What is it about?
Most drug targets are proteins, many are enzymes and some of these are proteases (enzymes that cut other proteins as part of their function). Its perhaps surprising but many nuances of fucntion are still not completely understood for drug targets, especially the more recent ones. In such cases, looking at the way the enzyme has evolved over millions of years (i.e. shows differences in ammino acid sequence across the animal kingdom) can provide insights into function and dysfunction associated with diseases. We have taken advantage of the recent increase in animal genome sequences to track the evolution of BACE1 and BACE2 that are both putative drug targets for different diseases.
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Why is it important?
The burden of Alzheimers disease (AD) needs no introduction but the develomment of effective treatments has proved extraordinarilly difficult (see recent review http://www.citeulike.org/user/cdsouthan/article/14061788). BACE1 is one of the frontrunner targets but, together with its paralogoue BACE2, these remain enigmatic enzymes in many respects. The deep phylogeny of targets can be informative and it turbed out that we could clearly delineate a vertrbrate gene duplication event fish. We could also track the pre-duplication single ancestor all the way back to the roots of invertebrate phyla and probable role in the primitive nervous system. Given the crucial importance of BACE1 as an AD target possible new functional insights from 1/2 a billion years ago can illuminate the contempory roles of the human enzyme.
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This page is a summary of: A tale of two drug targets: the evolutionary history of BACE1 and BACE2, Frontiers in Genetics, January 2013, Frontiers,
DOI: 10.3389/fgene.2013.00293.
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