This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polyketides are a group of compounds exhibiting remarkable diversity in terms of their structure and function. Polyketides natural products are known to possess a wealth of pharmacologically important activities, including antimicrobial, antifungal, antiparasitic, antitumor, and agrochemical properties. Erythromycin (antibiotic), epothilone (anti cancer), pikromycin (antibiotic), and rapamycin (immunosuppressant) are just few examples of the polyketide natural product family. Remarkably, these complex structures are synthesized in bacteria from simple carboxylic acids by multifunctional enzyme assemblies called modular, or type I, polyketide synthases (PKSs). While polyketide biosynthesis has been an active area of research, many structural and fundamental aspects of modular PKS enzymology still remain obscure. We have crystallized a didomain from the modular PKS. These crystals generally showed poor diffraction and radiation damage. After screening hundreds of crystals using the SSRL robot, we collected three MAD data sets. This enabled the location of 90 selenium sites and a traceable electron density map. This is the first structure of a didomain from PKS and further structure analysis is in progress. The preliminary results from the structural study have already answered several interesting biochemical questions.
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