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.
Perspectives
Usually in science putting any particular manuscript on the back-burner never turns out well. However, I'm pleased to say that, despite the long gestation period going way back before our 2009 poster (http://www.slideshare.net/cdsouthan/southanposterprotevojan09) the publication timing of this paper turned out just about right (see the PubMed Commons comment on the paper that came out at the same time on APP evolution). For me, digging into the evolutionary aspects (which JH has a stronger background in) of the strangest lowly and difficult to pronounce creatures were as fascinating as fixing dozens of incorrect gene prediction ORFs was tedious (n.b. comparing complete ORFs is an altogether more interesting bionformatics exersise) For the record I was involved in the discovery of BACE1/2 back in the SB golden age of genomics (US6025180 even gets cited in Google Scholar) so it was familiar territory for drug discovery. I also picked up the first Ciona Ur-BACE EST back in ~2000 and had been collecting interesting homologues since them. As ever, there is a lot more to be looked at as new genomes get argued about in respect of the deepest roots of metazoan evoltion and theories on the origin of the CNS are continously wrangled. In addition, we could now make some better guesses as to when the "oily tail" might have first got attached to thos C-terminal Cys positions. It is also of interest that the status of BACE2 as a drug target has taken some extrodinary twists and turns since the paper and may have been de-validated for T2D.
Dr Christopher Southan
Read the Original
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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