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Articles by Y Mu
Total Records ( 3 ) for Y Mu
  B Wang , L Li , F Ni , J Song , J Wang , Y Mu , X Ma and Y. Cao

Pluripotency associated transcription factor, SAL-Like 4 (SALL4), might play an important role in conferring totipotency on oocytes. In the present study, we screened SALL4 coding regions for mutations in 100 Han Chinese women with non-syndromic ovarian failure and discovered two novel non-synonymous variants in the SALL4 gene: c.541G>A (p.Val181Met) and c.2449A>G. (p.Thr817Ala). The former variant was located in an evolutionary conserved region of SALL4 protein and might affect its function. This is the first report to suggest that SALL4 might be a potential candidate gene of premature ovarian failure.

  F. M Gregoire , F Zhang , H. J Clarke , T. A Gustafson , D. D Sears , S Favelyukis , J Lenhard , D Rentzeperis , L. E Clemens , Y Mu and B. E. Lavan

MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)- that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR- agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR- target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR- agonists, MBX-102 displays differential interactions with the PPAR- ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR- or / agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR- modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR- side effects and may represent the next generation insulin sensitizer.

  M Kotaka , R Kong , I Qureshi , Q. S Ho , H Sun , C. W Liew , L. P Goh , P Cheung , Y Mu , J Lescar and Z. X. Liang

The biosynthesis of the enediyne moiety of the antitumor natural product calicheamicin involves an iterative polyketide synthase (CalE8) and other ancillary enzymes. In the proposed mechanism for the early stage of 10-membered enediyne biosynthesis, CalE8 produces a carbonyl-conjugated polyene with the assistance of a putative thioesterase (CalE7). We have determined the x-ray crystal structure of CalE7 and found that the subunit adopts a hotdog fold with an elongated and kinked substrate-binding channel embedded between two subunits. The 1.75-Å crystal structure revealed that CalE7 does not contain a critical catalytic residue (Glu or Asp) conserved in other hotdog fold thioesterases. Based on biochemical and site-directed mutagenesis studies, we proposed a catalytic mechanism in which the conserved Arg37 plays a crucial role in the hydrolysis of the thioester bond, and that Tyr29 and a hydrogen-bonded water network assist the decarboxylation of the β-ketocarboxylic acid intermediate. Moreover, computational docking suggested that the substrate-binding channel binds a polyene substrate that contains a single cis double bond at the C4/C5 position, raising the possibility that the C4=C5 double bond in the enediyne moiety could be generated by the iterative polyketide synthase. Together, the results revealed a hotdog fold thioesterase distinct from the common type I and type II thioesterases associated with polyketide biosynthesis and provided interesting insight into the enediyne biosynthetic mechanism.

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