Here is the molecular structure of erythromycin. Like many polyketides it is circular, which at first appears to be a bit of a headache to synthesise. The way it's put together, though, is actually very clever. The backbone of the circular section is made up first, using a system of modular enzymes that pass the growing chain along like a conveyor belt, adding new residues at each stage. Then the straight chain is curled up into a ring, and finally the two side residues (the ones on the bottom right of the chemical structure, that look a bit like squashed rectangles with dents in them) are stuck on.So here is the picture that has appeared on every slide show in every lab meeting we've had this term, showing the formation of the straight-chain backbone before it gets curved into a circle:
Ignoring the little letters (which are just names of enzymes) it really does look a lot like a conveyor belt. At each stage the chain is lengthened, before finally being taken off and twisted around onto itself (to form a circular molecule called DEB). The modular nature of this system is fascinating to work with, but a real problem to sequence. DNA sequencing techniques work mainly by chopping the genome up, sequencing the bits, then trying to stick them back together and modular repeats tend to confuse them.
The last stage, going from DEB to erythromycin, is just a matter of decoration. Although the squashed-rectangle additions (glycosylases, added by glycosylation I believe) look complex, they are quite common molecules that get added onto things in the cell. Glycosylase residues and glycosylation enzymes are very common.
And that's how bacteria make polyketides :)
That's pretty awesome! Reminds me of organic chemistry courses, though, which were markedly more unpleasant than necessary.
ReplyDeleteOut of curiosity, when you say that the aromatic rings are glycosylases, do you mean that they're the active sites of a glycosylase or that they're added by the glycosylase? My specialty is elsewhere, so I haven't come across the -ase ending as anything but an enzyme marker before. To me, the residues just look like id tags made of sugar. :)
oh gawd organic chemistry. I used to do insane reaction pathways, trying to get get the free electrons of oxygens on carbonyl carbons to attack things. mental.
ReplyDeleteah yes, they are sugar tags. They do have a name though, I'll have to look it up later. They are added by glycosylases though, yes :)
Glycosylose, mayhaps?
ReplyDelete(I don't actually know- that would just seem an appropriate name...)