and Gerald J. Wyckoff
  We examined the synonymous vs. nonsynonymous substitution rate ratios (Ka/Ks, aka evolutionary rate) between human and chimpanzee for 166 successful drug target genes and compared them with a larger (10,298) set of genes representative of average human-chimpanzee evolutionary rates. We found that evolutionary rates differ significantly between successfully marketed drug targets and the broader set of genes (p<0.005 by ANOVA). Evolutionary rates were lower for successfully marketed drug targets versus non-target genes (0.311 versus 0.497). This rate discrepancy demonstrates that more conserved genes, even within protein families such as GPCRs (successful target GPCRs 0.391 versus non-target GPCRs 0.855) and protein kinases (0.131 versus 0.337), are better targets for traditional small molecule drug development than less strongly constrained genes. Evolutionary rate, therefore, is a factor that could be taken into account when selecting candidate target genes for drug discovery, in addition to the biochemical properties of the proteins these genes encode. We suggest therefore, that links be established between identified disease-causal or -associated genes and genes that are suitable targets for traditional small molecule pharmaceutical development.
  Lei Li , Wei Deng , Jie Song , Wei Ding , Qun- Fei Zhao , Chao Peng , Wei- Wen Song , Gong -Li Tang and Wen Liu
  Saframycin A (SFM-A), produced by Streptomyces lavendulae NRRL 11002, belongs to the tetrahydroisoquinoline family of antibiotics, and its core is structurally similar to the core of ecteinascidin 743, which is a highly potent antitumor drug isolated from a marine tunicate. In this study, the biosynthetic gene cluster for SFM-A was cloned and localized to a 62-kb contiguous DNA region. Sequence analysis revealed 30 genes that constitute the SFM-A gene cluster, encoding an unusual nonribosomal peptide synthetase (NRPS) system and tailoring enzymes and regulatory and resistance proteins. The results of substrate prediction and in vitro characterization of the adenylation specificities of this NRPS system support the hypothesis that the last module acts in an iterative manner to form a tetrapeptidyl intermediate and that the colinearity rule does not apply. Although this mechanism is different from those proposed for the SFM-A analogs SFM-Mx1 and safracin B (SAC-B), based on the high similarity of these systems, it is likely they share a common mechanism of biosynthesis as we describe here. Construction of the biosynthetic pathway of SFM-Y3, an aminated SFM-A, was achieved in the SAC-B producer (Pseudomonas fluorescens). These findings not only shed new insight on tetrahydroisoquinoline biosynthesis but also demonstrate the feasibility of engineering microorganisms to generate structurally more complex and biologically more active analogs by combinatorial biosynthesis.
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