Determining the conformations of several polyketide synthases in the presence of various substrates

Today, many microorganisms are becoming resistant to the drugs that doctors are administering to their patients at an exponential rate. If this rate continues, it won’t be long until all microorganisms are resistant to the drugs we have developed. As a result, there has been a surge in the amount of research being conducted on antibiotics found in nature. In particular, polyketides have recently been discovered, and the Keatinge-Clay group, like many other groups around the world, has been focusing their efforts on this area. In this paper, the mechanisms by which different polyketides are made by machines known as polyketide synthases (PKSs) will be mentioned. This will then be followed by an examination of how these different PKSs incorporate and allow their substrates to enter into the active site groove. As of now, the Keatinge- Clay group has been able to obtain a crystal structure of Amphotericin ketoreductase (KR) domain 2 in the presence of 2-methyl-3-oxopentanyl-SNAC and NADP+ at a 2.3Å resolution. However, the electron density of this protein will be used as a model for how 2-methyl-3-oxopentanyl-SNAC enters the active site groove. Meanwhile, further work will involve obtaining crystal structures for erythromycin KR1, tylosin KR1, and pikKR3 in the presence of the aforementioned substrates. In addition, efforts have been placed on crystallizing PikKS-AT-ACP0 and producing ACP proteins which can be co-crystallized later with the various KRs.