Regulatory Molecular Biology University of Pittsburgh调控分子生物学匹兹堡大学.pptVIP

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Regulatory Molecular Biology University of Pittsburgh调控分子生物学匹兹堡大学.ppt

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Regulatory Molecular Biology University of Pittsburgh调控分子生物学匹兹堡大学

* Mis-regulations of genetic and biochemical processes are at the root of cancer. And conversely, ‘the pathological illustrates the normal’. By way of background, a half century ago three molecular biological mechanisms for regulation of gene expression and function were discovered. One is enzyme induction, a mechanism by which production of a protein from a gene is controlled. The second is covalent modifications of proteins by phosphorylation, which can greatly increase or decrease their catalytic and binding activity and stability, especially in eukaryotes. Third is feedback inhibition by non-covalent binding of a small molecule to an enzyme’s non-catalytic but regulatory sites Thereby enzyme activities and the corresponding entire metabolic pathways are rapidly and sensitively regulated. * The best known development by James Watson and FrancisCrick is establishment of DNA’s double helical structure that provides the mechanism for Cell Cycle e2transfer of information to progeny. The enzymology of its synthesis,base sequencing and the genetic code by which DNA provides informationvia mRNAs for creation of proteins were worked out. ErwinChargaff called these investigations “practicing biochemistry withouta license”. * * * * Convincing demonstrations that an end-product can inhibit the initial enzymatic reaction was identified for pathways synthesizing isoleucine-valine 8 by Edwin Umbarger in 1956, and for pyrimidines by Yates and Pardee where the firstenzyme in the seven successive enzyme-catalyzed reactions (aspartatetranscarbamylase, ATCase) is feedback inhibited by added uracil.9As expected mutant bacteria could accumulate the metabolite priorto their missing reaction, but only when the end product of thepathway was not provided. This observation led to perhaps the firstreview on regulation of metabolism.10 Feedback mechanisms havenow been verified for numerous pathways.11 Some of these arecomplex, involving metabolic branching as investigated b